>> GOOD MORNING, EVERYONE. THANK YOU FOR COMING TODAY. WE'RE REALLY EXCITED ABOUT THIS MEETING. WE HAVE HAD A LOT OF INTEREST. WHEN WE PUT THIS TOGETHER. WE HAVE OVER 400 PEOPLE REGISTERED TO ATTEND IN PERSON AND THERE ARE WELL OVER 100 VIEWING BY VIDEOCAST SO WELCOME TO ALL OF YOU. WHEN WE FIRST STARTED PLANNING THIS MEETING NIAID CAME ONE THE IDEA WE ADDED THEM TO THE MIX. (INAUDIBLE) SO IN THE END MANY AGENCIES CAME TOGETHER TO ORGANIZE THIS MEETING. OUR APOLOGIES TO THOSE WHO COULDN'T MAKE THIS MEETING BECAUSE OF RASH HOSHANA. THAT EXPLAINS A LOT WHY THE DATES WERE AVAILABLE FOR THIS AUDITORIUM. BUT THE GOOD NEWS IS BECAUSE THIS IS VIDEO COST AND PEOPLE CAN VIEW THIS LATER, PEOPLE WON'T MISS THE CONTENT. SO AS YOU KNOW, WE CANNOT PROVIDE FOOD OR DRINK ASSOCIATED WITH THIS MEETING BUT FORTUNATELY IN THIS FACILITY THERE'S THE CAFETERIA UPSTAIRS. I DO WANT TO POINT OUT THAT THERE'S ANOTHER MEETING AT THE SAME TIME THEIR LUNCH BREAK IS AT THE SAME TIME AS OURS. SO PLAN ACCORDINGLY THERE. HOPEFULLY THERE WON'T BE TOO MUCH CONFUSION IN TERMS OF THE POSTER SESSIONS BECAUSE I UNDERSTAND THE OTHER MEETING ALSO HAS A POSTER SESSION. GOING ON SO IF YOU HAVE ANY QUESTIONS SEE PEOPLE AT THE REGISTRATION DESK ABOUT THAT. I THINK WE'LL GET STARTED. WE'LL START WITH A HIGH LEVEL INTRODUCTION FROM EACH OF THE AGENCIES SPONSORINGHk—IS MEETING WITH THE EXCEPTION OF THEY WEREN'T ABLE TO SEND SOMEONE TODAY THIS MORNING THEY'LL BE HERE LATER IN THE MEETING. SO WE'RE GOING TO GET STARTED WITH THE AGENCY INTRODUCTIONS REALLY TO GIVE YOU A SENSE OF THE VARIOUS AGENCIES INVOLVED AND HOW THEY SUPPORT ANIMAL MODEL DEVELOPMENT AND THEN WEAL MOVE INTO THE TALKS IN THE FIRST SESSION. SO MIC K O R I L L A WILL START BY INTRODUCING NIAID. >> THANK YOU, JUDY. IT'S A PLEASURE TO BE HERE, ANIMAL MODELS ARE A CENTRAL COMPONENT OF WHAT WE DO. I WOULD LIKE TO GIVE YOU A HIGH-LEVEL -- WHAT DID I DO NOW? THANK YOU. THANK YOU. HIGH LEVEL OVERVIEW. SO AT NIAID OUR MISSION IS QUITE STRAIGHT FORWARD AND SIMPLE. CONDUCTING SUPPORT BASIC AND APPLIED RESEARCH TO BETTER UNDERSTAND AND PREVENT AND TREAT AND PREVENT INFECTIOUS IMMUNOLOGIC AND ALLERGIC DISEASES. ANIMAL MODELS ARE A VERY CENTRAL COMPONENT IN TERMS OF SUPPORTING AND MEETING THAT MISSION. WE KNOW FROM A LOT OF EXPERIENCE THAT WHILE ANIMAL MODELS ARE NOT PREDICTIVE OF WHAT WILL BE SUCCESSFUL IN HUMANS WHEN YOU'RE TALKING INTERVENTIONS SUCH AS VACCINES AND THERAPEUTICS, I KNOW IN GENERAL FAILURE IN ANIMAL MODELS IS A GOOD INDICATOR THAT IT'S NOT LIKELY TO WORK. AND IN FACT, ONCE YOU HAVE SUCCESS IN AN ANIMAL MODEL THE ABILITY TO ACHIEVE THE NECESSARY EXPSURE AT ACCEPTABLE TOXICITY LEVEL IS GENERALLY QUITE PREDICTIVE OF ABILITY TO MOVE FORWARD WITH THE SUCCESSFUL INTERVENTION IN HUMANS. THE BREADTH AND DEPTH OF OUR ANIMAL MODEL PROGRAM, THERE ARE SOME LISTINGS HERE THAT GIVE YOU AN IDEA. WE HAVE A VERY LARGE SERIES OF ANIMAL MODEL CONTRACTS THAT WE ISSUED BACK IN 2010. 38 DISTINCT CONTRACTORS ARE INVOLVED CURRENTLY WE HAVE ONGOING APPROXIMATELY 61 TASKS AT THE PRESENT TIME THAT NUMBER VARIES BUT ROUGHLY STAYS ABOUT THAT. CURRENTLY WE'RE LOOKING AT ABOUT 30 PATHOGENS BUT OUR REPERTOIRE OF WHAT WE HAVE AVAILABLE SPANS VIRTUALLY ANY DISEASE CAPABLE OF INFECTING HUMANS AND CAUSING DISEASE AS WELL AS THOSE UNKNOWN AGENTS THAT WE'RE NOT AWARE OF YET THAT MAY IN THE FUTURE ARISE. IN ADDITION ANIMAL MODEL CONTRACTS SUPPORT A WIDE ARRAY OF DEVELOPMENT CONTRACTS THAT WE HAVE ONGOING BOTH IN THE CONTEXT OF WHAT MEETS OUR BIODEFENSE MISSION WITH REGARD TO GREATER HHS PROGRAMS AS WELL AS OTHER INFECTIOUS DISEASES AND PUBLIC HEALTH ISSUES THAT WE ARE CURRENTLY FOCUSED ON. IN SUPPORT OF THOSE -- THE ANIMAL MODELS WE HAVE UNDERTAKEN PREVIOUSLY A NATIONAL AND REGIONAL BIOCONTAINMENT LAB CONSTRUCTION PROGRAM AND THE MAJORITY OF THOSE FACILITIES ARE ONLINE AND IN MANY INSTANCES ARE SUPPORTING AND CONDUCTING A LOT OF ANIMAL MODEL WORK WHICH DOES REQUIRE IN FACT BSL-3 AND/OR BSL-4 CONTAINMENT. FINALLY, WE OFFER TO THE BROAD RESEARCH COMMUNITY NOT JUST THE NON-PROFIT BUT ALSO THE FOR PROFIT SECTOR, A REPOSITORY BEI BIOEMERGING AND INFECTION DISEASES REPOSITORY A WIDE ARRAY OF REAGENTS AVAILABLE, MANY -- SOME OF THOSE ARE IN FACT PRODUCED IN UTILIZING ANIMAL MODELS TO ACTUALLY PRODUCE THOSE REAGENTS AND CONTINUE TO SUPPORT THE STOCKING AND INVENTORY OF THE THE REPOSITORY. SO THAT GIVES YOU A FLAVOR FOR REVIEW OF ANIMAL MODELS, THE TOOL AND OUTPUT WE REGARD AS A COMPONENT NECESSARY COMPONENT MEETING OUR MISSION. THE LAST COMMENT WE ADDRESSED IS UNIQUENESS COMPARED TO OTHER AGENCIES. ONE AREA THAT SETS US APART IS WE'RE NOT FOCUSED ON A PARTICULAR LIST OR COLLECTION OF AGENTS. WE ARE RESPONSIVE TO THE EXISTING KNOWN INFECTIOUS DISEASES, THE RELEVANT PUBLIC HEALTH ISSUES THEY RISE, BUT WE ALSO HAVE TO BE RESPONSIVE TO NEW AND EMERGING INFECTIOUS DISEASES AND BE PREPARED TO BRING OUR RESOURCES TO BEAR WHICH INCLUDES ANIMAL MODELS IN ORDER TO SUPPORT THE CHARACTERIZATION AND THE INTERVENTION FOR NEW AND UNKNOWN DISEASES AS THEY EMERGE. SO WE REGARD THAT AS A CRITICAL COMPONENT AND BUILD INTO OUR CONTRACTS AND ANIMAL MODEL CAPABILITIES, THE FLEXIBILITY TO RESPOND AS NIMBLY AS POSSIBLE WHEN THREATS EMERGE. SO I'LL END THERE AND TURN IT OVER TO DR. KORCH. >> NEXT IS TOM DRYER WHO WILL INTRODUCE BARTA. >> THANK YOU VERY MUCH. I'M GOING TO GIVE A BRIEF FOR BARTA. BEEN WORKING ON THIS PROGRAM FOR A LITTLE WHILE BUT I WAS ASKED TO GIVE LIKE MIKE SOME OF THE -- WHOOPS, WRONG WAY. THE BARTA MISSION IS HERE, I'M NOT GOING TO READ IT. UNLIKE A LOT OF OTHER ORGANIZATIONS THAT WE HAVE WITHIN THE -- THIS ORGANIZATION OR THIS COMMUNITY, OURS IS FOCUSED ON DEVELOPMENT AND DELIVERY OF PRODUCTS THROUGH THE STOCK PILE. THAT'S OUR ULTIMATE GOAL, THAT'S WHAT WE WORK FOR. SO WITHIN THAT, WE HAVE TO PUT IN THE ANIMAL MODELS. WITHIN BARTA ARE A SERIES OF AREAS THAT WE HAVE TECHNAL EXPERTISE WE HAVE BROUGHT TOGETHER. ONE IS OUR NON-CLINICAL9/ DEVELOPMENT NETWORK. THE GOAL IS THE CIRCLE ON THE RIGHT HERE OF THE VARIOUS THINGS WE ARE LOOKING AT TO DO IN OUR ANIMAL MODEL DEVELOPMENT PROGRAM. IT SHOULD BE HIGHLIGHTED THAT WE STARTED THIS PROGRAM SEVERAL YEARS AGO IN HISTORICALLY EACH MANUFACTURERS OR PRODUCT DEVELOPERS WAS RESPONSIBLE FOR THE DEVELOPMENT AND EVERYTHING ASSOCIATED WITH ANIMAL MODEL. WE'RE GETTING A LOT OF DUPLICATION. THERE WAS A LOT OF ADD D COST, PEOPLE DOING THE SAME EXPERIMENTS AGAIN AND AGAIN, AND THIS ALSO DRIVES THE ETHICS OF THE NUMBER OF ANIMALS WE USE. SO OUR EFFORTS WAS FOCUSED ON REDUCTION OF COST AND REDUCTION AND IMPROVEMENT OF THE ETHICAL TREATMENT OF ANIMALS. IN OTHER WORDS, THE USE OF THE ANIMALS. WITHIN OUR NETWORK WE HAVE THREE PRIMARY AREAS. ONE IS SCIENTIFIC VALIDITY AND REGULATORY COMPLIANCE, I LIKE TO LOOK, MANY OF US HAVE BARTA CONSIDER BARTA IN MANY WAYS A VENTURE CAPITAL ORGANIZATION. WE DO NOT GO TO THE THE FDA WITH ANYTHING PER SE FOR OUR PARTICULAR DEVELOPERS. THAT IS THE DEVELOPERS RESPONSIBILITY. BUT WE WORK WITH OUR DEVELOPERS TO ADDRESS THINGS IN A SCIENTIFIC MANNER UNDER THE REGULATORY UMBRELLA. TIME AND COST SAVINGS IS THE PRIMARY DRIVER OF OUR DATA PROGRAM. THE THIRD IS DATA SHARING. THAT COMES TO THE STEP ABOVE THE TIME AND COST SHARING. AS YOU WOULD SEE IF YOU HAD A CONTRACT WITH BARTA. WITH YOU'RE A DEVELOPER OR IN YOU'RE A MODEL DEVELOPER, THE GOVERNMENT MAINTAINED CONTROL OF ALL THE DATA TO PUT IT IN TO ONE SPOT. OUR GOAL IS TO SHARE THIS INFORMATION AS WE GO DOWN. THERE ARE SOME PROGRAMS THAT HAVE BEEN GRANDFATHERED IN BECAUSE THEY WERE THERE BEFORE WE SET THIS PROGRAM. FUNDAMENTALLY OUR DRIVER STO GET DATA SHARING, TO GIVE IT -- TO SHARE WITH THE FDA AND OTHER AGENCY TO UNDERSTAND HOW DO WE DEVELOP A MODEL WITHIN FOR THE PURPOSE OF LICENSURE. WITH THAT, I'M GOING TO STOP. THAT'S THOUSAND CONTACT US. >> NEXT WE'RE GOING TO HAVE HEATHER W ARGO FROM TMT INTRODUCE THEIR PROGRAM. >> I'M FROM THE JOINT MANAGEMENT OFFICE FOR TRANSFORMATIONAL TECHNOLOGIES OR TMT. IT'S AN ADVANCED DEVELOPER FOR POST SYMPTOMATIC TREATMENTS WITHIN THE BIODEFENSE PROGRAM. OUR MISSION IS TO PROVIDE THE WAR FIGHTER AND THE NATION WITH INNOVATIVE MEDICAL SOLUTIONS TO PROTECT AND TREAT EMERGING GENETICALLY ENGINEERED OR UNKNOWN BIOTHREATSCH BECAUSE WE DO IT WITHIN THE CONSTRAINTS OF FDA APPROVAL PROCESS WE USE KNOWN PATHOGENS AS MODEL SYSTEMS AN EVALUATE PRODUCTS WITH PROMISE OF EFFICACY AGAINST THE GENETIC MY LIVE MODIFIED OR UNKNOWN BECAUSE THEIR MECHANISM OF ACTION SUGGESTS A BROAD SPECTRUM OF ACTIVITY OR BECAUSE THEY'RE BASED ON A PLATFORM TECHNOLOGY THAT CAN BE READILY ADAPTED TO ADDITIONAL PATHOGENS AND ADDITIONAL THREATS AS THE DOD PROGRAM PATHOGENS OF INTEREST TO US WILL TYPICALLY DICK KATE OUR PRODUCTS FOLLOW THE ANIMAL RULE WHEN THEY PURSUE REGULATORY APPROVAL. THE BREADTH AND DEPTH OF OUR PROGRAM, WE HAVE DEVELOPED A FAIRLY ROBUST ANIMAL MODEL CAPABILITY AREA TO SUPPORT OUR MISSION. WE INVEST IN ANIMAL MODEL DEVELOPMENTS TO SUPPORT THE ADVANCED STUDIES FOR PRODUCTS THAT ARE CURRENTLY IN OUR PIPELINE SUCH AS OUR EBOLA AND MARBERG ANIMAL MODELS. WE ALSO INVEST IN ANIMAL MODELS TO SUPPORT FOLLOW ON INDICATIONS FOR CURRENT PRODUCTS AS WELL AS NEW PROGRAMS WE ANTICIPATE INITIATING NEAR TERM. WE INVEST IN INNOVATION, INNOVATIVE APPROACHES THAT MEET ONE OF THE FIRST TWO CRITERIA BUT AT THE SAME TIME ALSO SERVE TO PROGRESS THE FIELD OF ANIMAL MODEL DEVELOPMENT AND REGULATORY SCIENCE. EXAMPLES ARE MARMOSET MODELS FOR PIVOTAL ANIMAL STUDIES AN EFFORT TO MOVE THE FIRST ANIMAL MODEL DATA PACKAGE SUBMITTED TO FDA QUALIFICATION PROCESS FOR DRUG DEVELOPMENT TOOLS FORWARD. A FEW DISTINCTIONS OF OUR PROGRAM FROM OTHER ORGANIZATIONS HERE. FIRST AS ADVANCED DEVELOPER OUR INVESTMENTS ARE SOLELY IN ANIMAL MODELS THAT CAN SERVE AS TOOLS FOR ADVANCED DEVELOPMENT OF MATURING PRODUCTS MOVING TOWARD REGULATORY APPROVAL. WE DON'T INVEST IN MODELS THAT WOULD SERVE SIMPLY TO SCREEN FOR POTENTIAL MEDICAL COUNTER MEASURES. AS DOD PROGRAM OUR PRIMARY INTEREST IS IN PATHOGENS THAT CAN BE AEROSOLIZED AND WEAPONNIZED. SO THE MAJORITY OF OUR INVESTMENT GOES TOWARD ANIMAL MODELS WITH AN AEROSOL CHALLENGE ROUTE. WE ARE ALSO -- ONE -- DESPITE DISTINCTIONS WE ALSO SHARE COMMON INTEREST WITH EVERYONE HERE TODAY. WE'RE INTERESTED IN A COLLABORATIVE APPROACH TO ANIMAL MODEL DEVELOPMENT TO MAKE SURE WE MAXIMIZE THE BENEFITS OF OUR INVESTMENTS AND WE'RE PLEASED TO CURRENTLY BE CO-CHAIRING TWO ANIMAL MODEL WORKING GROUPS. ONE IS THE ANIMAL MODEL SUBGROUP UNDER THE FIELD VIRUS ANIMAL NON-CLINICAL GROUP AND THE NEWLY CHARTEDDED ANIMAL MODEL DEVELOPMENT AND QUALIFICATION COORDINATION WORKING GROUP. WHICH UNTIL RECENTLY I THOUGHT WAS THE ABSOLUTE WORST ACRONYM WE COULD COME UP WITH INTIL THIS WEEKEND I LEARNED THERE WAS ACTUALLY A GROUP IN THE GOVERNMENT CALLED THE REGIONAL EMERGENCY COORDINATORS. AND THEY ABBREVIATE THEIR EMERGENCY PLAN PLANNING GROUP REC AND PRONOUNCE IT WRECK. SOY THINK THERE ARE SOME ADVANTAGES TO NOT HAVING A PRONOUNCEABLE ACRONYM. WE ARE PLEASED TO BE CO-SPONSORS OF THIS WORKSHOP AND LOOK FORWARD TO TALKING WITH YOU OVER THE NEXT COUPLE OF DAYS A COUPLE OF MY COLLEAGUES FROM TMT THAT ARE HERE ARE GEORGE CHRISTOPHER, YUSEF, JOHN BURNS, KEN TUCKER AND DENISE (INDISCERNIBLE) IS AROUND IF YOU GUYS CAN GIVE A WAVE. WE WOULD BE HAPPY TO TALK ABOUT OUR PROGRAM AND ALSO BE SURE TO PICK UP ONE OF OUR BROCHURES THAT DESCRIBES OUR INVESTMENTS. THANKS. >> THANK YOU, HEATHER. LASTLY BUT NOT LEAST WE HAVE TRACY MCGILL FROM THE FDA WHO WILL INTRODUCE THEIR PROGRAM. >> THANK YOU, JUDY. I'M GOING TO PROVIDE A VERY BRIEF HIGH-LEVEL OVERVIEW OF THE FDA MEDICAL COUNTER MEASURES INITIATIVE. MCM LITTLEI. THIS IS A NEW PROGRAM AT FDA, THE INITIATIVE WAS LAUNCHED IN 2010. IN RESPONSE TO A COMPREHENSIVE YEAR LONG REVIEW OF THE PUBLIC HEALTH EMERGENCY HEALTH COUNTER MEASURES ENTERPRISE OR ALSO KNOWN AS THE FEM SERKSI OR THE ENTERPRISE. THE INITIATIVE NOW HAS FUNDING AND IS DIRECTED FROM THE OFFICE OF COUNTER-TERRORISM AND EMERGING THREATS IN OFFICE OF CHIEF SCIENTIST AND OFFICE OF COMMISSIONER UNDER THE LEADERSHIP OF DR. LUCIANA BOREO. THE OBJECTIVE OF THE INITIATIVE IS TO BUILD ON EXISTING FDA ACTIVITIES WITHIN THE MCM ARENA AND USING A PILLAR STRATEGY TO FACILITATE MEDICAL COUNTER MEASURE DEVELOPMENT EVALUATION AND AVAILABILITY. BY ENHANCING THE REVIEW PROCESS, THIS FALLS UNDER OUR PILLAR ONE, DR. ALAN LIZ IS DIRECTOR OF THAT PILLAR. ADVANCING MEDICAL COUNTER MEASURE REGULATORY SCIENCE FOCUS OF PILLAR 2, DR. HENSLEY WILL SPEAK LATER THIS MORNING AND MODERNIZING LEGAL AND REGULATORY AND POLICY APPROACHES AN STRENGTHEN WORK FORCE EXPERTISE WHICH FALLS UNDER PILLAR 3, LIZ SATO IS LEAD OF THAT PILLAR. WE'RE FORTUNATE TO HAVE MEMBERS OF ALL THE PILLARS ATTENDING THE MEETING OVER THE NEXT TWO DAYS. SO PLEASE FEEL FREE TO ASK THEM ANY QUESTIONS AND LEARN MORE ABOUT OUR NEW PROGRAM. OF COURSE ALL OF THESE EFFORTS DONE IN CLOSE PARTNERSHIP WITH THE MEDICAL PRODUCT CENTERS AS WELL AS OFFICE OF REGULATORY AFFAIRS. AS PREVIOUSLY STATED BY THEE WE ARE, WE WERE HAPPY TO BE ASKED TO CO-SPONSOR THE MEETING. DEVELOPING AND ADVANCING ANIMAL MODELS FOR PRODUCT APPROVAL AND LICENSURE IS NOT ONLY CRITICAL TO SUCCESS OF OUR PROGRAM BUT ALSO TO PROTECTING OUR NEIGH'S HEALTH. THANK YOU. >> THANK YOU, EVERYONE. SO WE'RE GOING TO MOVE ON TO THE REAL MEAT OF THE FIRST SESSION, THE TALKS STARTING WITH DR. GEORGE KORCH. ON LOAN FROM THE GOVERNMENT TO JOHNS HOPKINS. HE'S GOING TO TALK ABOUT ANIMAL MODEL WHAT IS DO WE KNOW AND WHERE DO WE GO. >> THANKS VERY MUCH, JUDY. A PLEASURE TO BE HERE FIRST SHANATOVA TO ANYBODY CELEBRATEING A NEW YEAR TODAY. ALSO WANT TO POINT OUT FROM HISTORICAL PERSPECTIVE WE'RE TALKING ABOUT PATHOGENS AND DANGERS THAT CAN CAUSE NASES PUBLIC HEALTH CONSEQUENCE AND WE'RE SITTING ABOUT 60-MILES FROM ON THIS DAY 150 YEARS AGO SOME OF THE LARGEST LOSS OF LIFE IN THIS COUNTRY OR LARGEST NUMBER OF CASUALTIES EVER IN THE THE BATTLEFIELD. THIS IS THE 150th ANNIVERSARY OF THAT PARTICULAR BALT. SO FOR MY MILITARY COLLEAGUES IN ROOM AS WELL AS HISTORY BUFFS A VERY INTERESTING DAY IN TERMS OF AMERICAN HISTORY. ALSO WANT TO ACKNOWLEDGE I AM AWAY FROM HHS FOR A PERIOD OF TIME BUT TO MY COLLEAGUES PHIL FAIR ROW, MELISSA WILLIS, TOM DWIER REPRESENTING ASPR AND HHS BARTA THAT JUST ALSO WANT TO POINT OUT ONE CONGRATULATIONS, HE'S NOT HERE TODAY BUT YOU ARE PROBABLY AWARE THAT DR. ART FREELANDER RECENTLY RECEIVEDDED AND WAS HONORED WITH ONE SAMMY AMERICAN SERVICE AWARDS SO FROM OUR MIDST OF INDIVIDUALS HERE DOING WORK IN THE GOVERNMENT IN VERY IMPORTANT WAY THERE'S RECOGNITION ELSEWHERE. SO LET'S GET INTO ANIMAL MODELS. WHAT DO WE KNOW, WHERE DO WE GO. SO THIS IS GOING TO BE A MAD ROMP THROUGH SOME OF THE ISSUES MORE RECENTLY. I THINK AREAS THAT WE'RE STARTING TO MAKE SOME REAL PROGRESS IN. SO WHAT IS IT THAT WE KNOW? PRODUCTS ARE NEEDED TO PROTECT AND RESPOND TO ANY OF THESE THREATS WE'RE TALKING ABOUT. RAD NUC BIO. UNIQUE EMERGING DISEASES SO NOT JUST DELIBERATE THREATS BUT ALSO EMERGING THREATS OF GREAT AND PUBLIC HEALTH IMPORTANCE. WE ALSO KNOW GOVERNMENT WILL DERIVE OR BE THE FOCUS FOR THE PRODUCTION OR THE MEANS BY WHICH MEDICAL PRODUCTS WILL BE ULTIMATELY FUNDED. WE ALSO KNOW EVEN WITH RESPECT TO INDIVIDUALS FROM THE COMMERCIAL SECTOR THAT MAYBE HERE IN THE AUDIENCE TODAY, FOR THE MOST PART THESE PRODUCTS DO NOT ENGENDER A LOT OF PROFIT. THEREFORE, THEY'RE NOT REALLY COMMERCIALLY AVAILABLE OR VIABLE, THEY'RE AVAILABLE SOME BUT NOT VIABLE, AT LEAST IN TERMS OF PUBLIC HEALTH RESPONSE TO SOME OF THESE RARE BUT HIGH CONSEQUENCE EVENTS. THERE IS ALSO FOR MOST DISEASES WE TALK ABOUT GENERALLY, A PAUCITY OF HUMAN CLINICAL DATA MAKING THE JOB A LOT MORE DIFFICULT. NOT JUST WITH RESPECT TO ANIMAL MODELS THAT I'LL TALK ABOUT BUT IN GENERAL BEING ABLE TO LOOK AT THE THREATS AND UNDERSTAND THE NATURAL HISTORY, ET CETERA, BY WHICH WE CAN HAVE THE DATA FOR THE HUMAN -- FOR EVALUATING HUMAN VERSUS ANIMAL DISEASE PROGRESSION. BUT ULTIMATELY WE MUST HAVE THESE ANIMAL MODELS TO DEMONSTRATE MEDICAL COUNTER MEASURES. WE WERE GIVEN A WONDERFUL TOOL BY THE FOOD AND DRUG ADMINISTRATION. THE MECHANISM TO GET THESE PRODUCTS AT LEAST TO LEVEL OF APPROVAL WHERE THEY CAN BE USED UNDER EMERGENCY CIRCUMSTANCES WE ALSO KNOW IT HAS BEEN NOT THE EASIEST ROAD TO FOLLOW RIGHT NOW WITH THE ANIMAL EFFICACY RULE, LARGELY BECAUSE IT'S FAIRLY NEW, IT'S BEEN A DECADE OR SO NOW BUT IT'S STILL SOMETHING WE'RE STARTING TO REALLY UNDERSTAND ALL THE RAMIFICATIONS. A VISION WAS SET FORWARD BY THE FEMSI BY THE SECRETARY OF HEALTH AND HUMAN SERVICES BACK IN 2010. SECRETARY SEBELIUS SAID THAT OUR NATION MUST HAVE THIS NIMBLE FLEXIBLE CAPACITY TO PRODUCE THESE MEDICAL COUNTER MEASURES RAPIDLY IN THE FACE OF ANY SORTS OF ATTACK. NOTICE IN THE STATEMENT INCLUDED NOVEL PREVIOUSLY UNRECOGNIZED DISEASE AS WELL AS ONES WE CLASSICALLY THINK ABOUT. AND MULTIMITTLY MEMBERS OF THIS PARTICULAR STUDY, REALIZE WHAT WE'RE LOOKING AT IN THE ASSEMBLAGE OF THINGS TO PRODUCE MEDICAL COUNTER MEASURES I'LL TOUCH ON IN A SECOND, PRODUCT FAILURE SHOULD HAPPEN ONLY FOR ONE OF TWO REASONS. EITHER PRODUCT SNOT SAFE, DOESN'T HAVE SAFETY CHARACTERISTICS OR IS NOT EFFICACIOUS AND THEREFORE OUR INABILITY TO PRODUCE MEDICAL COUNTER MEASURES SHOULDN'T BE A FUNCTION OF LACK OF INVESTMENT, THE TECHNICAL, THE BUSINESS OR THE REGULATORY PERSPECTIVES BUT STAND ALONE ON THE SCIENCE ITSELF. THAT WAS THE UNDERPINNINGS FOR THE REPORT THAT WAS GENERATED IN 2010 ABOUT MEDICAL COUNTER MEASURES THE ENTERPRISE ITSELF. O FISH NANO DOES IN THE KNOW OF WHAT FEMSI LOOKS LIKE, KIND OF A FLOWCHART, IT LOOKS LIKE A PRODUCT DEVELOPMENT PIPELINE, IT SHOULD. BUT STARTS WITH REQUIREMENTS BASED ON MEDICAL CONSEQUENCE MODELING, USUALLY DERIVED FROM MATERIAL DETERMINATIONS AND ASSESSMENTS THAT COME FROM THE DEPARTMENT OF HOMELAND SECURITY AND FROM THERE WE SPEND TIME LOOKING WILL WHAT WILL THE IMPACT B POPULATIONS IMPACTED WHAT MEDICAL COUNTER MEASURES DO WE HAVE PROTECT PRIOR TO OR MAYBE AFTER OR TO TREAT. FROM THERE WE ARE THEN ALONG THE LINE OF THIS VALUE CHAIN WITH THE NATIONAL INSTITUTES OF HEALTH SPENDING TREMENDOUS AMOUNT OF TIME, ENERGY AND RESOURCE IN RESEARCH AND DEVELOP, THE REASON THAT ONE OF THE REASONS WE'RE ALL HERE TODAY. AS FOR BARTA IS RESPONSIBLE TO LOOK AT ANY SORT OF NOVEL APPROACHES OR WHAT'S COMMERCIALLY VIABLE OR WHAT'S THERE ALREADY IN THE COMMERCIAL SPACE IN TERMS OF ADVANCE DEVELOPMENT. I FAILED TO MENTION CAROL AS WELL IN THIS. THEN ACQUISITION STOCK PILING LOOK AT WHAT WE DO TO ACQUIRE MATERIALS TO PUT THEM IN THE HAND OF THIS CDC AND STRATEGIC NATIONAL STOCK PILE FOR STORAGE FOR PRODUCTS THAT CAN BE EITHER USED UNDER EMERGENCY AUTHORIZATION IF THERE'S NOT INDICATION, APPROVAL FOR THE PRODUCT ITSELF OR HOPEFULLY IF IT'S ALREADY APPROVED TO BE USED UNDER THE INDICATIONS. THAT ARE REPRESENTED BY THE PRODUCT. FINALLY CDC AND TO CERTAIN SMALL LEVEL ASPR OFFICE OF PREPAREDNESS EMERGENCY OPERATION, ASSISTS IN DEPLOYMENT BUT THIS IS STILL LARGELY SOMETHING THAT HAPPENS AT THE STATE AND LOCAL LEVEL IN TERMS OF PLANNING FOR DEPLOYMENT. THEN THERE'S THIS EVALUATION PERIOD CDC ASPR AND OTHERS WILL BE AND PROBABLY NIH ALSO INVOLVED IN POST MARKETING SURVEILLANCE, ANOTHER IMPORTANT PART UNDER THE ANIMAL RULE AND EVALUATION. IN ADDITION TO AGENCIES DESCRIBED HERE, THERE ARE A VARIETY OF OTHER INTERAGENCY PARTNERS THAT WORK TOGETHER TO HELP THE NEEDS AND THE POLICIES AND THE PROGRAMS OF THE FEMSI. FORWARD, BACKWARD. MICHAEL MENTIONED A FAIRLY BROAD REMIT FOR THE TYPES OF THINGS THAT WE'RE LOOK AT BUT WHEN IT BOILS DOWN TO WHAT WE'RE MAKING, WHAT IS THE INDUSTRY INTERESTED IN KNOWING WE'RE TRYING TO PRODUCECH THIS IS A SNAP SHOT OF PRODUCTS WE'RE INTERESTED IN AND THIS COMES FROM THE 2007 FEMSI STRATEGY IMPLEMENTATION PLAN. IT'S STILL LARGELY TRUE IN TERMS OF PRODUCTS. WE HAD GREAT SUCCESS IN TERMS OF EARLY INVESTMENTS IN VACCINES, SMALLPOX AND ANTHRAX AND THERAPEUTICS DRUGS TO ACUTE RADIATION INJURY STARTING TO SHOW ON UP IN THE PIPELINE OR HAVE ALREADY BEEN PURCHASED, PROCURED AND PUT IN THE NATIONAL STOCK PILE SO YOU CAN SEE MIDTERM INVESTMENTS ALONG THE MAJOR THREAT AREAS, ANTHRAX VIRUSES, SMALLPOX, ARS, CHEMICAL INSULS AS WELL. BROADER SPECTRUM COMMERCIALLY VIABLE PRODUCTS AS WELL. SO THERE'S A RANGE OF PRODUCTS WE'RE DEVELOPING AND LOTS OF OPPORTUNITY STILL. BUT ALL HAVE ONE FUNDAMENTAL UNDERLYING BACKBONE TO THEM. THEY ALL GENERALLY RELY ON ANIMAL MODEL FOR EVALUATION OF EFFICACY AND CERTAIN DEGREE FOR SAFETY AS WELL. SO WHEN WE LOOK AT RISKS PRODUCT DEVELOPER SPACE IN FEDERAL SECTOR AS WELL AS COMMERCIAL SECTOR AS WELL OR ACADEMICS, WHAT ARE AREAS OF RISK AND HOW DO WE MITIGATE THOSE AREAS FOR PRODUCT P DEVELOPER? THERE WERE FOUR MAJOR AIR JAS OF RISK WE TALKN'T OR FOUND THAT WAS A TECHNICAL RISK. SO THOSE ARE ONES YOU'RE MOST FAMILIAR WITH IN THIS ROOM. IF YOU'RE AN ACADEMICIAN, RESEARCHER OR ADVANCED DEVELOPER SO ACCESS TO CORE MANUFACTURING SERVICES. RECENTLY BARTA ANNOUNCED THE THE CENTER FOR INNOVATION ADVANCED DEVELOPMENT MANUFACTURING, THREE AWARDS WERE MADE EARLIER THIS YEAR TO ASSIST IN DEVELOPING OR PRODUCING CORE CAPABILITIES FOR PRODUCT DEVELOPMENT AND ALSO ALLIANCE AND ANIMAL EFFICACY RULE, BIOCONTAINMENT, THESE ARE TECHNICAL AREAS THAT HAVE TO BE MITIGATED. THE REGULATORY RISKS WE HEARD FROM FDA COLLEAGUES THAT THIS IS UNDER SERIOUS UNDERTAKING AND LISA HENSLEY WILL DISCUSS MORE HOW WE MITIGATE REGULATORY UNCERTAINTY BOTH FOR OWN FEDERAL PARTNERS AS WELL AS COMMERCIAL PARTNERS AS WELL. THERE'S A BUSINESS RISK ASPECT TO THIS THAT UNLESS YOU'RE IN A STARTUP COMPANY OR TRYING TO MAINTAIN A BIOTECHNOLOGY ENTERPRISE, THE FINANCIAL PRESURES FOR CAPITAL STARTUP FOR MATURING BUSINESS AND THE FACT THAT MANY OF THE NEWER BUSINESSES DON'T HAVE FULLY INTEGRATED CAPABILITY SO WE HAVE LOOKED TO HOW TO MITIGATE THAT AND THERE IS A PROPOSAL ON THE TABLE AND HOPEFULLY CONGRESS WILL PASS THE STRATEGIC INVESTOR. FINALLY THERE'S THE GOVERNMENT RISKS EVERYBODY FACES. THIS IS THE FACT THAT IT'S SOMETIMES DIFFICULT FOR FEDERAL AGENCIES TO COORDINATE SO WE HAVE BEEN DOING A LOT OF WORK TO COORDINATE ACROSS FEDERAL AGENCIES AND PRIORITIZE LONG RANGE NEEDS. SO THE FINDING CAME OUT OF TREMENDOUS NEED AND ENHANCING REGULATORY INNOVATION AND SCIENCE SCIENCE CAPACITY, PROVIDING CORE DEVELOPMENT MANUFACTURING SERVICE. I MENTIONED THAT TO MCM DEVELOPERS. THE USE AND ABILITY TO EXPAND RAPIDLY DURING TIMES OF NEED, ESPECIALLY FOR THINGS LIKE PANDEMIC INFLEW INFLUENZA, THAT CAPABILITY IS COMING ON LINE FOR THE CI ADM. NOVEL WAYS TO WORK WITH PARTNERS IN ACADEMIA, PUBLIC PRIVATE PARTNERSHIPS THAT HAS ALSO BEEN A TOUCH STONE OF WHAT'S GOING ON IN FEMSI. IMPROVING THE FINANCIAL IP INCENTIVES FOR MCM DEVELOPMENT AND ADDRESSING ROAD BLOCKS AND IMPROVING MANAGEMENT ADMINISTRATION. THESE ARE ALL FOUND IN THE 2010 FEMSI REVIEW IF YOU'RE INTERESTED IN IT. TURNING TO ANIMAL EFFICACY RULE, YOU'RE PROBABLY GOING HEAR MORE FROM ROSE MARY ROBERTS AND OTHERS IN TERMS OF ANIMAL EFFICACY RULE BUT I WOULD IMAGINE MOST PEOPLE IN THE AUDIENCE ARE AWARE OF WHAT THE RULE IS IN TERMS OF 21-CFR-314 AND 601. REALLY IT ALL IS -- BOILS DOWN TO A COUPLE OF MAJOR THINGS. NUMBER ONE, THE ISSUE OF THE MECHANISM. REASONABLY UNDERSTOOD, WELL UNDERSTOOD PATHOPHYSIOLOGICAL MECHANISMS. NUMBER 2 GETS THE PREDICTIVE VALUE. THE DEMONSTRATION IN ONE OR SEVERAL ANIMAL MODELS THAT WE WILL HAVE PREDICTIVE RESPONSE TO THAT THAT WOULD BE SEEN IN HUMANS. THIRD, A BENEFIT, WHAT YOU'RE DOING DEMONSTRATES DESIRED BENEFIT FOR HUMANS AND FINALLY THAT THE PKPD, KINETICS AND PHARMACODYNAMICS THE DATA PRESENTED IN THAT ANIMAL MODEL REALLY ASSISTS IN SELECTION OF DOSE RANGING AND EFFECTIVE DOSING IN HUMANS SO THAT IS THE NUTS AND BOLTS OF WHAT THE ANIMAL RULE IS ALL ABOUT. FROM 2002 TO ABOUT 2008, 9, 10 AS WE APPLY THESE THINGS AN UNDERSTANDING WHAT REALLY IS NEEDED TO SATISFY THE RULE, FOOD AND DRUG ADMINISTRATION ALSO UNDERTOOK SERIES OF CONVERSATIONS WITH INDUSTRY AND LEARNED THAT THERE WERE SEVERAL OTHER REALLY IMPORTANT THINGS THAT NEEDED TO BE CLARIFIED QUALIFYING ANIMAL MODELS. MORE RECENTLY, WE EEL HEAR MORE ABOUT IT, THE GUIDANCE INDUSTRY ON WHAT THEY'RE LOOKING FOR IN A LITTLE MORE FORMAL FASHION WITH REGARD TO CHALLENGE AGENT PATHOGENIC DETERMINANTS, ROUTES OF EXPOSURE, AND QUALIFICATION AND -- ON THE CHARACTERISTICS OF THE CBER AGENT, THE NATURAL HISTORY STUDIES, HOSE SUSCEPTIBILITY, TRIGGERS FOR INVENTION, WHAT'S GOING TO TRIGGER THE INTERVENTION AND WHAT ANIMAL DATA CAN YOU ASSUME, ARE THERE BIOMARKERS, CERTAIN THINGS THAT YOU START USING AS A RESULT OF SAYING IT'S TIME TO MOVE THIS PARTICULAR COUNTER MEASURE TO THE INDIVIDUAL AFFECTED. CHARACTERIZATION OF THE MEDICAL INVENTION HIMSELF, MECHANISM OF ACTION, PKPD. SYNERGY OR ANTAGONISM OF OTHER MEDICAL PRODUCTS LIKELY USED DURING AN EVENT ITSELF IN COMBINATION. THEN ALSO THE END POINTS, THE TIMING FOR INTERVENTION, THE ROUTES OF ADMINISTRATION. THESE ARE THINGS THAT ARE COVERED IN GUIDANCE TO INDUSTRY WITH THE HOPE IT WILL BE IMPROVING ACCESSIBILITY OF THE RULE AND PROVIDING A LITTLE MORE GUIDANCE IN TERMS OF WHAT FDA IS LOOKING FOR WHEN YOU APPROACH THEM WITH DATA FOR APPROVAL UNDER ANIMAL RULE. TMT, HEATHER WARGO MENTIONEDDED ALREADY THE ROLE OF TMT OR DITRUS PROGRAM TO LOOK HOW TO PRODUCE MEDICAL COUNTER MEASURES AGAINST UNKNOWN THREATS, IT'S NOT BAD ENOUGH THAT WE HAVE THREATS THAT DWOA KNOW IT'S HARD TO PRODUCE A COUNTER MEASURE. BUT UP THE APPROXIMATETY AND -- ANTI AND HOW WE DEVELOP COULDN'T COUNTER MEASURE AGAINST THAT. SO THEY CAME TO INSTITUTE OF LAB ANIMAL RESEARCH FOR HELP IN IDENTIFYING WHAT DO WE KNOW ABOUT ANIMAL MODELS WHY PARTNERS IN CRIME HERE, YOU'LL HEAR FROM LATER ON, JIM SWEARENGEN WAS ON THIS PARTICULAR COMMISSION OR COMMITTEE. THEY ASKED US THE FOLLOWING QUESTIONS. THE RESULTS WERE DEVELOPED, PRODUCED IN 2011. THEY ASKED US TO HELP IN DEVELOPMENT, A LONG STANDING CONCERN. THE ABILITY TO IDENTIFY THE MOST RELEVANT MODEL FOR WHAT KNOWN SETS ARE, THE FACT WE HAVE UNIQUE DIFFICULTY OF UNKNOWN THREATS WE EMBARKED ON LOOKING AT HOW TO EVALUATE THE CURRENT LANDSCAPE AND PRODUCE RECK NISMS HOW TO MOVE FORWARD. THIS WAS THE CHARGE. EVALUATE HOW WELL EXISTING PROPOSED ANIMAL MODELS REFLECT THE CURRENT KNOWN PATHOPHYSIOLOGY CLINICAL PICTURE AND TREATMENT. ADDRESS THE PROCESS AND/OR FEASIBILITY OF DEVELOPING NEW ANIMAL MODELS FOR THIS CRITICAL AREA OF RESEARCH. PLACING EMPHASIS ON PROBUST EXPEDITIOUS VALIDATION PROCESSES IN TERMS OF ANIMAL RULE AND VALIDATION IMPLIES A WHOLE SERIES OF CAPABILITIES AND NEEDS AND UNDERSTOOD INFORMATION THAT QUITE FRANKLY DOES NOT EXIST TO A LARGE DEGREE. EVALUATE ALTERNATIVES FOR USE OF ANIMAL MODELS, VIS-A-VIS THE ANIMAL RULE AND FDA LICENSURE AND FOCUSING MOSTLY ON REFINEMENT, REDUCTION, REPLACEMENT. AND FINALLY CONSIDER THE DEVELOPMENT OF HUMANE ANIMAL MODELS FOR INFECTIOUS DISEASE RESEARCH THAT DO NOT INCORPORATE DEATH AS NECESSARILY AN END POINT. SO THAT WAS THE CHARGE TO THE COMMITTEE. FORMULATION OF THE REPORT, 14 MEMBERS WE HAVE TWO CO-CHAIRS, MY OTHER WAS STEVE MIMI FROM MASS GENERAL. WE HAD A GREAT REPRESENTATION FROM INDUSTRY, ACADEMIA AND NGOs, WE CONSULTED WITH ALL THE MAJOR ORGANIZATIONS THAT ARE PRESENT TODAY. IN TERMS OF INFORMATION FROM A VARIETY OF ACADEMIC ORGANIZATIONS, OTHER FEDERAL PROGRAMS AND NGOs, ET CETERA, AND INDUSTRY AS YOU SEE HERE. SO WHAT DID WE HOPE FOR ACHIEVING SUCCESS UNDER THE ANIMAL RULE AND IN TERMS OF THIS SORT REALLY SOME OF THE THINGS THAT WE IDENTIFIED IN THE REPORT, WERE THAT BASED ON OUR CURRENT LEVEL OF SUCCESS JUST IN PHARMACEUTICAL MODELS IN GENERAL, NOT NECESSARILY APPLIED SPECIFICALLY TO BIODEFENSE, APPROVAL UNDER THE CURRENT RULES CERTAINLY WOULD BE -- HAVE TO BE CONSIDERED A BEST CASE SCENARIO. THAT'S FOR REASONS PATHOGENESIS OF THESE RARE OR UNKNOWN INFECTIONS REALLY DIFFICULT IN TERMS OF GUIDING US WITH DEVELOPMENTAL PROCESSES FOR THE ANIMAL MODELS THEMSELVES. THE PATHOGENS THAT HAVE TO BE OPTIMIZED WITH INTERVENTIONSCH EVENTS THEMSELVES PRODUCE A CLINICAL SETTING THAT WAS VERY ATYPICAL MOST PRODUCTS CAN BE EVALUATED PRE-MARKETING OR POST MARKETING IN WELL CONTROLLED STUDIES AND WE WOULDN'T HAVE THAT CAPABILITY FOR BEING ABLE TO APPROACH MEDICAL PRODUCTS THIS WAY. IN GENERAL MENTIONED EARLIER LESS THAN AVERAGE FINANCIAL SUPPORT AND THERE ARE LIMITATIONS OF COURSE IN BIOCONTAINMENT, THESE WE IDENTIFIED AS HOW MIGHT WE ACHIEVE SUCCESS UNDER THE ANIMAL RULE, WHAT'S THE POSSIBILITY AND WE SAID UNDER THE BEST OF ALL CIRCUMSTANCES WOULD BE ABLE TO OVERCOME ALL THESE COMPETING NEEDS. FINALLY THE FACT WE KNOW IN ADDITION ROOM ANIMAL MODELS ARE ANALOGOUS, THEY ARE NOT HOMOLOGOUS TO HUMAN SYSTEMS SO WHAT CAN CAN WE DO TO TRY TO IMPROVE OR INCREASE THE REPORT USES AS ONE EXAMPLE ANTHRAX AND ANOTHER ONE USES FUEL VIRUSES BUT WE DO COMPARISONS OF WHAT WE KNEW OF THE VARIOUS MODELS AND AS YOU CAN SEE HERE THE AMOUNT OF NOT UNCERTAINTY BUT VARIABILITY MODEL TO MODEL TO MODEL REALLY BECOMES DIFFICULT. SO THE ISSUES OF CONSOLIDATING THESE APPROACHES, WE%1 DIFFERENT APPROACH, WE NEED A THE DATA TO CONSOLIDATE AND I'LL HAVE A COUPLE OF SLIDES SOME OF THE WAYS FORWARD ON THAT. THE REPORTS PRINCIPLE POINTS THAT TO IMPROVE ON THE ANIMAL MODEL SYSTEMS THAT WE HAVE TO GATHER AND TO SHARE THE DATA WE NEED TO SIGNIFICANTLY INCREASE EFFICIENCY AND THE PRODUCTIVITY OF THE RESEARCH THAT'S GOING ON. AND WE SHOULD CONSIDER THE FOLLOWING AREAS. ONE IS COME PART ANYONE TALLIZATION. NOT LOOKING AT THE WHOLE ANIMAL AS THE WHOLE HUMAN BUT TRY TO COME COME PART COMPARTMENTALIZE THE PATHOPHYSIOLOGICAL PROCESS BEST MODELED IN WHAT SPECIFIC ANIMAL SYSTEM AND USE A SYSTEMS APPROACH AND HOPEFULLY WITH THE ACQUIESCENCE OF THE FDA IN USING THIS APPROACH TO SAY IN THIS PARTICULAR ANIMAL MODEL MAYBE FOR CERTAIN DETERMINE TO LOGICAL ASSOCIATION WITH A DISEASE, A CERTAIN ASSOCIATION WITH REGARD TO -- THE BRONCO PULMONARY PATHWAYS, WHATEVER IT IS WE LOOK AT AS MORE COMPARTMENTALIZED. THEN TO USE WHAT DATA IS NOW GENERATED IN TERMS OF BIG DATA ON SYSTEMS BIOLOGY APPROACHES. WE THOUGHT IT IMPORTANT TO LOOK AT OTHER MECHANISMSCH THERE'S A LOT HAPPENING IN TERMS OF IMAGING AND IN VITRO APPROACHES. I THINK PETER JARLING WILL DISCUSS THE OPPORTUNITIES IN TERMS OF PATHOLOGY AND IMAGING THAT GIVE US A DIFFERENT APPROACH. IT'S REALLY IMPORTANT TO SYSTEMATICALLY COLLECT ACCESS THIS DATA IN WAYS THAT DON'T CURRENTLY EXIST, THERE ARE NO CENTRAL REPOSITORIES OF DATA. AND EVEN THINKING THROUGH WHAT THAT MEANS IN TERMS OF HOW WE ARCHIVE AND DEVELOP DATA STRUCTURES THAT WOULD BE ALLOWING US TO MAKE COMPARISONS ACROSS MULTIPLE STUDIES. VERY IMPORTANT TO PUBLISH NEGATIVE RESULTS. MANY INDIVIDUALS IN THIS ROOM HAD ANIMAL MODELS THAT THEY USE WHERE RESULTS ARE LESS THAN PUBLISHABLE BUT THAT'S STILL IMPORTANT. NOT REPEATING EXPERIMENT SOMEBODY HAS DONE THAT DEMONSTRATES IT DOESN'T WORK IS TIME SAVING, COST SAVING AS WELL ON THE IMPACT OF ANIMALS THEMSELVES. AGAIN, HUGE INCREASE OF EMPHASIS ON COLLECTION AND ANALYSIS OF HUMAN CLINICAL DATA. THERE ARE SMALL POCKETS OF CAPABILITY WHERE THIS IS AFFECTED AND WE NEED TO TAKE ADVANTAGE OF THAT. THAT MEANS MONEY SPENT UNFORTUNATELY AND INCONVENIENT EPIDEMIOLOGICAL TRIALS, INSTANCES AROUND THE WORLD BUT WHERE BETTER THAN THOSE TO START COLLECTING THE DATA. THEN FINALLY, HUGE EMPHASIS ON CLINICAL CARE THAT I'LL COVER IN A SECOND. SO CONCLUSIONS AND RECOMMENDATIONS FROM THIS MODELS OF COURSE HUGELY IMPORTANT FOR UNDERSTANDING PATHOGENESISCH WE ARE BOUND TO ANIMAL MODELS FOR YEARS OR DECADES TO COME TO FORM THE EFFECTIVENESS OF MEDICAL COUNTER MEASURES. THERE ARE IMPERFECTIONS BUT THEY'RE NOT MEANINGLESS. LACK OF SUFFICIENT HUMAN DATA FROM NATURAL HISTORY STUDIES IS NOT USEFUL IN TERMS OF BEING ABLE TO IDENTIFY WHAT THE BETTER ANIMAL MODELS ARE WITH REGARD TO HUMAN RESPONSE T. THERE ARE METHODOLOGICAL VARIANCES APPLIED BETWEEN SPECIES OR WITHIN SPECIES THAT NEED TO BE WORKED OUT. THE LIMITATIONS ARE WORKING IN BIOCONTAINMENT. THAT DEMONSTRATED UNRELIABILITY OF SOME OF THE SURROGATES, EVEN CONVENTIONAL DISEASES AS PREDICTORS OF SAFETY, EFFICACY, WE SHOULD BE LOOKING AT THE DATA THAT COME FROM DISEASES THAT WE KNOW VERY WELL AND TRY TO LOOK AT HOW TO QUALIFY BETTER. NEW ANIMAL MODELS CANNOT RESOLVE THESE LIMITATIONS SO FOCUSING ON CREATION OF NEW ANIMAL MODELS UNDER THE CIRCUMSTANCES DESCRIBED IS PROBABLY NOT GOING TO GIVE US THE RETURN ON VALUE THAT WE'RE THINKING. TO ADDRESS DERTH OF HUM POPULATION WE'RE CALLING EVERYBODY TO EXPAND DATA COLLECTION, TAKE ADVANTAGE OF POST MARKETING OPPORTUNITY AVAILABLE AND DEVELOP DATABASES OF HUMAN AND CLINICAL ANIMAL VALUES. SO EVALUATE WHICH COMPARTMENTS ARE USEFUL AND ENGAGING AND LOOK AGENT THE PATHOPHYSIOLOGY. FINALLY SUPPORT THE QUALIFICATION OF ANIMAL MODELS AS ALTERNATIVE TO VALIDATION TO LOOK AT COMPARATIVE DATA SETS TO FIND APPROPRIATE CRITERIA. A LOT OF PROGRESS IS IN THE WORKS. AS AN EXAMPLE, I KNOW ED NEWSOM IS WILLING TO DISCUSS THE FANG, TALK ABOUT ACRONYMS HERE IS ONE, FANG. FILLY VIRUS ANIMAL CLINICAL GROUP, A LOT OF MATCH NATIONS TO GET TO THAT PARTICULAR ACT NISM. THE WAY LOOKING ATYk’ STANDARDIZING THE CHALLENGE STRAINS, THE REAGENTS AND UNIVERSITY LABS TO EXPAND CLINICAL DATA WHENEVER POSSIBLE. THE FDA REGULATORY RESEARCH PROGRAM. HELPING Y'ALL OR US IDENTIFY WHAT IS THE MEAT FOR BIOTERRORISM, A LOT OF WORK, OTHER PARTS OF THE STUDY I DIDN'T TOUCH ON HERE, LOOKING AT OTHER WAYS OF ANIMAL MODELS ESPECIALLY NON-HUMAN PRIMATES TO THE EXTENT POSSIBLE LOOKING AT THEM AS HUMAN PATIENTS AND USING SUPPORTIVE THERAPY WE WOULD POSSIBLY BE USING IN HUMANS, BECAUSE POTENTIALLY THAT WOULD IMPROVE EFFICACY OF THE COIRNT MEASURE WE'RE LOOKING AT. SO WE DISCOUNT THAT IN FAVOR OF HOPING THAT MEDICAL COUNTER MEASURE IS GOING TO BE A SILVER BULLET. BUT IN FACT EVEN IN HUMAN STUDIES FOR EBOLA VIRUS THE GREATER AMOUNT OF SUPPORTIVE THERAPY GIVEN TO THE PATIENT THE GREATER THE POTENTIAL POSITIVE OUTCOME. SO WE LOOK WITH A GREAT DEAL OF THANKS BY THE FDA FOR ANIMAL MODEL POX VIRUSES. THIS IS A MAJOR TOUCH STONE FOR BEING ABLE TO MOVE PRICTS FORWARD. THE FDA ANIMAL MODEL QUALIFICATION PROGRAM YOU'RE GOING TO HEAR ABOUT. BARTA MENTIONED THIS IDIQ CONTRACT FOR ANIMAL MODEL STUDIES ACROSS TEN VENDORS THAT SHOULD PROVE A LOT IN TERMS OF BEING ABLE TO MOVE THESE FORWARD. SPECIAL CALL OUT AND APPRECIATION TO JUDY AND MIKE AND OTHERS. CLINICAL INDICATION FOR PNEUMONIC PLAGUE JUST APPROVED I BELIEVE. SO THIS IS DONE BACK IN MAY TIME FRAME WITH FDA ANTI-EFFECTIVE COMMITTEE. SO WE'RE MAKING PROGRESS. KEEPING IF I CANNERS CROSSED, NOT SURE IF THERE'S LATE BREAKING NEWS ON SUCCESSFUL APPLICATION UNDER THE ANIMAL RULE FOR DIZ FOR HUMAN GENOME STUDIES SO THE ADDED BENEFIT STUDIES WERE PART OF HOW THEY -- THE FDA DECIDED TO PROCEED FORWARD. SO POSSIBLE FUTURE GAINS IN ANIMAL MODELS REALLY LOOK FORWARD. AGAIN TO GATHER HUMAN DATA I THINK TREMENDOUS AMOUNT OF ENERGY SPENT ON EXVIVO SYSTEMS FOR UNDERSTANDING CELLULAR AND SUB CELLULAR PATHOPHYSIOLOGICAL SYSTEMSCH THERE'S OPPORTUNITIES TO LOOK AT FUNCTIONAL ORGAN PNEUMONIC MODELS, THINGS OUT OF THE INSTITUTE AND ELSEWHERE HAVE A TREMENDOUS POSSIBLY FOR IMPROVING OUR UNDERSTANDING. SOME OF THE WORK YOU'LL HEAR ON TELEMETRY AND REDUCTION AN AL MODELS THROUGH USE OF TELEMETRY. EXPANDED USE OF TRANSGENICS IN THE COMPARTMENTALIZED SYSTEMS. IMPORTANCE OF HAVING SOME CENTRAL DATA REPOSITORY FOR ANIMAL MODELS EXPERIMENTS AND MORE STANDARDIZED METRICS AND DECISION TOOLS FOR EUTHANASIA CRITERIA, ESPECIALLY. SO I WANT TO ACKNOWLEDGE THE LEADERSHIP AT NIAID AND BARTA AND FDA PROVIDED. CERTAINLY UNDER JUDY HEWITT, A GREAT ADMIRATION FOR JUDY AND WORK AT NIAID. BARTA FDA, CBER, CDER. TO HIRE IMPORTANT THERE. THE DOD FOR DECADES OF WORK AND REALLY BEING A DRIVING FORCE OF CONSOLIDATED INFORMATION FOR ANIMAL MODEL DEVELOPMENT. I SEE SOME OF MY COLLEAGUES. THEY'RE NOT OLD. FORMER COLLEAGUES FROM DOD WITH RESPECT TO THAT. AND THEN FINALLY TO PLACES LIKE ILR AND THE NATIONAL ACADEMY OF SCIENCE FOR THE WORK HERE AS WELL. SO THAT IS ABOUT IT FOR ME. I'M GOING TO APOLOGIZE BECAUSE I'M GOING TO TAKE OFF SO THAT I CAN DO SOME OF MY OTHER NEEDS FOR TODAY. THANKS VERY MUCH. QUICK QUESTION IF THERE'S ONE. >> ONE OR TWO QUESTIONS FOR DR. KORCH, IF OFF QUESTION GO TO MICROPHONE IN THE AISLE BECAUSE THIS IS BEING VIDEOCAST. WE WANT TO BE HERE THAT PEOPLE IN TV LAND CAN HEAR THE QUESTION. >> WE USE THE TEN SECOND RULE. GONE. OKAY. WE HAVE GOT ONE. WE HAVE GOT ONE. >> GEORGE YOU MENTIONED NEED FOR CLINICAL DATA. MANY PATHOGENS WE WORK WITH, AEROSOL IS NOT A NATURAL ROUTE OF INFECTION. HOW ARE YOU GOING TO ACCOUNT FOR THAT? >> OBVIOUSLY WE HAVE A TREMENDOUS GAP IN THAT PARTICULAR AREA. THERE ARE NO NATURALLY OCCURRING LARGE SCALE EVENTS. EVEN WITHOUT SPECIFIC EXPOSURE ROUTE OF AEROSOL THERE ARE FOR MANY OF THESE PATHOGENS PAST THAT INITIAL ENTRY POINT, A LACK OF INFORMATION. RECENTLY WORKING WITH A GROUP AT CDC ON ANTHRAX IN PREGNANT WOMEN AS A SPECIAL POPULATION WE WERE REACHING BACK TO CLINICAL HISTORY IN THE LATE 1800s LOOKING AT EVEN THE SPARSE AMOUNT OF INFORMATION AVAILABLE TO US. SO I AGREE. THERE'S GOING TO BE IN CERTAIN ESPECIALLY MAJOR ROUTES OF INHALATION ALMOST A NULL SET BUT THERE IS TREMENDOUS INFORMATION YET TO BE GAINED AT THE SUB CELLULAR LEVEL POST EVENT OR POST THE INITIAL TRANSMISSION ROUTE ITSELF. SO ANIMALS ARE HUGELY IMPORTANT IN THAT DOMAIN BUT IN OTHER AREAS WE STILL CAN BENEFIT A GREAT DEAL WITH HUMAN CLINICAL INFORMATION. THANKS VERY MUCH FOR THE QUESTION. THANKS, EVERYBODY. >> THARNLG THANK YOU VERY MUCH, GEORGE. [APPLAUSE] >> THAT'S A GREAT SEGUE INTO THE NEXT PART OF OUR SESSION, WHICH IS LISA HENSLEY FROM FDA WILL TALK ABOUT HOW WE START TO BREECH ANIMAL MODELS TO WHAT WE KNOW ABOUT HUMANS. >> GOOD MORNING. >> GOOD MORNING, EVERYONE. JUDY, THANK YOU VERY MUCH FOR HAVING ME HERE TODAY TO TALK HE DOES A WONDERFUL JOB OF LAYING THE GROUND WORK FOR THE NEXT SPEAKER. SO WITH THAT, I'M GOING TO GO AHEAD AND JUMP INTO MY TALK. THE TITLE IS BRIDGING THE GAP BETWEEN CLINICAL AND ANIMAL MODEL DATA. THE QUESTION, IS IT ACHIEVABLE? AND IF SO, HOW DO WE GET THERE. THE GOAL OF MY TALK IS TO HOPEFULLY LAY GROUND WORK FOR THE NEXT SPEAKER. BEFORE I MOVE FORWARD, I WANT TO MAKE SURE THAT I GIVE THE TYPICAL DISCLAIMER THAT THE VIEWS ARE MY OWN VIEWS, THEY ARE NOT NECESSARILY THE VIEWS OF THE AGENCY. THOSE WHO COME FROM DOD, YOU HAVE SEEN THAT ON THE SLIDES MANY TIMES SO I'M SURE YOU'RE USED TO IT. SO I WANT TO LAY OUT A FEW POINTS, FIRST DEFINING THE THE PROBLEM. WE CAN ACCOMPLISH THAT TODAY KNOWING WHAT WE KNOW, THAT'S SOMETHING WE CAN ACCOMPLISH TODAY. WHAT IS POSSIBLE, THIS IDEA OF COLLECTION OF HUMAN DATA AND I'LL TALK ABOUT WHY WE'RE DOING THIS AND THIS -- AND WHY I'M TALKING AT THING BEGINNING OF THIS MIGHT BUT HOPEFULLY PLANNING WHAT IS POSSIBLE. AND LAST IS TAKING ON THE PROBLEM. I HEARD DATA FROM THE AGENTS MAYBE TOO HARD TO DO. (INAUDIBLE) IF WE LEAVE IT THERE. SO HOPEFULLY BY THE END OF THE TALK I WILL HAVE INSPIRED SOME TO TAKE ON THIS CHALLENGE. SO THE PROBLEM WITH OPPORTUNITY, AGAIN I DON'T BELIEVE -- THESE ARE CHALLENGES AN THERE ARE THINGS THAT WE CAN IF WE WORK TOGETHER AS A COMMUNITY WEB TACKLE L AND GET THERE. THE REASON I TALK AT THE BEING IS TO LAY THE GROUND WORK AND INSPIRE YOU TO THINK ABOUT ISSUES AS YOU DEVELOP ANIMAL MODELS AN CHARACTERIZING THESE MODELS. SO BECAUSE OF THE NATURE OF MANY AGENTS THAT WE ARE WORKING WITH, AND THAT WE'RE TRYING TO DEVELOP CANDIDATE COUNTER MEASURES WE'RE GOING TO REQUIRE USE OF THE ANIMAL RULE. WE HAVE DR. ROBERT WHOSE WILL BE TALKING AND SHE HAS FOLKS HERE WHO CAN ANSWER QUESTIONS MUCH BETTER THAN I CAN. BUT UNDERNEATH THE ANIMAL RULE IT'S CRUCIAL THAT ANIMAL MODEL RES FLECT HUMAN DISEASE AND LIKELY TRANSLATES TO HUMAN USE. SO WHAT DOES THIS MEAN? NOT ONLY DO WE NEED TO HAVE WELL DEVELOPED CHARACTERIZED MODELS BUT ALSO THEY ACCURATELY REFLECT HUMAN DISEASE. AS GEORGE POINTED OUT WE MAY NEED MORE THAN ONE MODEL. IT MAY TAKE MULTIPLE MODELS TO CAPTURE THAT FULL SPECTRUM OF CLINICAL DISEASE. WHAT WE'RE TRYING TO SAY IS DO OUR MODELS LOOK LIKE THIS, DO THEY REFLECT DISEASE OR ARE THEY CLOSER TO THIS, CAN WE SAY WITH CONFIDENCE THAT WE BELIEVE WHEN WE TEST THE THERAPEUTIC OR POST EXPOSURER OR THE VACCINE IN THAT ANIMAL MODEL THAT WE THINK IT WILL WORK IN PEOPLE. WE BELIEVE IT SO MUCH WE'RE MOVING FORWARD TO ADMINISTER THAT TO PEOPLE. SO DEVELOPING A GAME PLAN. AGAIN, THE GOAL IS TO LAY GROWN WORK AS WELL AS GET ALL OF YOU THINKING ABOUT POSSIBLE CHALLENGES AN WAYS TO GET AROUND THE CHALLENGES. SO I'M GOING TO MOVE FORWARD SERVE THRILLED TO BE HERE AND IS WILLING TO TAKE THE FIRST LEAP OF FAITH, WE BELIEVE THIS DATA CAN BE COLLECTED. FOR ALL THE -- IT IS COLLECTED, WHAT DO WE NEED TO THINK ABOUT. I DID THESE QUESTIONS INTO EASIER AND HARDER. THE EASY QUESTIONS WE HEAR ARE NOT THAT EASY. WHEN YOU START THINKING ABOUT THIS AND THINKING HOW WE'RE GOING TO COLLECT THIS DATA, WE NEED TO THINK ABOUT WHAT DATA NEEDS TO BE COLLECTED. THERE MAYBE SITUATIONS WHERE WE HAVE LIMITED RESOURCES AND WHEN YOU HAVE LIMITED PERSONNEL AND SAMPLES WHAT REALLY NEEDS TO BE COLLECTED AS WELL AS WHAT IS ACCEPTABLE TO BE COLLECTED. DEPENDING UPON WHERE YOU'RE WORKING, WHAT ARE THE CULTURAL SENSITIVITIES FOR COLLECTION OF THAT DATA. WHAT ARE THE PRACTICES, WHAT THE BELIEFS. WILL THE IMMUNITY PROVIDE BUY IN. CAN YOU GENERATE SAMPLES. NEXT IS WHO SHOULD COLLECT THE DATA. DEPENDING WHERE YOU'RE WORKING THERE MAYBE SENSITIVITIES WITH DOD COLLECTING THE DATA. AND FOR MANY OF THESE REASONS WHEN I WAS AT DOD WORKING ON THIS FOR VIRAL FEVERS WE TRIED TO FORM PARTNERSHIPS WITH WHO AND WITHJ MSF OR DOCTORS WITHOUT BORDERS WORKING IN THE FIELD. THESE INDIVIDUALS, INDIVIDUALS WITH OTHER NON-PROFITS AS WELL AS CDC ARE RESPONDING TO THESE OUTBREAKSCH THESE ARE PEOPLE WE'RE ASKING TO TAKE SAMPLES OR WHO HAVE THE BEST CHANCE COLLECTING THE SAMPLES. THE NEXT QUESTION WE HAD TO TABLG WAS WHO OWN IT IS DATA. THIS COMES BACK TO AGAIN, KNOWING WHERE YOU'RE WORKING AND DEVELOPING THOSE COMMUNITY PARTNERSHIPS. THERE MAYBE SUSPICION WHY YOU'RE CHECKING THE DATA. WHAT ARE YOU GOING TO DO WITH THE DATA. HAVING A TRANSPARENT WORKING ENVIRONMENT AS WELL AS UP FRONT CLEAR DEFINED GOALS AND WORKING WITH THE COMMUNITY COULD ALLOW US TO ACCOMPLISH THIS. THE REQUIREMENT FOR HUMAN USE PROTOCOLS. BUILDING PARTNERSHIPS. CAN THESE BE PRE-POSITIONED. CAN YOU BUILD PARTNERSHIPS WITH THE LOCAL MINISTRIES OF HEALTH, CAN YOU GET THE COUNTRY TO BUY N. AS WE FOUND FROM THE RECENT EBOLA OUTBREAK THE MINISTRY OF HEALTH DIDN'T LIKE THE FORM PROPOSED TO BE SUBMITTED, IT ENDED UP REJECTED. MANY OBSERVATIONS WERE COLLECTED ON BLANK SHEETS OF PAPER. AND LASTLY AS WE WORK WITH COUNTRIES THEY WANT TO KNOW WHAT IT'S IN IT FOR THEM. WHY SHOULD THEY HAVE YOU COME IN THE COUNTRY AND ARE YOU COMING BACK WITH POTENTIAL THERAPEUTICS AND HELPING WITH TRAINING WITH LONG TERM PLANS. NOW, IF THOSE WEREN'T HARD ENOUGH NOW WE GET INTO MORE CHALLENGING QUESTIONS. THESE ACHIEVABLE, THIS IS WHY SIMON IS TALKING AFTER ME BECAUSE HE'LL TALK ABOUT HOW TO ACHIEVE THIS. WE'RE TALKING HUMAN COLLECTION. WHEN YOU START THINKING ABOUT THE HUMAN DATA, WE NEED TO KNOW WHETHER OR NOT SUPPORTIVE CARE WAS IMPLEMENTED. IF THERE'S NO SUPPORTIVE CARE IMPLEMENTED, HOW DO YOU INTERPRET THIS DATA? MORE IMPORTANTLY AS YOU BEGIN TO THINK ABOUT HOW TO FLEMENT SUPPORTIVE CARE AND DO IMPLEMENT SUPPORTIVE CARE HOW DOES THAT FEEDBACK INTO ANIMAL MODEL DEVELOPMENT. WE'LL HEAR MORE FROM JIM SWEARENGEN ABOUT CARE THESE ARE THINGS TO THINK ABOUT. WE NEED TO REALIZE MANY OF THESE DISEASES OCCUR IN RESOURCE SETTINGS THAT JUST BECAUSE THAT IS THE CASE DOESN'T MEAN SUPPORTIVE CARE CAN'T BE IMPLEMENTED. OTHER THINGS TO THINK ABOUT, CONCOMITANT INFECTIONS AND SELECTION BIAS REVIEWING AND COLLECTING THE CLINICAL DATA, WHO COMES TO THE HOSPITAL, PEOPLE THAT CAN AFFORD IT? PEOPLE WHO ARE WILLING TO WORK WITH OUTSIDERS? PEOPLE WHO AREN'T AFRAID OF THE HOSPITAL? THERE IS A FEAR OF COMING TO MANY HOSPITALS DURING SOME OF THESE OUTBREAKS. WE NEED TO KNOW WHAT IS THE TRUE INFECTION RATE. IF WE ONLY SEE A SMALL SUBSET, HOW MANY ARE ACTUALLY GETTING SICK? AND MORE IMPORTANTLY WHAT IS THE CASE FATALITY? HOW DO YOU DEAL WITH DIFFERENT ROUTES OF INFECTION? THE CASE MORTALITY MATTERS DEPENDING ON ROUTE OF INFECTION. AND HOW TO IMPLEMENT THE SUPPORTIVE CARE AN TRANSLATES TO YOUR MODEL DEVELOPMENT. I'M REITERATING THAT BECAUSE THE VERY IMPORTANT QUESTION. THEN MOVE TO HARDER QUESTIONS. YOU HEARD ABOUT ONE QUESTION OF GEORGE, WHAT DO WE DO WITH ENGINEERED THREATS OR WEAPONNIZED OR ALTERED AGENTS OR ONE THERE'S AN ARTIFICIAL ROUTE OF EXPOSURE SO THE VIRUS IS THROUGH CLOSE CONTACT BUT WE'RE INTERESTED IN PROTECTING AGAINST ALSO AEROSOL EXPOSURES. SO WHAT DO YOU DO WHEN YOUR NATURAL ROUTE OF EXPOSURE IS ARTIFICIAL? HOW DO YOU BUILD BRIDGES WITH ANIMAL MODEL TO HUMAN DATA? RANGES OF DOSE. HOW DO YOU DEAL WITH THOSE QUESTIONS? VARIABILITY OF SEQUENCING. HOW IS WHAT CIRCULATING REFLECT WHAT YOU YOU HAVE A LABORATORY ARE USING FOR ANIMAL MODEL DEVELOPMENT. HOW DOES GROWING UP STOCK CHANGE THAT VIRUS? THESE WITH QUESTIONS TO THINK ABOUT AND QUESTIONS THAT CAN BE ADDRESS. WE NEED TO COME TO TERMS AS REGULATORS THEY MAYBE THINGS WE JUST DON'T KNOW AND DOSE PEOPLE ARE SEEING OR EXPOSURE ROUTE OR TIME SINCE EXPOSURE. SO TWO EXAMPLE I'LL GO THROUGH AND PUT INTO CONTEXT BECAUSE MOST TAKE HOME LESSONS WHEN THEY APPLY TO SOMETHING THEY KNOW. ONE IS I BO LA -- EBOLA AND MARBERG, ASCENTS THAT PROVIDE TWO OPPORTUNITIES. ACADEMIC IN NATURE AS YOU HEARD TMT IS MOVING FORWARD WITH A DATA PACKAGE THROUGH FDA SO THIS IS GOING TO BECOME TIMELY AND IMPORTANT FOR THEM. EBOLA AND MARBERG ARE ACADEMIC IN NATURE, HIGHLY LETHAL AND OCCUR IN REMOTE AN DIFFICULT TO REACH E LOCATIONS AN MULTIPLE STUDIES THAT HAVE AND ARE LOOKING AT THE DISEASE COURSE IN NON-HUMAN PRIMATESCH THIS IS A SITUATION WE PROBABLY KNOW MORE ABOUT THAT DISEASE THAN NON-HUMAN PRIMATES AND I SHOULD SAY DEFINITELY KNOW MORE ABOUT THE DISEASE THAN WE KNOW WHAT HAPPENS IN PEOPLE. THE OTHER SIDE IS LOSS OF FEVER, IT'S EPIDEMIC AS WELL AS ENDEMIC IN NATURECH THERE'S MORTALITY, THERE'S STRAIN DIVERGENCE. WE KNOW WHERE THIS VIRUS OCCURS THERE'S A HOSPITAL,‡‡ FEVER AWARDS SET UP WHERE THEY SEE CASES ROUTINELY. SO WE HAVE TWO SCENARIOS AND TWO OPPORTUNITIES TO MOVE FORWARD ON THIS IDEA OF IMPLEMENTING SUPPORTIVE CARE AND COLLECTION OF DATA. SO NOW I PULL THIS SLIDE FROM TALK GIVEN AT DOD BUT ONE QUESTION THAT WE RAISED IS DOES THE DATA REFLECT -- DOES THE DATA FROM ACADEMIC MODELS REFLECT HUMAN DATA. AS GEORGE MENTION THERE HAD IS A TREMENDOUS AMOUNT BEING PUBLISHED IN THE LITERATURE AND THERE IS QUITE A BIT THAT WE HAVE BEEN STARTING TO DO DRAW PARALLELS. I WON'T GO THROUGH THIS SLIDE, JUST TO MAKE THE POINT THAT THERE IS A NUMBER OF PUBLICATIONS AND WE CAN LOOK AT ANIMAL MODELS TO SAY DO THESE REFLECT. THERE IS ALSO A NUMBER OF PROBLEMS THOUGH. WITH THIS DATA, AS GEORGE POINTED OUT YOU SEE CONFLICTING DATA. SO HOW DO YOU INTERPRET THIS DATA IN THE LITERATURE WHEN THERE'S A NUMBER OF ISSUES. THERE COULD BE SELECTION BIAS, ISSUES WITH CHAINS YOU MAY NOT BE AWARE OF. COULD BE YOU DON'T KNOW THE CASE HIst HISTORY. THERE'S SPECIES, DIFFERENCES, THERE'S FURTHER VIRUSES WHEN STARTING TO DO AND THIS BUILD BRIDGES WE CAN FIND SOME DATA ON LIVER ENZYMES FOR (INDISCERNIBLE) SPECIES BUT THEN WE CAN FIND CYTOKINE DATA FOR THE SUDAN SPECIES. SO AS WE START MOVING ACROSS THESE, HOW DOES THIS AFFECT YOUR DATA. THAT DOESN'T MEAN THAT DATA IS NOT IMPORTANT OR VALUABLE AND CERTAINLY CAN CAN HELP NARROW DOWN FOR FUTURE STUDIES PARTICULARLY WHERE YOU CAN SEE DISCONNECTS IN ANIMAL MODELS BUT YOU MAY SEE A POTENTIAL CONCERN. IT MAY BE SOMETHING TO REALLY FOCUS ON. SO AS WE STARTED AT DOD HOW DO WE TACKLE THIS PROGRAM TO BEGIN TO TRY TO MAKE HEADWAY WITH THE IDEA OF PARTNERING. WE UNDERSTOOD THE CULTURAL SENSITIVITIES, WE UNDERSTOOD THIS WAS NOT SOMETHING WE COULD DO ALONE SO WE REACHED THROUGH WHO TO A NUMBER OF GROUPS AND STARTED TO REACH OUT TO MSF AS WELL AS OTHER FOLKS WHO ARE RESPONDING TO OUTBREAKS AND SAY CAN WE WORK WITH YOU. CAN CAN WE POTENTIALLY PROVIDE YOU EQUIPMENT. WE ACTUALLY TALKING ABOUT POINT OF CARE EQUIPMENT, NOW MSF IS TAKING (INAUDIBLE) OUT TO FIELD WITH THEM SO IT WAS A SMALL STEP BUT IT WAS SOMETHING EASILY ACHIEVABLE. IT'S A GREAT EXAMPLE HOW IF YOU PARTNER WE HAVE A LOT OF EXPERIENCE WITH POINT OF CARE EQUIPMENT AND THERE'S MANY PEOPLE IN THIS ROOM THAT HAVE MORE EXPERIENCE THAN I DO. BUT PERHAPS BY WORKING TOGETHER WE CAN LOOK AT DEPLOYING POINT OF CARE EQUIPMENT, WE CAN LOOK AT THROWING OUT THIS WIDE NETWORK AND PERHAPS LOOK AT CATCHING SOME OF THESE OUTBREAKS WITH THE APPROPRIATE EQUIPMENT AND QUESTIONS TO BE ASKED. SO MOVING FORWARD WITH THE FEL A VIRUSES, AND SIX WE WEREN'T ABLE TO GET HIM HERE, I TOOK ARTICLE PUBLISHED BY NSF IN THE SUPPLEMENT AND PUBLISHED BY PAUL RADI, MATT LEM AT HHS WHO COULDN'T JOIN US AS WELL AS JAMES WALLER AND OTHER FOLKS WORKING THROUGH WHO TO LOOK AD IDENTIFYING CLINICAL DATA POTENTIAL -- CLINICAL DATA COLLECTION POTENTIAL AS WELL AS DEVELOPING SUPPORTIVE CARE. MUCH OF WHAT HAS BEEN DISCUSSED IN THOSE MEETINGS IS ACTUALLY HIGHLIGHTED IN THIS ARTICLE. NOW GIVEN THE FACT THAT I'M A RESEARCHER AND NOW I'M AT FDA I ACTUALLY TOOK THE LIBERTY OF COPYING FROM THE ARTICLE DIRECTLY BECAUSE THESE ARE THE FOLKS WHO GO IN THE FIELD. AND THESE ARE FOLKS PUTTING THEIR LIVES ON LINE BY COLLECTING THIS DATA SO I THOUGHT IT BETTER TO SHARE DIRECTLY FROM THEM. ONE THING THEY SAID WAS THAT SUPPORTIVE CARE HEMORRHAGIC FEVER TREATMENT, ORAL FLUID REHYDRATION, NUTRITIONAL HYDRATION AND PSYCHOSOCIAL SUPPORT. MEDICATIONS INCLUDE ALLEVIATE HEMORRHAGIC FEVER RELATED SYMPTOMS SUCH AS NAUSEA, VOMITING, ANXIETY AND PAIN. THIS IS IN THE IDEAL SITUATION, I SHOULD ALSO POINT THAT OUT. BECAUSE LIMITED ABILITY TO LOOK AT CONCOMITANT INFECTIONSTHEY EAR RECOMMENDING YOU TREAT PREEMPTIVELY FROM MALARIA AS WELL AS WITH ANTIBIOTICS. ALSO PUSHING THE INTRAVENOUS VIEWP -- THE PROVISION OF INTRAVENOUS VOLUME REPLACEMENT AS A CORNERSTONE OF EFFECTIVE SEPSIS TREATMENT. SO ALSO SAYING BECAUSE THE VHS LOOKS SO MUCH LIKE -- WE'LL HEAR FROM MARK AND OTHERS THAT WE SHOULD BE PUSHING FLUID MANAGEMENT AS WELL. THAT IS THE IDEAL SITUATION BUT WE HEARD THIS CAN BE DIFFICULT. AND SIMON WILL TALK ABOUT HOW WE CAN TAKE THIS ON. BUT THEY SAID THERE IS A LIMITED ACTUAL PATIENT STANDARD MONITORING THAT OCCURSCH VITAL SIGNS RESPIRATORY RATE, PULMONARY SCIENCE FLUID INTAKE OUT TAKE, NOT SYSTEMATICALLY MANAGED AND THAT EXPANDED SUPPORT OF CARE TREATMENT LACKS ESSENTIAL COMPONENTS OF INTENSIVE CARE SUCH AS CORRECTION OF ELECTROLIGHTS AND METABOLIC DERANGEMENT, GOAL DIRECTED MANAGEMENT, ET CETERA. BUT THIS SNOT SOMETHING THAT CAN'T BE ACCOMPLISHED. THEY SAY IF WE PUT IN BASICS WE CAN POTENTIALLY DO THIS. WHAT THEY FOUND FROM SOME OF THE OUTBREAKS THEY HAVE BEEN ABLE TO PUT BASIC FLUID MANAGEMENT IS IT MADE A DIFFERENCECH THERE'S A PAPER PUBLISHED WHERE IT WAS FELT THE IMPLEMENTATION OF SUPPORTIVE CARE DID IN FACT MAKE A DIFFERENCE. COMMUNITY ENGAGEMENT BECOMES VERY IMPORTANT. THERE IS A GREAT FEAR IN IMMUNITIES ABOUT GOING TO THE HOSPITALS AND ABOUT THESE OUTSIDERS COMING IN. I'M HAPPY TO MAKE THE SLIDES AVAILABLE, I'M NOT GOING THE GO THROUGH IT ALL BUT MANY OUTBREAKS PATIENTS REFUSE TO COME TO THE HOSPITALS AND FAMILY HAVE HID INDIVIDUALS BECAUSE OF THE WAY THE COMMUNITIES MAY RESPOND TO THEM N. ADDITION THERE'S BEEN SUCH AN UPROAR OR SUCH A REFUSAL IN SOME COMMUNITIES THAT THE OUTBREAK TO SPEND THEIR RESPONSE, THIS IS NOT A TRIVIAL CONCERN. I ALSO WANT TO POINT OUT WORKING THE LONG TERM PART SHIPS. THERE ARE LONG TERM HEALTH CONSEQUENCES TO THE VIERGS INFECTIONS WELL AS OTHER HEMORRHAGIC FEVERSCH THERE'S A FEAR P F THAT PEOPLE COME IN AND RESPOND TO THE OUTBREAK AND THEN THEY LEAVE. AND WHAT HAPPENS TO THE PEOPLE THAT ARE LEFT BEHIND? DO THEY DEVELOP LONG TERM SEQUELLA? WHAT IS THE -- WHAT HAPPENS WHEN THEY RETURN TO THE THEIR COMMUNITIES? WE HEARD STORIES FROM FOLKS WHO RESPONDED WHO HAVE TALKED ABOUT EVEN DOCTORS OR NURSES WHO SLOWNL TIERED ON THE WARD WERE BASICALLY OSTRACIZED BY COMMUNITIES. THEIR COMMUNITIES WERE SO AFRAID OF WHAT HAD HAPPENED AND SO AFRAID OF THESE VIRUSES THAT THEY DIDN'T WANT THEM BACK. WE HAVE ALSO HEARD FROM SEVERAL OTHER FOLKS THAT THERE ARE LONG TERM HEALTH CONSEQUENCES AND HOPEFULLY WE HAVE PAPER COMING OUT ON THAT. WHERE WE WOR WORKING IN THIS PAPER THERE'S SEVERAL RECOMMENDATIONS THAT WERE MADE THEY SET THE STAGE NICELY FOR THIS NEED FOR DATA COLLECTION ARE SAYING THIS IS POSSIBLE. THEY'RE SAYING THAT'S POSSIBLE THAT REALLY SHOULD TELL US BUT THIS IS WHAT THEY RECOMMENDED AS PATH FORWARD. MSF AND THE WORLD HEALTH ORGANIZATION MUST CREATE COLLABORATIVE PLATFORM AIMED AT DEVELOPING A COMPREHENSIVE SUPPORTIVE TREATMENT PROTOCOL APPROVED BY INSTITUTIONAL AND OUTBREAK PRONE COUNTRIES MINISTRY OF HEALTH ETHICAL REVIEW BOARDS. DEFINITION OF COMPREHENSIVE SUPPORTIVE TREATMENT THAT CAN BE ADMINISTERED UNDER CONDITIONS, ESTABLISH AN APPROPRIATE EVALUATION SCHEME, DEVELOP PROTOCOL AND IMPLEMENT STUDY PROTOCOL. SO THAT MAY SOUND SLIGHTLY INSURMOUNTABLE BUT I'LL BRING YOU BACK TO THE SECOND EXAMPLE THAT I GAVE YOU WHICH IS LOSS OF FEVER. THIS IS A VIRAL HEMORRHAGIC FEVER THAT'S ENDEMIC THAT OCCURS IN 300 TO 500,000 PEOPLE EACH YEAR. THAT'S ABOUT 5,000 DEATHS. THERE IS AN ESTABLISHED HOSPITAL THAT SEES CASES EVERY YEAR. PERHAPS PROTOCOLS COULD BE FIELD TESTED, EQUIPMENT COULD BE FIELD TESTED AND WE COULD DEVELOP THE SKILLS AND DEVELOP THOSE PARTNERSHIPS WHERE REACHING OUT COULD BECOME MUCH EASIER. SO WITH THAT, I'M GOING TO GO AHEAD AND WRAP UP AND THANK EVERYBODY FOR THEIR ATENSION AS WELL AS TO ASK ANY QUESTIONS AND ALSO POINT OUT TO YOU IF I HAVE INSPIRED YOU AND INTRIGUED YOUR INTEREST THAT FDA DOES HAVE AN OPEN BAA, THAT IS FOR REGULATORY SCIENCE AND THE LAST NUMBER SEVEN OF THAT IS ACTUALLY MEDICAL COUNTER MEASURES. SO IF YOU HAVE A BURNING DESIRE TO PERHAPS LOOK AT THESE QUESTIONS OR PERHAPS OTHER QUESTIONS AND REGULATORY SCIENCE I ENCOURAGE YOU TO GO TO OUR WEBSITE, THERE IS A LINK THERE. WITH THAT I'LL OPEN TO ANY QUESTIONS ON THE SUBJECT. THANK YOU. [APPLAUSE] >> ANY QUESTIONS FOR LISA? >> I MIGHT ASK ONE. GEORGE PREVIOUSLY DISCUSSED THE IMPORTANCE OF SUPPORTIVE CARE AND PRIMATES I THINK. A LOT DON'T NECESSARILY TALK WITH PRIMATES. YOU TALK ABOUT SUPPORTIVE CARE TOO. WHAT ARE THE RECOMMENDATIONS FOR SMALLER ANIMALS? IS IT LOGICAL TO PLAN, TO GIVE THEM SUPPORTIVE CARE AS MUCH >> WONDERFUL QUESTION AND IT MAKES -- THAT MEANS PEOPLE ARE LISTENING TO TH MORNING. IT IS A GOOD QUESTION. AND ISSUE OF SUPPORTIVE CARE AND I ALSO WANT TO SAY, I THINK JIM WILL COVER THIS LATER ON. AS A COMMUNITY WE E NEED TO UNDERSTAND THE VETERINARY CIR AND SUPPORTIVE CARE. THAT SUPPORTIVE CARE MAYBE BASIC VETERINARY CARE AND OFTENTIMES I'M GOING TO COME BACK TO YOUR QUESTION BUT IT WAS A GREAT OPPORTUNITY TO MAKE THIS POINT. WE HEAR PEOPLE ARE NOT IMPLEMENTING SUPPORTIVE CARE BUT THEN WHEN WE SAY YEAR NOT GIVING THE ANIMALS FLUIDS, YOU'RE NOT DOING THIS, THE RESEARCHER COMES BECOME AND SAYS I'M DOING THAT. THAT'S BASIC VETERINARY CARE. AS WE GO THROUGH THE MEETING WE NEED TO THINK ABOUT WHAT IS SUPPORTIVE CARE. VERSUS -- ARE THEY THE SAME THING OR ARE WE MOVING BEYOND BASIC VETERINARY CARE TO MORE EXTENSIVE MEASURES. MORE HEROIC MEASURES AN CAN THEY BE P IMPLEMENTED IN A CONTAINMENT LAB AS WELL AS IF YOU TRY TO IMPLEMENT THEM AND THEY DON'T -- THAW CAN'T IN THE FIELD, WHAT IS THAT DISCONNECT GOING TO CREATE. WITH THAT, LET ME GET BACK TO YOUR QUESTION WHICH IS SMALL ANIMALS. I JIESES, JIM WILL TACKLE THIS, BUT IDEALLY WHERE SUPPORTIVE CARE IS IMPLEMENTED, IT'S IDEAL TO DO THAT. BUT WITH SMALL ANIMALS THERE IS GOING TO BE REASONABLY SO LESS THAT YOU CAN DO SO YOU'LL HEAR THAT WHEN YOU CAN IMPLEMENT BASIC SUPPORTIVE CARE, FOR THAT IT MAYBE JUST FLUID THAT MAYBE JUST FOOD, THAT WOULD BE IDEAL BUT THERE IS THAT REASONABLE -- THERE'S THE UNDERSTANDING THAT IT'S A VERY DIFFERENT CASE. >> YOU BOTH DESCRIBE THE STANDARDIZING IT. IF YOU USE ITS FOR THE FDA YOU NEED A STANDARD. THAT IS ONE OF THE QUESTIONS THAT WE GET, ONE OF THE QUESTIONS WE GET IS WHAT DO YOU MEAN BY THAT? AND CAN THERE BE STANDARDS? I THINK THAT'S ONE OF THE REASONS WE'RE HAVING THIS MEETING, THAT'S ONE OF THE REASONS THERE'S ANOTHER WORKSHOP AND I HAVE IT UP HERE AT UTMB, 20 12-RBGS WE NEED TO UNDERSTAND WHAT IS ACHIEVABLE. AND WE NEED TO HELP -- HOPEFULLY DEVELOP THAT BASED ON RECOMMENDATION. SO HOPEFULLY AT THE END OF THE MEETING AS WE MOVE FORWARD WE WILL BE MOVING IN THAT DIRECTION. NEXT QUESTION. >> GREAT TALK. I THINK YOU IMIEND COUPLE OF KEY ISSUES THAT COLONEL KORCH HAD TOUCHED UPON AND TO SORT OF COMPOSITE, BOTH THE RELEVANCE OF CLINICAL CONTENT TO HELP ASSESS AN DEVELOP AND APPROVE THESE MEDICAL COUNTER MEASURES. BUT ALSO HOW SUPPORTIVE CARE COMES INTO PLAY. BECAUSE YOU WERE TALKING ABOUT CLINICALLY RELEVANT OUTCOMES AND SCENARIOS AND SETTING, THE SUPPORTSIVE CARE ENDS UP BEING SOMEWHAT BOUND BY LO JISESSIC -- LOGISTICAL OPPORTUNITIES FOR DOING THAT IN ENVIRONMENTS AND SETTINGS. WE ARE LOOKING AT APPROVING DRUGS WITH THE FDA HERE, WE WOULD BE LOOKING POTENTIALLY MORE ROBUST SUPPORTIVE CARE SYSTEMS. WONDER IF YOU CAN COMMENT HOW THAT -- WHAT YOU WERE TALKING ABOUT IN TERMS OF LOOKING WITH WHO AND DOCTORS WITHOUT BORDERS AND THE LIKE HOW THEY WANT TO LOOK AT THAT IN RESOURCE LIMITED SETTINGS. HOW THAT IMPACTS DEVELOPMENT OF MODELS HERE FOR SCENARIOS THAT INVOLVE TREATMENT HERE. THOSE ARE GREAT POINTS. SO I THINK WE'RE AWARE IMPLEMENT OF SUPPORTIVE CARE IN LOW RESOURCE SETSING IS DIFFERENT THAN HAVING ACCESS TO INTENSIVE CARE UNITS. THAT U.S. OR IN THE UK. BUT THERE ARE, SIMON WILL PROBABLY -- I'LL TALK A LITTLE BIT ABOUT IT AND HE CAN JUMP IN AND CORRECT ANYTHING I GET WRONG BUT THERE ARE QUITE A BIT OF BASIC THINGS THAT CAN BE IMPLEMENTED INTO THE SETTING. I THINK WE NEED TO STAKE THE STEP WISE. WE NEED TO FIRST SAY WHAT CAN BE DONE IN THAT SETTING. ULTIMATELY TO ME WHAT CAN BE DONE IN THAT SETTING MAY NOT BE DIFFERENT FROM WHAT CAN BE ACHIEVABLE IN A CONTAINMENT LABORATORY. IF WE CAN ACHIEVE IT, PERHAPS WE CAN ACHIEVE ANYTIME CONTAINMENT LABORATORY, MAY NOT ALWAYS BE THE CASE. THERE'S A NUMBER OF PEOPLE WHO WORK THAT AFTER SIMON TALKS MAY SAY THEY AGREE OR DISAGREE WITH THAT STATEMENT AND IT WILL BE A GREAT SUBJECT FOR DISCUSSION DURING THE BREAK. SO STEP ONE TO ME IS FIRST DEFINING WHAT CAN BE DONE IN THAT LOW RESOURCE SETTING. WHAT CAN BE DONE IN THE CONTAINMENT LABORATORIES WHETHER THEY BSL-3 OR 4. HOW CAN THOSE MODELS RELATE BACK TO EACH OTHER, HOW CAN THAT DATA WE HAVE DONE WITH HUMAN OR THE DATA WE HAVE COLLECTED AFTER IMPLEMENTED CARE INFORM OR MODEL DEVELOPMENT. REQUEST IT TELL US THE -- CAN IT TELL THE FLUID MAINTAINING APPROPRIATE FLUID BALANCE DOES MAKE A DIFFERENCE FOR SURVIVAL. SO DO WE NEED TO BE MORE AGGRESSIVE WITH CONTAINMENT LABORATORIES WITH IMPLEMENTING THAT MORE AGGRESSIVE FLUID MANAGEMENT OR ELECTROLIGHT BALANCE OR PICK YOUR FAVORITE VARIABLE IN THIS. SO THAT TO ME IS STEP ONE, THE NEXT STEP BECOMES IN A LARGER SITUATION. WE HAD MULTIPLE SCENARIOS TO THINK ABOUT. ONE A SITUATION WHERE THERE'S ONLY A SMALL NUMBER OF CASES. THE ABILITY TO IMPLEMENT MUCH MORE INTENSIVE CARE MEASURES IS ONE THING BUT IN A LARGE SCALE YOUR ABILITY TO IMPLEMENT THAT, IT -- YOU MAY RAPIDLY BECOME OVERWHELMED. SO YOU NEED TO THINK ABOUT THE SETTING AS WELL AS THE DATA. SO AS WE MOVE FORWARD THAT LOW RESOURCE OR THAT VERY LOW LEVEL MAYBE THE BARE MINIMUM YOU'RE ABLE TO IMPLEMENT IN WIDE SCALE EVENT BUT MOVING FORWARD THINKING HOW CAN -- THIS IS WHERE RESEARCH COMES BACK TO IT, IF YOU CAN IMPLEMENT MORE SETTINGS OR MORE ADVANCEDDED HOW CAN YOU TAKE THAT BACK TO YOUR MODEL AND INFORM YOUR PRODUCTS AND THE EXPECTED EFFICACY. IF I DIDN'T GOAT YOUR QUESTIONS RIGHT CATCH ME AT THE BREAK AND I CAN ANSWER MORE. I'M WAY OVER TIME NOW WITH THE QUESTIONS, THIS WAS A GOOD DISCUSSION SO I'LL INTRODUCE OUR NEXT SPEAKER WHO IS DR. SIMON MARDELL. I THINK USE THE MICROPHONE WHILE HE GETS HOOKED UP. >> SO I HAD THE PLEASURE OF MEETING SIMON AND ATTENDING AND WORKING WITH A NUMBER OF WHO WORKING GROUPS. SIMON IS A TRULY ENERGETIC SPEAKER. HE HAS BEEN A HUGE ADVOCATE FOR IMPLEMENTATION FOR BASIC SUPPORTIVE CARE MEASURES AN LOW RESOURCE SETTINGS. AND HAVE TAKEN THIS ON AS ONE OF HIS MISSION AND HAS DONE A GREAT JOB HELPING TO CHAMPION THIS CAUSE. SIMON, ONE OF THE THINGS THAT I'M SO IMPRESSED WHEN I MET HIM AT A MEETING, HE HAS RESPONDED TO OUTBREAKS AND HE HAS SEEN SOME OF THESE CASES. SO HE CAN SPEAK WITH THE AUTHORITY OF WHAT CAN BE ACHIEVABLE IN THESE LOW RESOURCE SETTINGS. HE'S GOING TO BE TALKING ABOUT SOME OF THE WORK HE'S BEEN DOING AND SOME OF THE WORK THAT HE'S BEEN DOING TO DEVELOP STANDARDIZED FORMS FOR DATA COLLECTION AS WELL AS FOR HELPING TO DRIVE SOME OF THE CLINICAL CARE. JUST AS OUR FIRST QUESTION ASKS, THIS IDEA OF DEVELOPMENT OF STANDARDS, THIS IS SOMETHING BEING LOOKED AT FOR CLINICAL CARE MANAGEMENT AND FOR US DEVELOPING ANIMAL MODEL IT IS QUESTION BECOMES CAN WE TAKE THIS AND BRING IT BACK TO THOSE ANIMAL MODELS. AND DRAW PARALLELS AS WELL AS THOSE LESSONS LEARNED AND IMPLEMENT FROM THERE. SO WITH THAT I'LL LET SIMON TAKE OVER. THANKS THE INTRODUCTORY SLIDE PAVES THE WAY FOR MY QUESTION KNOWING WHAT IS POSSIBLE. SO MAYBE I'LL GIVE YOU AN IDEA WHAT I THINK IS POSSIBLE AND BE INTERESTED IN YOUR REACTION. SO THANK YOU VERY MUCH FOR HAVING ME HERE AN ALLOWING ME TO PRESENT. NOT JUST ON THE VIRUS THE VIRUS OF E BOW LARKS MARCHBERG AND CLINICAL PICTURE AN TREATMENT BUT ALSO WIDER PICTURE ABOUT HEALTH ECONOMICS. YOU MIGHT BE SURPRISED AT THAT. WHY AS CLINICIAN WHO IS ENTIRELY CLINICAL IN BACKGROUND SUDDENLY GETTING UP AND TALKING ABOUT ECONOMICS. BUT I'M -- I HOPE THAT WILL BECOME CLEAR.fS? SO I THINK THERE ARE WINDOWS MY BACKGROUND I'M ESPECIALLY -- I USED TO BE AN ANESTHETIST BEFORE THAT. BUT I WORKED A LOT IN DIFFERENT COUNTRIES. OFTEN -- ALL RESOURCE POOR SETTINGS. I FOUND IT ALWAYS A CHALLENGE WHAT CAN YOU DO WITH RESOURCES YOU HAVE GOT BUT WE'RE OFTEN IN A POSITION, INTERNATIONAL STAFF TO NOT JUST WORK WITH THE RESOURCES WE HAVE GOT THAT LOBBY FOR RESOURCES, BE A CONDUIT FOR RESOURCES AND START TO THINK OUTSIDE THE BOX. HANG ON A MINUTE, WHAT RESOURCES SHOULD WE BE WORKING BEYOND HERE. JUST OCCURRED TO ME ON THE LIST ON THE LEFT THERE'S A LOT OF DISEASES. NWF AND NGO HAS DISEASE Z THAT YOU COULD SCREAM LIKE THAT SOMETIMES. I HAVE GOT EXPERIENCE OF LA SRBA FEVER WORKING WITH AN NGO AND AS A RESULT OF THAT I ENDED UP WORKING WITH WHO WITH A LOT OF OUTBREAKS AND ALSO LOOKING WHERE THERE WAS FOR EXAMPLE CLUSTERS OF H 5N 1 WHERE THERE MIGHT HAVE BEEN HUMAN TO HUMAN TRANSMISSION URGENTLY RESPONDING AND HAVING A LOOK AT THOSE CASES, THERE WASN'T HUMAN TO HUMAN TRANSMISSION BUT ALONG THE WAY I LEARNED A LOT ABOUT THE CASES I SAW AS SEVERE H 5N 1 AND ABLE TO REALLY REALIZE THE IMPORTANCE I SAY SIMPLE BUT DIFFICULT TO DO IN THE FIELD SUPPORTIVE CAM. SO LET ME EXPLAIN AFTER WORKING IN BOSNIA, IN 1984 DURING THE (INAUDIBLE) OCCUPATION. IN BOSS NEIA I FOUND AS A CLINICIAN I WAS ASKED -- I WAS LOBBYING FOR RESOURCES BUT I DIDN'T HAVE -- I DIDN'T HAVE THE EXPERTISE TO ARGUE THEM IN A PUBLIC HEALTH OR HEALTH ECONOMIC SENSE. AND SOMETIMES FAILED. AFTERWARDS I MADE AN EFFORT TO DO MSC IN PUBLIC HEALTH AND HEALTH ECONOMICS RESEARCH, ACTUAL THRI DID MY THESIS ON COST BENEFIT ANALYSIS OF EMERGENCY HUMANITARIAN AID. I I TELL MY COLLEAGUES IN THE HOSPITAL IN IF I'M NOT PRESENT IN THE MEETING HAVE THAT LIST THAT SAYS IS IT ACCESSIBLE, IS IT SUSTAINABLE, IS THERE ACCOUNTABILITY? IS IT EFFECTIVE AND SAFE? AND IF IT IS, I'LL AGREE, BECAUSE IT SEEMS THESE ARE THE PRINCIPLES UPON WHICH I FIND RELYING MORE AND MORE IN DECISION MAKING MY OWN HOSPITAL IN THE UK AS WELL AS ANY ENVIRONMENT NO MATTER HOW CHALLENGING. I'M GOING TO START -- GET BACK INTO THE FIELD WITH SLIDES THAT U MIGHT SEEM STRANGE. HE DIED BEFORE I WENT OUT TO DEMOCRATIC REPUBLIC OF CONGO. (INDISCERNIBLE) I FELT I DID KNOW SOMETHING OF THE MAN BECAUSE WHEN I SAW A GOOD PRACTICE GOING ON, REMEMBER, THIS IS IN A CIVIL WAR IN DIZ TIZ A REALLY -- (INDISCERNIBLE) A REALLY REMOTE PART OF THE CONGO WHERE MARBERG APPEARED AND I WENT OUT THERE AFTER RECURRENCE OF CASES DECKED BY MSF AND WHO SENT ME OUT THERE. I ONLY SAW FOUR CASES BUT I HAD A LOT OF TIME BECAUSE I WAS ON MY OWN AND THERE ARE OTHER SUSPICIOUS CASES, BUT I HAD TIME ON MY HANDS TO LOOK AND TREAT CAREFULLY AND WORK WITH LOCAL STAFF AND REALLY UNDERSTAND WHAT WAS GOING ON. DR. (INDISCERNIBLE) WEDNESDAY AFTER TUTORIALS AND THE NURSING STAFF WOULD SAY THAT, AND THE MEDICAL STAFF AND I'M GOING TO EXPLAIN WHY I'M SO MOVED BY THIS PERSON. THEN I COME BACK TO WHO AFTERWARDS AND THEN THEY HAD ACTUALLY SENT HIS TELEGRAM. HE HAD DONE THE JOHN SNOW, YOU KNOW, THE COLOR OF PUMP, PUMP IN LONDON, HE SPOTTED THE PROBLEM. REALIZED WHERE IT WAS COMING FROM AND HE HAD A PLAN. AND HE SAID HEMORRHAGIC FEVER, HE DIAGNOSED HIMSELF, HE SAID IT'S DECIMATING THE POPULATION. HE DEFINED THE CASE DESCRIPTION, THE DEMOGRAPHY, MAINLY YOUNG MALE MINORS OF THIS AGE GROUP AND GIRL FRIENDS OR WIVE WHOSE LOOK AFTER THEM, IT'S TRANSMITTED TO THEM, URGENT HELP REQUESTED. EVEN SEND SEND AUTHORITIES TO CLOSE THE MINE. HE EVEN IDENTIFIED THE EXACT MINE THE CASES WERE ALL PRIMARY CASES WERE COMING FROM. THE THIS TALE OF THE SLIDES OF ENORMOUS SKILLS THAT ARE ACTUALLY OUT THERE AND EVERYWHERE. THERE'S ALSO A TALE OF TRAGEDY BECAUSE YOU SEND A SECOND RADIO MESSAGE, HE HIMSELF WAS ONLY A MONTH LATER WHEN HE DIED HIMSELF OF MARBERG, HE CONTRACTED THE DISEASE THAT AGENCIES RESPONDED. IT WAS DIAGNOSED I THINK ON HIS BLOOD SAMPLE BEING SAVED. SO A BIT SAD BUT ALSO A WINDOW OF WHAT'S GOING ON. MAYBE DR. BENZALI WOULD RECOGNIZE THIS ICONIC PUBLIC HEALTH GRAPH. EARLY INTERVENTION, THERE'S THE GEE DIE MARKER LASER. EARLY INTERVENTION STOPS THE LARGE CASES. WHAT I WANT YOU TO DO IS THINK OF THIS AS AN INDIVIDUAL PATIENT. EARLY INTERVENTION, STOCKS. THE COMPLEXITY OF CARE, THE HIGH COMPLICATION RATE. MORTALITY AND MORRED BITY IN INDIVIDUAL PATIENTS AND RISK OF THOSE THINGSCH IT'S THE SIMPLE EARLY INTERVENTIONS IS THAT GO UNSUNG, UNRECOGNIZED BECAUSE IT'S NOT HEROIC STUFF, IT'S CARRIED OUT BY NURSING STAFF. IF WE GET EARLY ESPECIALLY IF TIME CRITICAL INTERVENTIONS SO YOU CAN HEAR ME GOING AGAIN, I SUPPOSE IT'S NO SURPRISE BECAUSE I'M AN EMERGENCY MEDICINE PHYSICIAN THAT I'M INTO THE TIME PHYSICAL NATURE OF SOME OF THESE PROBLEMS. SO IF YOU CAN BEAR THAT IN MIND, AND ONE -- BEFORE GOING BACK TO THE CLINICAL AREA, A STRANGE SLIDE PERHAPS BUT THIS IS AN ARTICLE FROM AN ECONOMIST OVER A YEAR AGO POINTING OUT THE INCREASE IN PERCENTAGE GDP SPEND ON HEALTHCARE. THIS EXAMPLE IS U.S. HEALTHCARE SPENDING. GOING UP YEAR-ON-YEAR. EXCEEDING THE GD TBHRKS -- GDP. THIS IS UNSUSTAINABLE. IT'S NOT JUST YOUR COUNTRY, IT'S MY COUNTRY. IT'S UGANDA, IT'S SIERRA LEON. YOU'RE SPENDING PERCENTAGE OF GDP HEALTHCARE IN 200815% SO WAS SIERRA LEON OR 13%. THEY CAN'T AFFORD IT MORE THAN ANY OF US. THEY NEED THEIR ROADS DEVELOPMENT, COMMUNICATIONS, JUDICIARY. SO THERE'S -- THERE IS AN IMPERATIVE HERE. IF YOU COMBINE THAT WITH THE INTERVENTIONS WE KNOW MORE ABOUT HOW SUCCESSFUL AND HOW CHEAP SIMPLE INTERVENTIONS ARE. I WANT TO EMPHASIZE LOW COST OF THESE THINGS. SO WHAT CAN BE DONE? SO JUST ONE MORE ECONOMICS SLIDE. CAN CAN YOU GUESS HOW MUCH THE AVERAGE SIERRA LEON IS SPENDING OW OF POCKET PER ANNUM? ABOUT $90 PER CAPITA PER YEAR. I'M GOING TO FINISH WITH A TRAGIC KIND OF SLIDE OF ALL I THINK ABOUT WHAT EFFECTS THAT HAS ON OVERALL HEALTHCARE, VIABILITY AND SOCIAL COHESION. THIS IS NOT SORT OF FANCY ABOUT TRACT ECONOMICS. THERE'S A LOT OF MONEY SPENT ON HEALTH AND GETTING LITTLE IN RETURN FOR IT. SO I WHAT I COME TO CHAMPION IS WHAT I CALL NEGLECTED PROCESSES. JUST AS THERE WERE INDIVIDUAL NEGLECTED TROPICAL DISEASES I HAVE STOLEN FROM THEM BECAUSE EVERYONE KNEW THE INDIVIDUAL DISEASES WERE REALLY IMPORTANT. BUT THEY WERE—h7wz SMALL THAT THEY WEREN'T BIG ENOUGH TO GET ON MINISTER'S PORTFOLIO OR TO -- ON TO AN AID BUDGET OR ANYTHING. BUT BY BUNDLING THE NEGLECTEDDED TROPICAL DISEASES TOGETHER, NOW THEY'RE ON EVERYONE'S PORTFOLIO OR LIST, EVERY MEN INDUSTRY OF HEALTH IS DEALING WITH THOSE. BECAUSE TOGETHER THEY HAD UP -- ADD UP TO AN UNSTOPPABLE ARGUMENT AND IMPERATIVE ECONOMIC AND FOR THE BURDEN OF DISEASE OF POPULATION YOU'RE CARING FOR. SO LIKE THOSE NEGLECTED TROPICAL DISEASES EACH PROCESS UNDISPUTED BENEFIT, MOSTLY LOW COST, BUT THERE'S NO COST RECOVERY MECHANISM, VERY HARD TO CHARGE FOR IT HARD TOO MAKE MONEY OUT OF IT, HARD TO PUT EXTRA $10 ON THE BILL FOR IT. THE OUTCOMES ARE DIFFICULT TO MEASURE. BECAUSE NURSING PROCESSES, NO ONE ACTUALLY SEES THE COMPLICATIONS THAT WERE PREVENTED AS A RESULT OF THOSE. THERE ARE SOME OTHER SNEAKY FEATURES THAT MAKE THEM DIFFICULT TO OVERCOME. , THEY'RE DIFFICULT TO TUS STAIN, THEY INVOLVE A LOT OF DIFFERENT STAKEHOLDERS WHO DON'T SIT DOWN TOGETHER. THERE'S A LOCK OF ON THE OTHER HAND SHIP, OR IN THE CASE OF NURSING STAFF, THEY'RE NOT EMPOWERED TO GET THE RESOURCES TO CHAMPION AND CHANGE THEM. THERE'S OFTEN ENTERDEPENDENCY, YOU CAN'T FIX ONE WITHOUT FIXING A BUNDLE OF OTHER MEASURES. BUT OARNLD, IF YOU CO, -- BUT ON THE OTHER HAND IF YOU DO THERE'S SYNERGY. SO YOU GET A PROPORTION OF BENEFIT ONCE YOU START TO BUILD ON OTHERS SO I'M NOT GOING TO SAY ANY MORE ABOUT THESE BUT YOU'RE GOING TO BEAR THIS IN MIND, FOR EVERY SLIDE THAT FOLLOWS, I THINK YOU'RE GOING TO RECOGNIZE THERE IS A NEGLECTED PROCESS IN AT LEAST ONE OF THEM PER EVERY SLIDE. WORKING WAN NGO IN THAT AREA, IN '97 AND I WENT BACK THERE SADLY WHEN I HER IN WHO THAT DR. (INAUDIBLE) HEAD OF THAT UNIT WAS ILL AND DYING OF LASA. HE GOT ID FROM A NEEDLE STICK INJURY FROM TREATINGING A PEDIATRIC NURSE VOLUNTEER NURSE KNOWING WHAT UNIT FROM MANY YEARS AGO THERE WAS SOMETHING MIND THIS AND SOMETHING GOING ON AND HIS CARE OF HIMSELF WOULD PROBABLY LEAD TO TRANSMISSION, HE WAS SO DEVOTED AND IF YOU HAVEN'T GOT RESOURCES BUT CARE FOR SOMEONE YOU'RE GOING TO DO IT ANYWAY. IN THEVATION THAT FOLLOWED WE IDENTIFIED ABOUT 100 PEDIATRIC CASES ON THE GENERAL WARD. THAT OUTBREAK HAD BEEN GOING ON FOR MONTHS AND WAS UNRECOGNIZED SOMEONE IN THE MINISTRY OF HEALTH SAID HIS LAST DYING ACT OF THIS MAN WAS TO REVEAL THE TERRIBLE EPIDEMIC AND TO TRAN -- THE TRANSMISSION GOING ON FROM MULTI-DOSING OF VILES AND THAT'S WHY IT WAS PARTICULARLY SMALLER PEDIATRIC AGE GROUP BECAUSE IF YOU'RE A TWO-YEAR-OLD OR ONE-YEAR-OLD OR SIX MONTH OLD YOU SHARE ONE VILE OF CLOROQUIN BIG TIME. SO THERE'S -- EVERYONE WAS DIPPING THEIR OWN SYRINGE, SYRINGE GUIDED FOR THAT CHILD, DIPPING INTO A COMMON SEW SIMPLE MULTI-DOSING TOOK ME A LONG TIME TO WORK THAT OUT. IN '97 WHEN I WAS THERE, I NOTICED THAT THE INCIDENCE OF LASA SEEMED TO BE GOING UP. SEEMED TO BE DOUBLING EVERY MONTH. THAT WAS ON THAT GRAPH THERE. SO I GOT QUITE INVOLVED IN NOT SO MUCH CLINICAL CARE AT THAT TIME, BUT IN TERMS OF RESPONDING TO THE OUTBREAK AND TRYING TO FINE OUT ABOUT THE DISEASE ABOUT HOW TO PREVENT IT. BUT I CERTAINLY GOT THAT LASA FEVER WARD AND WHAT THEY DID. AND DON BOUSCH T FIRST PERSON I SAW TREATING CAREFULLY AND EFFECTIVELY ;Ö HEMORRHAGIC FEVER CASE, GAVE ME THE CONFIDENCE TO FEEL IT'S NOT MADNESS, YOU CAN DO THIS. AND PEOPLE DO. THIS HE'LL ALSO VOUCH FOR THE FACT THOUGH WE CAN BE SURE EXACTLY, THERE MAYBE OVERCOUNTING OF CASES SOMETIMES, THE CASE FATALITY IS OFTEN AROUND 29%, 17%, WHEN I WAS THERE IT WAS 20, 30%. EVERY NOW AND AGAIN THEY HAVE RIBO VIRIN AND THEY HALF TO 12%FUL. THEY DIDN'T HAVE FANTASTIC TREATMENT FOR THE REGIMES. YET THEY WERE GETTING THOSE SUCCESSES. SO THE PEOPLE THAT SAY OH, IT MUST BE A STRAIN AS I HEARD WITH EBOLA WHEN I WORKED IN UGANDA, A NON-VIRULENT STRAIN BUT WHEN YOU GET CLUSTERS OF CASES, OF THESE CASES APPEARING IN FREE TOWN OR IN UGANDA APPEARING IN OTHER HOSPITALS WHERE THEY'RE NOT USED TO TREATING THEM, THERE WOULD BE 100% MORTALITY. I SAW WHY. IT'S DEATH BY NEGLECT. AT THE SAME TIME IN GABON IN OUTBREAKS OF EBOLA I WENT TO ONE OF THEM THEY HAVE TROUBLE ISOLATING PATIENTS BECAUSE THEY WOULDN'T AGREE TO ISOLATION. AND I TOOK BLOOD SAMPLES FROM SURVIVORS IN THE VILLAGES. BEHIND EVERY SURVIVOR WAS A RELATIVE WHO HAD LOVINGINGLY GIVEN THEM ORAL FLUIDS. THAT'S CERTAINLY WAS IN COMMON. I THINK THERE IS A KEY MESSAGE HERE I WANT TO GET ACROSS. I'M DEEPLY CONCERNED THAT ON KNEE JERK REACTIONS TO INTRAVENOUS FLUIDS COULD BE A PROBLEM. THOSE WILL BE EXPLAINED IN THE FOLLOWING SLIDES. SO LASA FEVER IS THE TYPE OF LEAK SYNDROME, PUFFY EYE, PUFFY BRAIN AND IF YOU'RE REALLY UNLUCKY, PULMONARY EDEMA. BUT ON THE OTHER HAND IT'S NICE TO DIAGNOSE BECAUSE NOT MANY CONDITION GIVES YOU PUFFY EYES. IF YOU CAN'T RECOGNIZE IT YOURSELF BECAUSE KIDS ARE SCREAMING AT ME U YOU CAN ASK PARENTS AND RELATIVES AND THEY'LL SAY YEAH AND THE NECK IS SWOLLEN. I CAN NEVER SPOT THEY SAY YEAH THE NECK IS SWOLLEN AS WELL SO IT CAN BE (INAUDIBLE) SO WHAT ARE THEY DOING IN SIERRA LEON? LOOK AT THIS SLIDE HERE. THIS WOMAN, SCHE'S BEEN -- SHE'S BEEN FITTING WITH CEREBRAL EDEMA FROM LASA. SHE HAS SEIZURES TREATED WITH BENZODIAZEPINE INTRAVENOUS. SHE HAS IV FLUIDS BUT CAUTIOUS ON THAT UNIT, THEY SAY GOOD THING BUT BE CAREFUL. SO THEY USE THEM VERY CAREFULLY. JUST AT THE RIGHT TIME. ELECTROLIGHTS, ESPECIALLY POTASSIUM, YOU CAN GET POTASSIUM DEPLETED IF YOU'RE GIVING NON-POTASSIUM CONTAINING FLUIDS. THE AIRWAY, LOOK AT THIS PATIENT IN THE RECOVERY POSITION, ORAL PHARYNGEAL AIRWAY. THERE'S AN OXYGEN CONCENTRATION HERE THROUGH NASAL PRONGS. THAT IS AS GOOD AS IT GETS. IF I GET THIS IN MY HOSPITAL WHEN THEY NEED IT AND I FIND AN UNCONSCIOUS PATIENT IMMEDIATELY IN LATERAL POSITION I WOULD BE HAPPY. THIS ISN'T HAPPENING IN MOST PLACES AROUND THE WORLD. BUT IF DOWK THAT YOU'RE DOING WELL. WHY CAN'T WE DO IT? TELL YOU WHY. THERE'S LOTS OF DIFFICULTIES, SORRY I HAVE JUST GONE TRUE THAT SLIDE. LET'S LOOK AT EXPERIENCE OF EBOLA AND UGANDA, HUGE AMOUNT OF NOSE CHOAMIAL TRANSMISSION BUT HUGE NUMBER OF CASES. LIKE THE HEMORRHAGIC FEVER OUTBREAKS YOU'RE DEALING WITH PREVIOUSLY FIT PEOPLE OF RELATIVELY YOUNG AGE SIMILAR TIME SCALES. WHAT THEY DON'T DO IS BLEED EARLY SO IF YOU SEE HEMORRHAGE BY THIS PATIENT THEY'RE WORRIED ABOUT HE'S ISOLATEDDED HIMSELF IN THE JUNGLE BECAUSE HE THOUGHT HE HAD -- HE DIDN'T WANT TO TRANSMIT IT TO HIS VILLAGE OR FAMILY. BUT HE HAD HIV COMPLICATIONS, BUT IT GIVES YOU AN IDEA HEMORRHAGE IS NOT A FEATURE EARLY IN THESE DISEASES. NIDA I'M AFRAID IS A HIGH MEASURED FEVER IF YOU'RE USING AUXILLARY TECHNIQUE. EVEN WITH GOOD NURSING CONDITIONS AND A LOT OF SUPPORT ON THE WARDScq OUTBREAK IN UGANDA IN 2000 AND 2001, WE COULD NOT RELIABLY INDICATE USE TEMPERATURE TO SAY YOU HAVE GOT TO HAVE A HIGH FEVER TO TRIGGER YOUR DIAGNOSE KNOW SITION. NOT EVEN IN THE FIRST TWO OR FIRST THREE MEASUREMENT PES COULD IT BE RELIED UPON. AT LEAST WITH THE UNITS OF CURRENCY THAT ARE IN YOUR FAVOR, NOW WE'RE NOW IN CENTIGRADE. SO HIGH FEVER. WE EXPECT TO DEFINE HEMORRHAGIC FEVER WITH TEMPERATURE 38 AUXILLARY OF 38.5 CORE TEMPERATURE BUT YOU DON'T GET THAT WITH THESE THINGS IN PRACTICE. BUT THEY HAVE A HISTORY OF HIGH NEEFER. SO IT -- FEVER. SO MEASUREMENT AND TECHNIQUE. WHAT ARE THEY DOING WITH THAT TECHNIQUE? THEY USE A THERMOMETER THAT HAVEN'T CHANGED MUCH SINCE 150 YEARS AGO WHEN IT WAS INVENTED. IT TAKES THREE MINUTES AT LEAST TO MEASURE IT. AND MY HOSPITAL LINKS WITH THE SAME HOSPITAL IN UGANDA, THEY HAD ALIKE LEAK THERE FOR FOUR YEARS SO I -- ASSESS WHAT WAS -- HOW LONG IT WILL TAKE TO DO THE OBSERVATIONS THREE TIMES A DAY ON -- IN THAT SAME HOSPITAL. ON A 75 SURGICAL WARD IT TAKES 20 1/2 HOURS NURSING TIME. NEVER MIND THE PROBLEMS WITH EQUIPMENT LOSS AND MAINTENANCE. THAT'S WHAT WE'RE UP AGAINST. BUT IT DOESN'T HAVE TO BE THAT WAY. YOU CAN GET SOMETHING LIKE THIS FROM A HARDWARE SHOP JUST POINT AND YOU GET INFRARED THERMOMETER, IT'S JUST ONE I HAPPENED TO BRING HERE. INFRARED SYMMETRY, THESE ADVANCES ARE NOW INCREDIBLY CHEAP. I KEEP GETTING AWAY MY PULSE -- I BUY THEM 10 OR 11 POUNDS EACH AND JUST TO DEMONSTRATE TO PEOPLE AND GIVE THEM TO DECISION MAKERS AND MANAGERS. TO REASSURE THEM THIS IS NOT EXTREMELY EXPENSIVE MATERIALS. THE PRICE OF THESE HAVE COME DOWN 100 FOLD SINCE THEY FIRST -- SINCE I FIRST QUALIFIED. SO IMAGINE WHAT WE CAN DO IF WE PUT A CALL TO INDUSTRY AND SAID WE CAN EXPECT EVERY NURSE TRAINED TO END UP OWNING THIS MATERIAL. I THINK THAT THE PULSE (INDISCERNIBLE) IN PARTICULAR HAS A ICONIC FEATURE. IT GLOWS, IT'S ACCURATE, IT DOESN'T READ, IT TELLS YOU I GOT SHUT DOWN REALLY POORLY. GIVES YOU AN IDEA HEART RATE. THIS IS GOOD STUFF. YOU KNOW HOW DOCTORS AN NURSES LOVE THE HANG A STETHOSCOPE AROUND THEIR SHOULDERS AS AN ICON OF THEIR PROFESSIONALISM, PULSE OCCIMETERS COULD BE THAT IN THE FUTURE. IF SO, BRING IT ON, PLEASE. BECAUSE WE NEED TO TRANSFORM A NURSING STAFF BACK INTO BEING WHAT A COLLEAGUE OF MINE INVENTED FOR ME, THE TERMS PHYSIOLOGY DETECTIVES. THEY ARE THE PHYSIOLOGY DETECTIVES. WHY IS THAT IMPORTANT? I'M GOING TO SHOW YOU. WHY DO YOU THINK I'M ASKING FOR WALL CLOCKS WITH NO HOUR HAND IN ALL HEALTH PREMISES AROUND THE WORLD? ANY IDEA? THINK OUT OF THE BOX FOR THIS ONE. THEY GET NICKED OTHERWISE. IN MY COUNTRY WE HAVE TO ADJUST OUR DAYLIGHT SAVINGS ALL THE TIME SO THEY LIKE BUYING CLOCKS BECAUSE IT'S EXPENSIVE TO GET WIDE AND REMOTE AND -- SO FOR HEALTHCARE WE NEED THE SECOND HALF. OTHERWISE WE CAN'T COUNT RESPIRATORY RATE. IT HAS TO BE LINE OF SITE OF THE PATIENT AND HAVING IT BEHIND YOU OR NEXT ROOM. YOU HAVE TO LOOK ACROSS THE PATIENT'S CHEST AND SEE THE SECOND HAND, OTHERWISE IT WILL TAKE TOO LONG. WHAT A DIVIDEND WE GET WHEN WE COUNT RESPIRATORY RATE, IT'S A HUGE AMOUNT. SO BACK TO MORE BASICS IN CARE. PATIENTS YOU'LL SEE PICTURES IN THE NEXT FEW SLIDES NOTICE THE FIT YOUNG MAN WHO CAN'T SIT UP ON THE BED, CAN'T REACH FOR A GLASS OF WATER. THEY CAN'T -- OR ANY OTHER ORAL FLUIDS. THEY CAN'T REACH A VOMIT BOWL, THEY CAN'T TALK LATER. THIS MAN CAN'T REACH THAT FIVE LITER CAN OF ORAL REHYDRATION SOLUTION AT BEDSIDE. SO HE HAS TO HAVE HELP. THAT'S WHY BEHIND EVERY SURVIVOR OF THESE SEVERE DISEASES IS SOMEONE WHO REALLY CARED AND LOOKED AFTER THEM. THE TRICK IS TO SAVE GUARD THAT PERSON FROM INFECTION. IN GABON I TOLD YOU ABOUT THAT RELATIVE WHO LOOK AFTER THE SURVIVOR, THEY ALWAYS GOT IT. SO YOU CAN'T DO THIS. YOU CAN'T -- YOU HAVE TO PUT YOUR ARM BEHIND SOMEONE TO PROP THEM UP. THEY CONFERENCE SPLATTER I THEY CAN ONLY TAKE SIPS AT A TIME, IT HURTS TO SWALLOW. THE MOUTH IS SO TAPED THEY CAN'T FORM A SEAL AROUND A TRAW SO SO IT'S ITTRITY. IT -- SO TRICKY. EVEN THAT IS RARE IN MOST PARTS OF THE WORLD. CERTAINLY TO HAVE ORAL FLUIDS AVAILABLE IN YOUR HEALTHCARE ESTABLISHMENT IS A RARE THING. UNLESS YOU'RE IN A PEDIATRIC WARD SWITCHED ON, WHERE THEY TUNED IN, THEY'VE CLEANED UP THEIR ACT, THEY HAVE IT DOWN TO A GOOD SYSTEM SO PEOPLE WAITING TO HAVE ORAL FLUIDS CERTAINLY IN MY COUNTRY. SO THERE'S A LOT OF GASTRIC STYLE PROBLEMS, SOURS OF FLUID LOSS, THAT'S THE MAIN THING. THESE PATIENTS SO DEHYDRATED, DIARRHEA, JUST TAKE A NOTE OF PLASTIC SHEETING HERE, NOT MANY WOULD HAVE THAT TO TRY AND STOP SOILING OF THE ENVIRONMENT AND CONTAIN THE SOURCE INFECTION. THEY HAVE A TENDER LIVER PALPATION IN MOST CASES FROM MY CLINICAL EXPERIENCE WHICH GETS INCREASINGLY TENDER EACH DAY 7 OR 8 DAYS, PERCUSSION OVER THE LOWER CHEST WALL GIVES YOU PAIN. PERCUSSION OVER THE LIVER IS PAINFUL. YOU CAN NAJ ENTHUSIASTIC SURGEON TAKING THESE CASES TO THEATER WHEN FACED WITH SOMEONE WITH COLLAPSE CARDIOVASCULAR COLLAPSE AND SIGNS OF PER TO NISM. SO HYPOBOLEMIA. TACHYCARDIA, 132, RESPIRATORY RATE OF 36. WHAT ARE YOU GOING TO DO? YOU'RE GOING TO PUT UP A DRIP BECAUSE I HAVE SEEN THE SLIDES. TROUBLE IS, YOU CHASE THE NUMBERS WITH THE -- YOU'LL NEVER BRING IT DOWN. WHAT YOU WILL DO IS PUT THE RESPIRATORY RATE UP. I HAVE COUNTED RESPIRATORY RATE GOING UP. THAT RESPIRATORY RATE STAYS UP BECAUSE THAT FLUIDS HAS GONE ON TO THE LUNG AND I CERTAINLY FEEL TERRIBLE ABOUT THAT WHEN I FIRST TREATED CASES BUT I WANT THAT LESSON. SORRY I DIDN'T THINK WE HAVE IT OUT THERE OR AT LEAST BE PREPARED TO ADMIT THIS IS A POSSIBILITY SO I'M GOING TO CARRY ON A LITTLE BIT ABOUT THIS. ABOUT ORAL HYDRATION. WE FOUND PATIENTS ON THE WARD WHICH DIDN'T LIKE 100% ORS. THEY REALLY WON'T DRINK IT BUT IF YOU MAKE IT FOUR TO FIVE LITERS, WITH A BIT OF ORANGE JUICE CONCENTRATE. THEY SEEM FUSSY THESE PATIENT BUS LITERALLY GAVE A THUMBS UP AND THE PATIENTS SAID THEY REALLY APPRECIATED THAT. AND THEY WOULD DRINK A LOT MORE. SO I THINK THAT WAS A RECIPE FOR SUCCESS AND THE (INAUDIBLE) CAN. IT WAS FILLED EVERY MORNING, QUITE A BIT OPERATION TO MAKE UP THE ORS AND REPLACE IT AND IMAGINE YOURSELF ON THAT WARD, YOU WANT TO BE IN A SITUATION WHERE YOU NOART GOING TO GET INFECTED FROM CROSS CONTAMINATION OR MAKING UP OF THE FLUID. SO IT'S NOT AS EASY AS IT SOUNDS BUT THE FIVE LITTER JERRY CAN WAS A VISIBLE FLUID INTAKE CHART ON YOUR ROUNDS TO SEE HOW MUCH THEY'D HAD THAT DAY. REALLY USEFUL, ALL THE TIME TITRATING THE PATIENT'S CONDITION AGAINST WHAT THEY HAVE BEEN ABLE TO DRINK. ALL SURVIVORS OF EBOLA HAD PITTING EDEMA BUT WE RECOGNIZED QUITE EARLY THAT IF YOU HAD EDEMA IN THE EARLY PHASE OF THE DISEASE THIS WAS A BAD PROGNOSTIC DESIGN. I NEVER SAID THAT BEFORE AT MEETING. DR. (INDISCERNIBLE) WHEN HE CONTRACTED EBOLA I WAS EXAMINING HIM AND I JUST YOU'RE OUT OF SHEER ROUTINE LOOKED FOR EDEMA AND SAW THAT MARK. BENEATH OF US KNEW WHERE TO LOOK. I THINK THAT SIGN IN THE TEXTBOOKS ABOUT IT'S A DANGEROUS THING. I DON'T KNOW THE SIGNIFICANCE OF IT COMPLETELY FOR SURE BUT IT'S AN INDICATOR, IT'S NOT A PROTEIN LOSS. AND THE CAPILLARY LEAK, IT'S NOT JUST IMPORTANT FOR THE LIMB, IT'S IMPORTANT ABOUT THE LUNG THAT'S MY CONCERN ABOUT IV FLUIDS. THE COLLEAGUES WHO PUT FLUIDS UP ON COLLEAGUE OF HIS WHO WASN'T USED TO TREATING EBOLA, HE DIDN'T THINK HE HAD EBOLA, GAVE HIM TWO LITTERS OF FLUID QUICKLY. EARLY IN THE FIRST FEW DAYS OF DISEASE. I THINK AS I HAVE COME THE SAY WITH H1N1 SEVERE PNEUMONIAS, IT ONLY TAKES FIVE MINUTES TO PUT HALF A DOLLAR'S WORTH OF IV FLUID ON THE LUNG BUT IT CAN TAKE HALF A MILLION DOLLARS OF ICU INTENSIVE CARE TO BRING IT OFF TO GET IT BACK OFF AGAIN IF YOU HAVE RESPIRATORY DISTRESS SYNDROME OR COMPLICATED LUNG DISEASE. THERE IS NO GUARANTEED CHANCE OF SUCCESS. ONCE YOU GET RESPIRATORY COMPLICATIONS YOU'RE IN DEEP TROUBLE. TOWARDS THE END OF THE OUTBREAK WE HAVE X-RAYS, AND I CAN TELL THAT IS ACTUALLY MATTHEW'S X-RAY BECAUSE IT'S INTUBATED. HE WAS THE ONLY PATIENT WE VENTILATED. JUST VERY DIFFICULT TO TRY TO BRING UP THEon#N!c OXYGEN SATURATION, OTHERWISE THEY WOULD BE GOING ABOUT 65. YOU JUST DONE WANT TO SEE A PATIENT WITH THAT LEVEL OF OXYGEN. SO COUNTING THE RESPIRATORY RATE, WHY DON'T WE PROMOTE IT MORE OFTEN. SO EASY. A LOT CAN'T REMEMBER THE PEDIATRIC AGE RANGE. I I HAVE TO REFER TO A TABLE CONSTANTRY TO BE SURE BUT YOU GET SO MUCH FROM MONITORING RESPIRATORY RATE. YOU DON'T EVEN HAVE TO TOUCH THE PATIENT. SO THERE'S CERTAINLY PATIENTS WHO TAKE IT WITH ACIDOSIS BUT ONCE THEY HAVE GOT HIGH POXEMIA, THAT WAS EXTREMELY BAD PROGNOSIS. NO ONE SURVIVED THAT. THAT LIKED TO OVERHYDRATION. IT WAS NOTICEABLE THAT THE STAFF DID BADLY. EVEN THE NURSES STARTED TO SAY IF I GET EBOLA DON'T PUT A DRIP ON ME, I PAY TAI TOANG THE WHAT THE NURSES SAY. SO I HAVE GOT A BRIEF THING FROM A VIDEO I HELPED TO MAKE THE WHO ON SEVERE DENGI. CHANGING OF CAPILLARY LEAK. I HOPE THE SOUND COMES UP, IT TAKES A FEW SECONDS TO FADE IN. >> AS PLASMA LEVELS FALL THE HEMATOCRIT RISES SHARPLY BECAUSE THERE'S NOT ENOUGH FLUID IN PROPORTION TO THE RED CELLS. REMEMBER IF INTRAVENOUS FLUIDS ARE GIVEN WHEN NOT NECESSARY OR TOO QUICKLY THE EXTRA FLUID CAN CAN POUR OUT LEAKY CAPILLARIES INTO THE TISSUES. YOU MAY SEE THIS AS PU FINESS AROUND THE EYES OR EVEN ABDOMINAL DISTENCH DUE TO FLUID IN THE PERITONEAL CAVITY. FLUID EASILY LEAKS TO THE PLURAL SPACE CAUSING PLURAL EFFUSIONS. BY PRESSING ON THE LUNGS THIS MAKES BREATHER MORE DIFFICULT. DURING THE CAPILLARY LEAK PHASE JUST ENOUGH FLUID MUST BE GIVEN TO PROPREVENT CIRCULATORY SHOCK. THE PEED WRATRITIONS WILL REFER TO PUBLISHED GUIDELINES OR WALL CHARTS TO GIVE EXACTLY THE RIGHT AMOUNT OF FLUID AT THIS CRITICAL STAGE. A FALLING HEMATOCRIT. >> I'M NOT SAYING THEY'RE GOING TO GET PLURAL EFFUSIONS AS HAPPENS IN DENGI, IT GOES ON TO LUNG, NOT PLURAL EFFUSION. WE DIDN'T FIND EVIDENCE OF THOSE, BUT IT GOES ON TO THE LUNGS. SO THAT'S THE DIFFERENCE. I THINK WE HAVE TO BE CAUTIOUS WITH INTRAVENOUS FLUIDS. IF ORAL IS AVAILABLER, GOOD PRACTICE MEANS WE SHOULD BE USING IT. WE JUST GOT INTO BAD HABITS. SO EXISTING GOOD PRACTICE IS USED THE ORAL ROUTE WHEN AVAILABLE. ESPECIALLY CONSIDERING ELECTROLIGHTS ARE DIFFICULT TO JUGGLE IN THOSE RESOURCE POOR OR OVERPRESSED ENVIRONMENTS. WHAT ABOUT OXYGEN? HERE IS ANOTHER ONE. SIMON, YOU CAN'T DO OXYGEN, IT'S VERY EXPENSIVE AND THE TO LOGISTICS ARE A NIGHTMARE. GET A GRIP. NOT SO, MY FRIENDS. THIS IS AFGHANISTAN IN SOME REMOTE AREA IN 1984, A BIG JUMBO CYLINDER IN THE BACK THERE COMMONLY AROUND THE WORLD THOSE COST U.S. DOLLARS TO REFILL. YOU GETS 19 HOURS OF HIGH FLOW 10-LITER AS MINUTE OXYGEN OUT OF THAT. AND SO FOR SEVERE DISTRESS SYNDROMES, THIS IS -- YOU CAN'T -- THERE'S NO EXCUSE FOR LEAVING PEOPLE HYPOXIC. WE GOT INTO A NEW GENERATION. THEY'RE NOW GOING GUARANTEED WORKING LIFE OF ABOUT 40,000 HOURS OR SOMETHING. THEY -- THE CAPITAL COSTS WORK OUT OVER TIME IS .02 CENTS PER PERSON PER HOUR. THIS IS CHEAP AND THEY'RE RELIABLE IF YOU GO THROUGH THE RIGHT MAKE. SO THERE ARE GRAVEYARDS OF OXYGEN CONCENTRATORS. THE GENERATORS ARE MORE EXPENSIVE. BUT BEFORE GIVING OX GENERAL, LOOK AT SATURATIONS. IT -- IMPLEMENT OXYGEN SATURATION MEASUREMENTS, THEY MAKE THE NURSES DEMAND OXYGEN WHEN IT RUNS OUT. I WILL ALSO ALLOW YOU TO RATION RESOURCES OF OXYGEN MORE EFFECTIVELY. AND IT'S A DIAGNOSTIC TOOL IF YOU DON'T HAVE ANY OXYGEN. I SAID BEFORE, IT'S A POTENTIAL ICON, THE PRICES HAVE COME DOWN MASSIVELY. WHAT ABOUT CHART? WHAT AM I DOING STANDING UP HERE;nxJ%TALKI NG ABOUT THIS PAPER AS BEING IMPORTANT? THEY REALLY ARE. BECAUSE IN RESOURCE ENVIRONMENTS YOU RELY ON THE RESPONSE TO TREATMENT. AS A MEANS OF ASSISTING IN DIAGNOSIS OR PROBABILITY OF DIAGNOSIS. IF YOU'RE NOT SEEING THAT RESPONSE AND LINKING TO WHETHER IT'S FLUIDS, TRANSFUSION ANTI-MICROBIALS OR ANTI-MALARIA OR ANTI-BACTERIAL, NOWHERE AROUND THE WORLD EXCEPT THE EASTERN EUROPEAN COUNTRIES, NOT THAT THEY HAVE RESPIRATORY RATES ON THE ACCESS OR NOT PULSE OKAY SYMMETRY ON THE AXIS SO YOU'RE NOT MAKING YOUR OWN CHARTS EVERYWHERE. WE NEED A WORLDWIDE CHART. IT WILL BE A GIFT TO THE WORLD TO HAVE ONE STANDARD CHART THAT HAD IT ALL THERE PULSE OCCIMETRY, RAISE EXPECTATIONS, RAISE THE EXPECTATIONS THERE'S 400 OF THESE OUT THERE, I DON'T WANT YOU TO GO FOR THE LOT BUT YOU CAN HELP START A SAMPLE OF THIS, OUT IN THE FOIR, THIS IS WHAT WE USED IN THE UK. IN EVERY HEALTHCARE SETTING EVERY UTILIZED PATIENT I SHOULD SAY WE HAVE THIS P TPI CHART. BOLTED ON TO IT IS A SCORING SYSTEM, NOT TALKING INTENSIVE CARE, I'M TALKING AVERAGE MEDICAL WARD OR PEDIATRIC EARLY WARNING SCORING CHARTS FOR CHILDREN. OBSTETRIC WARNING CHARTS, OBSTETRICIANS, ESPECIALLY THE MID WIVES ARE SLOW ON THE UPTAKE WITH THIS. THERE WAS A LOT OF RESISTANCE. IT TOOK ABOUT 12 WREERS TO GET THIS WIDELY INTRODUCED ACROSS THE UK. DEPARTMENT OF HEALTH SUPPORTED IT, DON'T THINK IT'S GOING TO BE EASY. BUT WHAT THIS DOES, IT'S A REVOLUTION IN HEALTHCARE. YOU HAVE THE SCORING SYSTEM. THAT'S DEPENDING ON THE DEGREE OF ABNORMALITY OF RESPIRATORY RATE, HEART RATE, SO ON, CONSCIOUS LEVEL THEN THE THURSDAY IS MANDATED TO CALL SOMEONE. THE TOP LEVEL SCORE THE NURSE IS MANDATED TO CALL INTENSIVE CARE IN MANY HOSPITALS, OTHERWISE THEY GO THROUGH SOMEONE ELSE. THAT'S WHAT IT DOES. IT'S A REVOLUTION IN HEALTHCARE. WHAT IT MEANS IS THAT HEALTHCARE IS DELIVERED MORE EFFECTIVE RESPONSES DELIVERED MORE TIMELY. AND IS THAT IMPORTANT TIMING OF RESPONSE? WELL, IT'S NOT JUST SIMON SAYS, A LOT SAY IT'S IMPORTANT. BUN L PERSON AND ANN KUMAR LOOKS AT 15 DATABASES FROM CANADA AND HERE IN THE USA OF INTENSIVE CARES AND HE'S PRODUCED THIS ICONIC GRAPH, LOOK AT THIS. FOR EVERY DELAY IN ANTI-MICROBIAL AFTER ONSET OF HYPERTENSION WAS DOCUMENTED, YET TO USE LOCAL PRESSURE BUT JUST AS WAS SINGLE MARKER BUT FOR EVERY HOURS' DELAY YOU HAVE A 7.6 DROP IN SURVIVAL. THE AVERAGE DELAY IS JUST LIKE OUR SEPSIS STUDIES IN THE UK, ABOUT FIVE HOURS. THAT'S 35% PREVENTABLE MORTAL TI. YET YOU SPOTTED THE HYPERTENSION, GETTING THE ANTIBIOTICS. IF A NEW DRUG WAS INTRODUCED WITH THAT FANTASTIC IMPROVEMENT IN SURVIVAL WE WOULD ALL BE KIND OF SINGING FROM THE ROOF TOPS. BUT SOMEHOW STILL PUBLISHING AND PUSHING THIS AND WE SHALL ALL CHAMPION THIS EVERYWHERE. IMAGINE IF THIS IS IN OUR HEALTHCARE SETTINGS, IMAGINE HOW IMPORTANT THIS IS IN THE TROPICS IN RESOURCE POOR PLACES WHERE YOU HAVE ONE BITE OF THE CHERRY, YOU HAVEN'T GOT LATE RESCUE THERAPY, YOU HAVEN'T GOT LATE RESCUE STRATEGIES UP YOUR SLEEVE, YOU HAVE ONE CHANCE TO RESPOND AND IF YOU GET THAT LATE THIS IS WHAT YOU END UP WITH. IT'S THE SAME VERSION OF THAT CURVE, IT'S A PYRAMID. BUT YOU GET A LOT OF PATIENTS NEEDING INTENSIVE CARE OR I CALL IT EXPENSIVE CARE, THE NICKNAME, STILL WITH HIGH MORTALITY. SO GOING BACK TO THOSE POOR PEOPLE IN RESOURCE-POOR PLACES THEY'RE SPENDING DOLLARS, GETTING RELATIVELY INTENSIVE CARE OR SOPHISTICATED CARE, THEY'RE GETTING INTRAVENOUS THIRD GENERATION SO ON, GETTING A HEAP OF ANTI-MICROBIALS IV, BUT IT'S TOO LATE, IT'S VERY EXPENSIVE AND A POOR OUTCOME. THAT LED ME TO CHANGE PART OF MY JOB. I WAS A SEEN YOUR LECTURER IN THE UNIVERSITY AND I HAVE STOPPED -- I'M GOING OUT NOW TO TRY TO CHAMPION THIS. AS NEGLECTED PROCESS IT'S NO ONE'S JOB TO. I FOUND THAT THE KEY FEATURES AMONG THEM ARE THE -- SEEMS TO BE SO FAR, 7 PILLARS, THEY'RE ALL INTERCONNECTED. THERE'S NOT ENOUGH ATTENTION TO SELF-CARE, TO HELP PEOPLE USE APPROPRIATE DRUGS AND SERVICES AT HOME. SIMPLE EARLY PREVENTIVE THERAPIES TO REDUCE REQUIREMENTS FOR LATER CARE. EARLIER DIAGNOSIS IN EVERY SHAPE OR FORM, PHYSIOLOGICAL MONITORING, THE CHARTS COUNTING RESPIRATORY RATE, HAVING A CLOCK ON THE WALL, RESPONSIBLE PRESCRIEK AS WELL AS INFECTION PREVENTION CONTROL. OTHERWISE NEVER BEAT HEALTHCARE ASSOCIATED INFECTIONS ESPECIALLY WITH ANTI-MICROBIAL RESISTANCE COMING IN. GOOD RECORDKEEPING. RECORD KEEPING IN A WAY THAT SUPPORTS COMMUNICATION SO TRANSFER PATIENTS AND WEEF GOT T ACCOUNTABILITY THAT SAYS HEY, THIS PATIENT HAD A RAISED PRESS PRATORY RATE AND A REALLY FAST HEART RATE AND LOW BLOOD PRESSURE AND YOU DID NOTHING, YOU DIDN'T REFER THEM ON? AT THE CENTER OF ALL IS ACCESS TO INFORMATION. AND TREATMENT AL L GOR RHYTHMS. SO WE KNOW WHEN WE REFER SOMEONE, THEY KNOW WHEN TO GO TO NEXT STEPS. IT SUPPORTS, EDUCATES AND EMPOWERS AND RAISES EXPECTATION IN HEALTHCARE. WHICH KIND OF GET US BACK TO LIZ'S QUESTION WHAT SHOULD WE ASK FOR. WE HAVE TO FIRST OF ALL EXPECT EVERYONE TO WORK AS A TEAM. HEALTHCARE IS FULL OF REALLY GREAT FOOTBALLERS, PRIMA DONNAS NGOS IN THIS HUMANITARIAN WORLD, WE'RE ACTING INDEPENDENTLY WITH GREAT SKILLS BUTITE NOT A TEAM. WE DON'T HAVE A STRATEGY SAYING WE HAVE THIS CHART OR CLOCK ON THE WALL, WITH WE ALL HAVE PULSE OCCIMETRY AND WE DONE TRANSSEND THIS BOUNDARIES BECAUSE THE NEGLECTED PROCESSES OFTEN CROSS BETWEEN COMMUNITY EDUCATION, PRIMARY CARE AND SECONDARY CARE. WE HAVE TO BE LIKE THIS FOOTBALLER NOT LINKED STANDING ON THE GROUND. SORT OF CROSS BOUNDARIES. SO TO FINISH UP THE LAST TWO SLIDES, MARGARET CHIN COMMENTED ON HEALTH SYSTEMS FINANCING AT 20 TO 30% OF ALL HEALTHCARE SPENDING IS CURRENTLY WASTED THROUGH INEFFICIENCY. THE ASTERISKS ARE TYPICAL WHO STYLE TO SAY THIS IS A CONSERVATIVE ESTIMATE, BELIEVE ME, WHO IS CONSERVATIVE WHEN THEY MAKE ESTIMATES LIKE THAT. IT'S A HORRIFIC FIGURE. AND WHAT IS THE PROBLEM PER CAPITA ON HEALTHCARE? IN SOME COUNTRIES MORE THAN 40% OF PEOPLE WHEN THEY DO THAT ARE TIPPED TO FINANCIAL CATASTROPHE. CERTAINLY ACROSS THE BOARD 2% PER YEAR. IF YOU TIP A FAMILY INTO FINANCIAL CATASTROPHE, IT'S NOT JUST BAD FOR THEIR HEALTH, IT'S BAD FOR SOCIAL COHESION AND DOESN'T ALLOW A COUNTRY TO PROSPER. HOUSEHOLDS WITH A DISABLED MEMBER, THOSE WITH CHILDREN OR ELDERLY MEMBERS ARE MORE LIKELY TO EXPERIENCE CATASTROPHIC HEALTH EXPENDITURES SO THAT'S WHY I THINK THE NEGLECTED PROCESS IS IS BIGGEST BANG FOR THE BUCK IF WE CAN GET OUR ACT TOGETHER AND JOIN UP. I'M PLEASED TO SEE THE ECHOS OF THAT COORDINATION BEING ECHOED BY PREVIOUS SPEAKERS AND I I'M SURE SUBSEQUENT ONES. THANK YOU VERY MUCH. [APPLAUSE] >> I THINK WE HAVE TIME FOR ONE OR TWO QUESTIONS BECAUSE WE WANT TO STAY ON SCHEDULE WITH THE BREAK. ARE THERE ANY QUESTIONS? CAN I ASK ONE? >> YEAH. >> ACTUALLY THERE ARE A COUPLE OF -- I THINK THIS IS PROBABLY A SECOND OR THIRD TIME I HER YOU TALK. THERE'S ALWAYS SOMETHING THAT I PICK UP NEW. THERE'S COUPLE OF THINGS THAT YOU POINTED OUT, THIS IS MORE A COMMENT THAN A TALK BUT THE RECORDKEEPING. AND DISABILITY TO CAPTURE JUST THIS BASIC INFORMATION THAT'S NOT BEING CAPTURED FROM ANY OF THESE DISEASES. YOU HAVE BROUGHT UP A GREAT POINT, OFTENTIMES IT MAYBE TOO CUMBERSOME, IT IS POSSIBLE TO COLLECT THIS DATA AND TO COLLECT IT EFFICIENTLY IF THE STRATEGIES ARE IMPLEMENTED AS WELL AS ONE OF THE OTHER THINGS THAT PAUL POINTED OUT IS OFTENTIMES RECORDS ARE DESTROYED. EDUCATION AND THINGS YOU'RE IMPLEMENTING CERTAINLY BY DOING THIS AND GETTING THE BASIC DATA COULD HELP WITH THESE ASSESSMENTS OF ANIMAL MODELS. THAT'S MY FIRST COMMENT, THANK YOU FOR BRINGING THAT UP. YOU BROUGHT UP SOMETHING ELSE INTERESTING WHICH IS THE FLUID AS HE AS WELL. THE POTENTIAL FOR OVERAGGRESSIVE FLUID MANAGEMENT IS SOMETHING THE WORKING GROUP AT WHO STRUGGLED WITH WITH. I KNOW MARK PETER IS HERE AND HE MAYBE TALKING ABOUT THE WORK HE DID WITH JAMES WALLER AND ANNA (INDISCERNIBLE) AND JOSH JOHNSON ABOUT DOING FLUID MANAGEMENT AND BIOCONTAINMENT FOR THE NON-HUMAN PRIMATES AND THE OUTCOPS. AND SOME OF THE EDEMA THAT THEY ENCOUNTERED WHEN THEY DID THAT. BUT IT'S THE ORS AND THE THE ORAL REHYDRATION IS INTERESTING. DO YOU HAVE ANY ADVICE OF FOLKS DOING ANIMAL MODEL DEVELOPMENT FACED WITH A CONUNDRUM HOW TO MANAGE THE FLUID BALANCE AND HOW THEY IMPLEMENT FLUID BALANCE WHERE THEY HAVE POTENTIAL FOR OVERAGGRESSIVE FLUID MANAGEMENT CAN LEAD TO SOME OF THESE SAME THINGS IN THE NON-HUMAN PRIMATE MODELS. ANY ADVICE YOU MIGHT HAVE PROBABLY WOULD BE WELCOME. >> I THINK RESEARCH HAS GOT TO HELP WHAT'S GOING TO HAPPEN IN THE FIELD. THE REDWRAIL IS FLUIDS ARE GIVEN AS BONUSES. MAYBE THAT'S PART OF THE PROBLEM THAT IT'S IN OUR ALGORITHMS SO BE WARY, IF YOU'RE GOING THE GIVE FLUIDS GIVE THEM IN THE BOLUSES THAT WE WILL DO DO IN THE FIELD. REMEMBER THAT IN THE TROPICS PEOPLE USE IV FLUIDS VERY GENEROUSLY AND USUALLY TO GOOD EFFECT. AND PEOPLE FEEL BETTER AS WELL. BUT I THINK WE HAVE TO TACKLE L THIS BECAUSE ORAL FLUIDS ARE NOT BEING GIVEN. IT DOES MATTER, PEOPLE ARE GOING TO HAVE A CHALLENGING DISEASE, THEN AT LEAST ENTER THE SEVERE PHASE OF THAT DISEASE RELATIVELY WELL HYDRATED. I JUST CAN'T GET IT OUT OF -- ACROSS ENOUGH AND TO REITERATE THAT YOU CAN HAVE GUIDELINES THAT SAY SUPPORT USE OF IV FLUIDS BUT THERE IS A BIGGER GUIDELINE THAT SAYS THAT THOU SHALT USE THE ORAL ROUTE WHILE AVAILABLE. THAT ISN'T NECESSARILY INVASIVE CARE AND YOU CANNOT JUGGLE THE POTASSIUM IN THESE ENVIRONMENTS. SO THE RESEARCH HAS GOT TO HAVE EXTERNAL VALIDITY TO THESE ENVIRONMENTS. EITHER WAY, GIVE FLUIDS AND SEE WHAT HAPPENS INTRAVENOUSLY OR TRY ORAL FLUIDS. GASTRIC. INGLY THINK (INAUDIBLE) ANIMAL MODELS, IT'S HELPFUL FOR THEM BECAUSE THEY'RE FACED WITH THIS ISSUE WITH THE ANIMAL CARE AND USE AS WELL AS MANAGEMENT AND WHEN TO MOVE FROM ORAL VERSUS SUB Q OR CATHETERIZE ANIMALS WITH INTRAVENOUS FLUID SO IT'S VERY IMPORTANT FOR THEM AND THE REGULATORS TO HEAR THIS TYPE OF INFORMATION. SO THANK YOU VERY MUCH FOR YOUR TALK. >> THANK YOU. >> I WANT TO THANK ALL THE SPEAKERS FROM THE FIRST SESSION. I THINK THIS WAS A WONDERFUL SESSION. WE WILL GO ON BREAK AND WHETHER HE START UP AGAIN AT 10:15 AS IN THE PROGRAM. THAT'S A SHORT BREAK >> OKAY. WE'RE GOING TO START THE SECOND SESSION ENTITLED RECENT REGULATORY GUIDANCE, THE LATEST FROM FDA AND IMPLICATIONS FOR ANIMAL MODELS. MY NAME IS ED NEWSOM FROM D ISHAD AND TRACY MCGILL IS CO-CHAIRING THE SESSION. OUR FIRST SPEAKER IS DR. ROSE MARY ROBERTS. SHE'S DIRECTOR OF THE OFFICE OF COUNTER-TERRORISM AND EMERGENCY COORDINATION CDER, FDA AND TITLE OF HER TALK IS PRODUCT DEVELOPMENT UNDER THE ANIMAL RULE. >> THANKS, ED. GOOD MORNING. I WANT TO THANK THE ORGANIZERS OF THIS FOR PROVIDING ME THE OPPORTUNITY TO TALK TO YOU ABOUT THE ANIMAL ROLE. SEVERAL REFER TO MY TALK IS THAT'S GOING TO BE IT, THE BUCK STOPS WITH YOU. I CAN TELL YOU THOUGH I HAVE GIVEN A TALK ON ANIMAL ROLE SEVERAL TIMES OVER THE LAST FEW YEARS I LEARN SOMETHING EVERY TIME I COME TO A MEETING ABOUT WAYS WE CAN THINK ABOUT IMPLEMENTING THE ANIMAL ROLE. SO LET'S GET GOING. FIRST OF ALL, THIS IS -- REPRESENTS MY THOUGHTS AND NOT NECESSARILY THE AGENCY POLICY. I'M GOING TO TALK ABOUT WHAT IS THE ANIMAL ROLE. THE CHALLENGES TO THE ANIMAL ROLE. GOOD LABORATORY PRACTICE. EARLY COMMUNICATIONS WITH THE AGENCY AND THEN A SUMMARY. SO THE ANIMAL RULE. WHAT IS IT? IT IS A REGULATORY MECHANISM TO APRO-DRUGS AND LICENSED BIOLOGICS WHEN HUMAN STUDIES ARE NOT ETHICAL OR FEASIBLE. THAT IS HUMAN EFFICACY STUDIES. WHERE IT IS NOT, IT'S NOT A SIMPLIFIED PATHWAY. I RECALL IN THE EARLY YEARS, 2003, 2004 TALKING TO AUDIENCES ABOUT THIS, AND THEY WERE SURPRISED WHEN I SAID THIS IS NOT A SIMPLIFIED OR EXPEDITED ROUTE. I DON'T THINK I HAVE TO CONVINCE ANY OF YOU IN THIS AUDIENCE NOW THAT IT CAN BE EVEN MORE CHALLENGING THAN IF YOU COULD DO HUMAN STUDIES. THE ANIMAL RULE, THE SCOPE, IS FOR PRODUCTS THAT ARE TO BE DEVELOPED TO PREVENT SERIOUS OR LIFE-THREATENING CONDITIONS CAUSED BY EXPOSURE TO CERTAIN TOXIC SUBSTANCES. IT'S MORE THAN JUST THE CHEMICAL BIOLOGIC RADIO LOGIC OR NUCLEAR THREATS WE TYPICALLY THINK OF. IT CAN BE USED FOR ANY KIND OF CONDITION WHERE IT IS NOT ETHICAL L TO CHALLENGE A PATIENT OR -- AND YOU CAN'T DO FIELD STUDIES BECAUSE OF NUMBERS, RARITY, ET CETERA. THOSE COULD BE USED FOR DEVELOPMENT OF SNAKE VENOM. IT COULD BE USED FOR DEVELOPMENT OF SOME ANTI-TOXIN TO EMINITIS, THE MUSHROOM. HUMAN CHALLENGE STUDIES ARE UNeCAL TO PERFORM, AND FIELD TRIALS TO STUDY EFFECTIVENESS ARE NOT FEASIBLE. THERE'S LOTS OF REASONS THEY'RE NOT FEASIBLE. IT COULD BE THAT THE GEOGRAPHIC LOCATION SUN PREDICTABLE. IT COULD BE THERE'S NOT A CRITICAL INFRASTRUCTURE AND YOU HAVE HEARD ALREADY ABOUT SOME PLACES WHERE THERE IS SOME INFRASTRUCTURE THAT MIGHT BE VAIL TO BELIEVE DO STUDIES BUT THERE ARE AREAS OF WORLD WHERE THERE IS NO CRITICAL INFRASTRUCTURE. SUCH POLITICAL INSTABILITY THAT YOU CAN'T SAFELY HAVE PEOPLE GO THIS AN CONDUCT A STUDY. IT MAYBE THAT WE DON'T HAVE PERMISSION FROM THE APPROPRIATE MINISTRY OF HEALTH. THE OTHER THING TO UNDERSTAND ABOUT THE ABOUT MALL RULE -- ANIMAL RULE, WE CALL THE PEDIATRIC EQUITY VERGE ACT WHICH -- RESEARCH ACT, IF A PRODUCT IS DEVELOPED IN ADULT POPULATION WHERE THAT INDICATION IS APPLICABLE TO THE PEDIATRIC POPULATION, PEDIATRIC STUDIES NEED TO BE DONE. SOMETIMES HELD OFF UNTIL AFTER THE ADULT POPULATION HAS THE PRODUCT DEVELOPED. BUT THE ANIMAL RULE APPLIES THE PEDIATRIC AND ADULT POPULATION. SO WHAT ARE THE REQUIREMENTS? YOU HAVE SEEN THESE REQUIREMENTS AND YOU WILL SEE THEM SEVERAL MORE TIMES. BASICALLY A REASONABLY WELL UNDERSTOOD PATHOPHYSIOLOGIC MECHANISM OR TOXICITY OR THREAT OR SUBSTANCE IN ITS PREVENTION BY THE PRODUCT. WE DON'T HAVE TO GET DOWN TO THE ACTUAL MOLECULES OF MOLECULAR BASIS BECAUSE SOMETIMES WE DONE HAVE THAT INFORMATION. FOR INSTANCE, IF WE THINK ABOUT AN ANTIVIRAL BEING DEVELOPED FOR VIRAL THREATS, IF YOU CAN DEMONSTRATE IT IS INDEED ANTIVIRAL AND WHERE IT BLOCKS IN THAT PATHWAY, THAT MAYBE ALL YOU NEED TO DO. YOU DONE HAVE TO GET DOWN TO IT EXACTLY ET CETERA, ET CETERA. THIS IS A WAY OF SAYING THE AGENCY IS TRYING TO BE REALISTIC IN OUR -- IN THE WAY WE LOOK AT HOW THESE REQUIREMENTS CAN BE SATISFIED. SO WE ARE TRYING TO BE FLEXIBLE WHEN THERE IS LIMITED KNOWLEDGE AND THESE ENTITIES WHERE WE CAN'T GET MORE INFORMATION. IS THAT DEMONSTRATED IN MORE THAN ONE ANIMAL SPECIES EXPECTED TO REACT WITH A RESPONSE PREDICTIVE FOR HUMANSCH THERE'S THE SPECIAL EXCEPTION WITH WELL CHARACTERIZEDDED ABOUT MALL MODEL WHICH I'LL TALK ABOUT LATER BUT I THINK YOU HAVE ALREADY HEARD THAT WHEN WE THINK ABOUT COMPARTMENTALIZATION, IT MAY MEAN YOU HAVE TO STUDY MORE THAN TWO SPECIES. BECAUSE ONE SPECIES IS GOING TO HELP YOU THE TO UNDERSTAND ONE ASPECT, ANOTHER SPECIES MAY HELP YOU TO UNDERSTAND DIFFERENT ASPECTS. THE END POINT, GENERALLY THE ENHANCEMENT OF SURVIVAL OR PREVENTION OF MAJOR MORBIDITY. WE NEED INFORMATION ON PHARMACOKINETICS AND PHARMACODYNAMICS THAT WILL ALLOW US TO SELECT A DOSE FROM THE ANIMAL STUDIES FOR THE HUMAN. IN ADDITION TO THE TENANTS, THERE ARE THREE OTHER REQUIREMENTS THAT SPONSORS PRODUCTS LICENSED OR APROVED UNDER THE AN MA'AM RULE -- ANIMAL RULE MAY HAVE TO APPLY. FIRST, THEY HAVE TO ABIDE BY POST MARKETING STUDIES TO VERIFY THE CLINICAL BENEFIT AND ASSESS SAFETY OF THEIR PRODUCT. THESE PRODUCTS LOOK COMING -- WILL BE COMING AVAILABLE WITHOUT HUMAN EFFICACY DATA. THEREFORE, TIME TO GET IS DURING THE EVENT WHICH IS THE MOST DIFFICULT TIME TO GET IT. YOU HEARD TODAY SIMPLE PROTOCOLS HAVING PROTOCOLS DONE AHEAD. THAT IS WHAT WE ASK SPONSORS TO DO, TO THINK ABOUT WHAT THEY COULD DO, WHAT'S THE MINIMUM INFORMATION WE CAN TRY TO OBTAIN IN THE EVENT. APPROVAL WITH RESTRICTIONS TO ENSURE SAFE USE. THE MORE WE DON'T KNOW ABOUT A PRODUCT THAT GETS APPROVED OR LICENSED UNDER THE ANIMAL RULE BUZZ OF THE NATURE OF THE DISEASE ITSELF, FOR INSTANCE, ORTHO POX VIRUSES. VERYOLA IS ERADICATED. IT'S DIFFICULT TO DO THOSE STUDIES. THE AGENCY RECOGNIZED THIS. SO WE NOW HAVE TWO PRODUCTS MOVING FORWARD AS ANTIVIRALS. THAT ARE GOING TO BE PIVOTAL STUDIES WILL BE USING OTHER ORTHO POX VIRUSES. IN ESSENCE, THERE'S GOING TO BE LESS INFORMATION WE KNOW ABOUT THAT PRODUCT. HOWEVER, SHOULD THERE BE A VARIOLA EVENT, THAT PRODUCT WILL BE AVAILABLE TO BE USED. SO LIKELY MORE RESTRICTIONS ON THE USE OF THAT PRODUCT BECAUSE OF AMOUNT UNKNOWN. PATIENTS WHO RECEIVE THESE PRODUCTS ARE TO KNOW THESE PRODUCTS WERE STUDIED AND THEIR APPROVAL IS BASED UPON ANIMAL STUDIES. SO WHAT'S HAPPENED IN TEN YEARS? IN 2003 (INDISCERNIBLE) BROMIDE WAS APPROVED AS A TREATMENT AGAINST NERVE AGENT. IN 2006 HYDROXY CARBOLONIM WAS APPROVED FOR TREATMENT OF SUSPECTED CYANIDE POISONING. (INDISCERNIBLE) WAS APPROVED FOR TREATMENT OF PLAGUE, INCLUDING PNEUMONIC OR SYSTEMIC PLAGUE AND PROPHYLAXIS FOR PLAGUE IN WOMEN AN CHILDREN, CHILDREN 6 MONTHS OF AGE OR OLDER. WE OWE A DEBT OF GRATITUDE TO OUR COLLEAGUES HERE AT NIAID FOR WORKING TO DEVELOP THE MODELS AND GET THOSE STUDIES FUNDED. AND LOUISE PIT WHO DID THE FIRST NATURAL HISTORY STUDY AND FOLKS AT LOVE LACE AND BATELL WHO ACTUALLY TOOK THOSE -- TOOK THE NATURAL HISTORY STUDIES THAT WAS FIRST DEVELOPED AT USAMARIN IN THE AFRICAN MONKEY AND WITH THE FUNDING OF NIH IT WAS REPEATED AND REPLICATED AT LOVE LACE AND BATTELL. CHALLENGESCH THERE'S SEVERAL GAPS THAT PREVENT SUCCESSFUL MEDICAL COUNTER MEASURE DEVELOPMENT AND APPROVAL. LACK OF ANIMAL MODELS, THE LACK OF NATURAL HISTORY STUDIES IN THE ANIMAL MODELS. THAT IS THE PLACE TO START DEVELOPING AN ANIMAL MODEL. TO DATE,U ANIMAL MODELS WHILE MEDICAL COUNTER MEASURES ARE ALSO IN DEVELOPMENT. IT'S DIFFICULT TO DO BOTH AT THE SAME TIME. BUT IT'S A REFLECTION OF THE FACT THE ANIMAL RULE WAS FINALIZED IN MAY OF 2002 BUT WE DIDN'T HAVE A STACK OF ANIMAL MODELS SITTING ANYWHERE IN THE AGENCY. I HAVEN'T FOUND ANY OTHER AGENCY WITH THAT STACK OF ANIMAL MODELS. SO WHILE WE HAVE BEEN PUSHING TO DEVELOP MEDICAL COUNTER MEASURES, AT THE SAME TIME WE HAVE BEEN WORKING TO DEVELOP APPROPRIATE SUITABLE ANIMAL MODELS. THIS MEANS WE'RE OFTENTIMES CHASING OUR TAILS. THERE IS LIMITED CLINICAL DATA AND HUMAN EXPERIENCE WITH THREAT AGENTS AND HAMPERS OUR DEVELOPMENT OF PREDICTIVE ANIMAL MODELS. WE ALREADY REFERRED TO THE FACT THAT EBOLA IS PASSED BECAUSE OF CLOSE CONTACT, CONTACT WITH THE CONTAMINATED FLUIDS AND YET FROM A WEAPONS PERSPECTIVE, IF IT WAS TO BE USED WHERE A LOT OF PEOPLE COULD BE EXPOSED, IT WILL BE AEROSOLIZED. SO WE LOOK AT DEVELOPMENT OF ANIMAL MODELS IN AEROSOLIZED FASHION. I HAVE O TO AGREE WITH LISA WHO SPOKE BEFORE ME WE KNOW ABOUT EBOLA VIRUS AND NON-PRIMATES THAN WE KNOW HUMANS. THEN THERE ARE LIMITED RESOURCES, FUNDING, LIMITED ANIMALS, AND FACILITIES SUCH AS BSL-4 FACILITIES WHERE THESE ANIMAL RESEARCH STUDIES CAN BE DONE. OTHER CHALLENGES. THE LOOK OF ANIMAL MODELS WE TALK ABOUT, THERE'S ALSO A LACK OF PUBLICLY AVAILABLE ANIMAL MODELS. MANY OF YOU KNOW, YOU HAVE HEARD ALREADY TODAY BOTH -- NIAID USAMERON AND BARTA ARE ALL IN THE BUSINESS OF TRYING TO DEVELOP ANIMAL MODELS. AND PART OF THIS REASON FOR THEM DOING THAT IT'S NOT FINANCIALLY SUPPORTIVE OF OR FEASIBLE FOR THE INDIVIDUAL SPONSORS TO DEVELOP ANIMAL MODELS THEMSELVES. AS MANY OF YOU KNOW, YOU DONE HAVE A LOT OF BIG PHARMA PLAYING IN THE ANIMAL MODEL ANIMAL ROLE ARENA. WE ARE BEGINNING TO SEE IN THE LAST YEAR OR SO A GREATER INTEREST BY BIG PHARMA. IF ANYBODY HAS A DEEP POCKET, IT WOULD BE BIG PHARMA. THOUGH THEY DON'T HAVE POCKETS THAT DEEP. IF THEY DID THEY DEVELOP THAT ANIMAL MODEL, IT WOULD BE THEIR ANIMAL MODEL. SO THE GOVERNMENT ASSUMED PROMINENT ROLE IN DEVELOPING ANIMAL MODELS. SO THAT THESE MODELS CAN BE MADE PUBLICLY AVAILABLE FOR ALL SPONSORS TO USE. IN ADDITION, WE -- LACK OF THESE PUBLICLY AVAILABLE ANIMAL MODEL WHICH IS WE'RE WORKING ON, WE ALSO NEED PRODUCT INDEPENDENT MODELS SO WHAT'S A SOLUTION OR POTENTIAL SOLUTION? THE ANIMAL MODEL QUALIFICATION PROGRAM. WHICH WE'LL HEAR MORE ABOUT IN THE FOLLOWING TALK BY MY COLLEAGUE JERRY DAVISCH THIS IS A NEW DRUG DEVELOPMENT TOOL TO SUPPORT MEDICAL COUNTER MEASURE PRODUCT DEVELOPMENT. WE LAUNCHED THE PROGRAM IN JUNE OF 2011. YOU HAVE HER FROM HEATHER VARGO WITH THE EBOLA PACKAGE. FROM THE MILITARY, THEY CONTINUE TO DEVELOP THAT ANIMAL MODEL. AND WE HAVE HAD INTEREST IN ALL AREAS, WE HAVE HAD INTEREST IN ANTHRAX, PNEUMONIC PLAGUE FOR ARS. WE HAVE HAD ALSO QUESTIONS FROM PEOPLE WHO WANT TO DEVELOP ANIMAL MODELS AND QUALIFY THEM FOR CHEMICAL RISK. OFFICIALLY WELL CHARACTERIZED. I BET YOU WOULD LIKE TO KNOW WHAT THAT IS. ACCORDING TO THE THE PREIALABLE TO THE FR NOTICE, ICE A MODEL ADEQUATELY EVALUATED FOR RESPONSIVENESS. I HAVE ALWAYS INTERPRETED THAT TO MEN WE HAVE TO HAVE A PRODUCT THAT RAN THROUGH THAT—[ MODEL, GOT LICENSED THEN WE WERE ABLE TO SHOW THAT WAS INDEED PREDICTIVE. AND I'LL TALK ABOUT A MODEL WHERE IT HAS BEEN FELT TO BE WELL CHARACTERIZED BY THE AGENCY. ODDS ARE YOU'RE GOING TO NEED MORE THAN ONE ANIMAL MODEL IN MORE THAN ONE SPECIES. IF YOU HAVE PRIOR HUMAN EXPERIENCE WITH THE PRODUCT THAT CAN PROVIDE SUPPORTIVE EVIDENCE AND MAY ALLOW YOU TO GET AWAY WITH A SINGLE ANIMAL MODEL IN A SINGLE SPECIES. THE MOALTD NEEDS -- THE MODEL NEEDS TO BE REPRODUCIBLE IDEALLY REPRODUCIBLE IN DIFFERENT CONTRACT LENS. THAT ALWAYS ISN'T FEASIBLE. BUT WITH THE AFRICAN GREEN MONKEY MODEL FOR PNEUMONIC PLAGUE IT WAS INITIALLY DEVELOPED AT USAMRON AND FUNDING THROUGH NIAID GOT MOVED TO LOSS LACE -- LOVE LACE AND BATEL. SO THAT'S WHAT I MEAN BY THE MODEL BEING REPRODUCIBLE. NUMBER OF ANIMAL SPECIES TO SUPPORT APPROVAL. MANY. WHAT SPECIES. DO WE ALWAYS HAVE TO HAVE A NON-HUMAN PRIMATE SPECIES WELL, WE DON'T ALL HAVE TO HAVE A NON-HUMAN PRIMATE SPECIES. TWO EXAMPLES TO DATE. WE HAVE HYDROXY CARBOLOMIN APPROVED IN 2006 AND THAT WAS A DOG SPECIES. THAT WAS THE SINGLE ANIMAL MODEL THAT WAS RECOGNIZED BY THE DIVISION BEING ADEQUATE TO ASSESS CYANIDE POISONING. AND THEN THEY HAD SOME HUMAN EFFICACY DATA FROM PEOPLE WHO HAD BEEN EXPOSED TO SMOKE INHALATION OR OTHER EXPOSURES TO CYANIDE THAT SUPPORTED THAT. BASED FON ADVISORY COMMITTEE IN DECEMBER OF 2011 WHERE SMALLPOX WAS DISCUSSED, THE PRODUCT BEING DEVELOPED BY CHIMERIC CMX 001, CANNOT BE STUDIED IN NON-HUMAN PRIMATE BECAUSE IT HANDLES THAT VERY DIFFERENTLY SO WE WOULDN'T BE ABLE TO EXTRAPOLATE INFORMATION FROM THAT MODEL. THEREFORE, THEY ARE GOING TO BE USING RABBITS AN MICE IN ORDER TO STUDY THEIR PRODUCT. IS A SINGLE SPECIES ADEQUATE T? IT MAY BE IF YOU HAVE A WELL CHARACTERIZED MODEL THAT'S PREDICTIVE. IF YOU HAVE SUPPORTIVE HUMAN DATA THE LIKELIHOOD IS GREATER. SO YOUR SPECIES SELECTION, EXPOSURE IN ANIMAL MODEL PROVIDES A SIMILAR PATHOGENESIS, PATHOPHYSIOLOGY AND OUTCOMES. AS COMPARED TO HUMAN DISEASE OR CONDITION. ANIMAL SPECIES SHOULD BE SUSCEPTIBLE TO THE THREAT AGENT. THE THREAT AGENT AND THE CHALLENGE AGENT SHOULD BE THE SAME. IF THEY'RE NOT, JUSTIFY WHY YOU CAN'T USE THE SAME CHALLENGE AGENT THEY IS A THREAT AGENT FOR THE HUMAN. ACCEPTABLE THRESHOLD IN THE ANIMAL DIFFERS GREATLY FROM HUMAN T SUITABILITY OF ANIMAL SPECIES SELECTED MAYBE QUESTIONED. FOR THOSE WHO HAD THE OPPORTUNITY TO ATTEND THE DECEMBER 2011 AC ON ORTHO POX VIRUSES AND SMALLPOX, WE GOT TO HEAR THE VARIOLA MODELS, THE IV INFUSION, 10 TO THE 8, 10 TO THE 9TH AND WHAT HAPPENS TO THOSE ANIMALS. WHAT I LIKED BEST WAS A COMMENT THAT CAME FROM ONE OF THE ADVISORY COMMITTEE MEMBERS WHO SAID IT'S LIKE WE'RE TRYING TO PUT A SQUARE PEG IN A ROUND HOLE. WE HAD TO PUT SO MUCH VIRUS INTO ANIMALS BECAUSE THE HIEWCH IS THE ONLY NATURAL HOST FOR VARIOLA. ONE HAS TO QUESTION HOW WELL DOES THAT MIMIC THE HUMAN. WITH RESPECT TO THE SPECIES, IF YOU DEVIATE FROM THE -- YOU NEED TO NOTE AND JUSTIFY ANY DEVIATION. AND YOU NEED TO DISCUSS THIS WITH THE AGENCY BEFORE YOU START YOUR STUDY. WE DO BELIEVE IN TRYING TO REDUCE THE NUMBER OF ANIMALS THAT NEED TO BE USED IN ORDER TO BE ABLE TO LICENSE AND APPROVE PRODUCTS UNDER THE ANIMAL RULE. IF YOU INITIATE STUDIES THAT DON'T MEET THE OBJECTIVES DON'T HAVE INFORMATION THAT WE NEED TO MOVE FORWARD TO LICENSURE, YOU MAY HAVE TO REPEAT THAT STUDY BECAUSE YOU DIDN'T COME IN AND DISCUSS IT WITH THE AGENCY. ANOTHER CHALLENGE THAT YOU -- TWO MAIN END POINTS AND WE FOLLOW THE ANIMAL WELFARE POLICY STATEMENT NUMBER 12 WHERE WE CONSIDER ALTERNATIVES TO PROCEDURES THAT MAY CAUSE MORE THAN MOMENT TEAR OR SLIDE PAIN OR DISSTRETION TO THE ANIMALS. SO WE LOOK TO USE HUMANE END POINTS. THE ANIMAL RULE SAYS YOU HAVE GOT TO USE EITHER INCREASE IN SURVIVAL OR PREVENTION OF MAJOR MORBIDITY. FOR THESE STUDIES IT MAYBE NECESSARY THAT WE HAVE MORE FREQUENT OBSERVATION THAN IS TYPICAL IN ANIMAL RESEARCH STUDIES TO DATE. I SAID AT THE AEROBIOLOGY MEETING A COUPLE OF SUMMERS AGO, WE WOULD LIKE TO SEE 24/7 ONERVATION LIKE WE HAVE IN INTENSIVE CARE UNITS BECAUSE THESE STUDIES, ADEQUATE WELL CONTROLLED STUDIES REPLACE THE HUMAN STUDIES. I GOT QUITE A LAUGH FROM THE AUDIENCE, YES. SURE, 24/7 COVERAGE. IT IS SOMETHING WE NEED TO DISCUSS. WE DO NEED TO HAVE MORE FREQUENT THAN TWICE A DAY, TWICE A DAY MAY MEAN 7 IN THE MORNING AN 5 AT NIGHT WHEN THE LAST PERSON LEAVES. WHY DO WE NEED THOSE? IF YOUR ANIMAL DIES IN THE MIDDLE OF THE NIGHT AND YOU FIND THEM THE NEXT MORNING THEN THE DATA WE CAN GET FROM THAT ANIMAL IS PROBABLY PRETTY USELESS. SO MANY OF THESE ENTITIES WE DO HAVE AN IDEA WHEN THE ANIMAL GOES INTO LAST STAGES BEFORE THEY DIE. WE ASK IF YOU CAN AT LEAST TRY TO INCREASE THE FREQUENCY ARM THE TIME WHERE YOU SUSPECT DEATH TO BE OCCURRING. ANIMALSK PEERNSING SEVERE CHRONIC PAIN OR DISTRESS SHOULD BE PAINLESSLY EUTHANIZED. SO WE TALK EUTHANASIA CRITERIA AND USE OF HUMANE END POINTS. EUTHANASIA CRITERIA AND HUMANE END POINTS AND MORTALITY AS AN END POINT, FEET UP FEET DOWN SOUNDS OBJECTIVE. BUT THE REALITY IS BECAUSE WE DO FOLLOW THE ANIMAL WELFARE ACT, IS THAT END POINT FOR THE ANIMAL RULE HAPPENS TO BE WHAT EUTHANASIA CRITERIA ARE DEFINING AS THE END POINT. SO IT MAKES IT DIFFICULT. WE CERTAINLY WANT THE EUTHANASIA CRITERIA TO BE DEFINED PROSPECT ACTIVELY IN THE STUDY PROTOCOL. SUBMITTED TO THE AGENCY SO WE HAVE THE AT NO TIME TO LOOK AT THOSE CRITERIA AND COMMENT BEFORE THE STUDIES BEGIN. AND THESE CRITERIA ARE GOING TO BE BASED UPON THE ABILITY TO PREDICT DEATH IN THE ABSENCE OF TREATMENT. IF YOU LET THAT ANIMAL GO ON, THEY WOULD DIE. AND THE GREATER WE CAN ACTUALLY SELECT THESE CRITERIA AND HAVE THEM PREDICTIVE OF DEATH, THE BETTER OFF WE WILL BE. THE END POINTS VARY AMONG CHALLENGE AGENTS SO THEY DIFFER FOR DIFFERENT INCASES SUCH AS PRE-EXPOSURE PROF LACK AT THIS VERSUS TREATMENT AND -- PROPHYLAXIS VERSUS TREATMENT AND THE IAKUK HAVE ACTIVE ROLES IN IDENTIFYING END POINTS. THE ADVANTAGES OF DEFINED EUTHANASIA CRITERIA, ELIMINATED OR SIGNIFICANTLY REDUCED AND THE RESEARCH EFFORTS BENEFIT BECAUSE EXPERIMENTAL GOALS ARE MET MORE CONSISTENTLY. THE DATA THAT NEEDS TO BE TAKEN AT TIME OF DEATH, IF EUTHANIZED APPROPRIATELY, CAN BE OBTAINED AT THAT POINT. THE LABORATORY -- GOOD LABORATORY PRACTICE, WE ENCOURAGE GOOD LABORATORY PRACTICES BE USEDDED. THE GOP REGULATIONS WERE ACTUALLY DEVELOPED TO ENSURE QUALITY AND INTEGRITY OF THE NON-CLINICAL SAFETY DATA OR THE TOXICOLOGY STUDIES. THEY ARE NOT MANDATE FORD ANIMAL RULE STUDIES. HOWEVER WE DO ASK YOU USE PRINCIPLES SO THERE'S INTEGRITY AN QUALITY TO THE DATA. ESPECIALLY FOR EFFICACY, THE PHARMACOKINETIC AN NATURAL HISTORY STUDIES, AND BE FOREWARNED, THESE ARE STUDIES THAT ARE SUBJECT TO INSPECTION AND AUDIT BY THE AGENCY TO ENSURE QUALITY AND INTEGRITY OF THE DATA. ANY DEVIATION NEEDS TO BE DISCUSSED PREFERABLY PROSPECTIVELY WITH THE REVIEW DIVISION TO SEW HOW YOU MIGHT DO A WORK AROUND. IF THEY'RE ENCOUNTERED AT THE TIME THEY NEED TO BE LISTED AND THERE NEEDS TO BE ASSESSMENT HOW (INAUDIBLE) RESULTS. PLEASE COMMUNICATE WITH US EARLY. WE CAN TALK TO YOU ABOUT THINGS DETERMINING RATHER THE ANIMAL RULE IS THE APPROPRIATE PATHWAY, SELECTION OF YOUR ANIMAL MODEL. IF WE AGREE WITH YOU THE ANIMAL MODEL FOR WELL CONTROLLED STUDIES THEY QUALIFY FOR SPECIAL ASSESSMENT. EXTRAM LATING THE DOSE IN AN -- EXTRAPOLATING ANIMALS TO HUMANS AN SIZE OF HUMAN SAFETY DATABASE. SAFETY HAS TO BE DONE IN HUMANS. IN SUMMARY THE ANIMAL RULE APPLIES TO PEDIATRICS AS WELL AS ADULTS. CHALLENGES ARE MANY. FDA ENCOURAGES CONFORMANCE WITH THE GOP REGULATIONS SO THAT WE CAN HAVE RELIABLE QUALITY DATA IN WHICH THERE'S INTEGRITY. MAINTAIN COMMUNICATIONS WITH THE FDA, THE DRAFT ANIMAL RULE GUIDANCE IS BEING REVISED TO ADDRESS THE ISSUES THAT ARE DISCUSSED. I KNOW YOU HAVE BEEN WAITING FOR IT. IT IS COMING. IT IS EXPANDED, A LOT, FROM WHAT YOU SAW IN 2009. AND IT IS AN EXPANSION AS WE LEARN EVERY DAY AS WE COME TO MEETINGS LIKE THIS, AS WE REVIEW PROTOCOLS, WHAT NEEDS TO BE DONE AND WE WERE TRYING TO INCORPORATE THIS LAST MINUTE INFORMATION. HERE IS A COUPLE OF RESOURCES, AND THEN FINALLY THIS IS MY CONTACT INFORMATION. THANK YOU VERY MUCH FOR YOUR ATTENTION. >> QUESTIONS. >> I HAVE A QUESTION. IF YOU CAN COMMENT IN THE SETTING OF EXPOSURE, WHETHER CANCER PATIENTS RECEIVE TOTAL BODY RADIATION, THE DATA CAN BE USED TO SUPPLEMENT EFFICACY DATA OR WHETHER THE DATA IN HUMAN TOTAL BODY RADIATION CANCER PATIENTS CAN BE USED AS SAFETY DATA. >> I DIDN'T CATCH, DO YOU WANT ME TO REPEAT? IT >> THIS IS TO RADIATION COUNTER MEASURE DEVELOPMENT. THERE'S ONE ANIMAL MODEL FOR EXAMPLE, CAN YOU USE HUMAN, THAT'S IN THE CANCER PATIENTS RECEIVE TOTAL BODY RADIATION AND USE THAT DATA TO SUPPLEMENT EFFICACY DATA TO THE ANIMAL EFFICACY DATA IF YOU ONLY HAVE ONE MODEL. THE SECOND QUESTION IS, IN THE SAME CONTEXT, BECAUSE YOU CAN'T HAVE HEALTHY ADULT OBTAIN SAFETY DATA AFTER TOTAL BODY RADIATION, CAN YOU USE CANCER PATIENTS AFTER TOTAL BODY RADIATION SAFETY DATA AS THE HUMAN SAFETY DATA. >> IF I UNDERSTAND YOU CORRECTLY, FIRST QUESTION IS COULD YOU USE EFFICACY DATA FROM PATIENT WHOSE HAVE AN UNDERLYING MALIGNANCY AND GET TOTAL BODY RADIATION AS EFFICACY. I CAN TELL YOU THAT IS A DISCUSSION THAT IS ONGOING. PART OF THE PROBLEM IS THAT AS YOU WELL KNOW, RAIDIATION, ACUTE RADIATION SIN DROAM CAUSES HUGE IMPACT ON IMMUNE SYSTEM. AND CYTOKINE RESPONSE. THE DIFFICULTY IN USING A CANCER PATIENT WITH TOTAL BODY ERADIATION IS THAT YOU'RE DEALING WITH A PERSON WHOSE IMMUNE SYSTEM IS NOT APPROPRIATE AND IS DEPRESSED. SO ALTHOUGH WE CONTINUE TO HAVE PEOPLE ASK US ABOUT THAT AND WE CONTINUE TO CONSIDER IT, WE STILL ARE VERY CONCERNEDDED THAT THAT USING THAT POPULATION FOR ADVOCACY IS NOT GOING TO BE PREDICTIVE OF THE POPULATION THAT ACTUALLY GETS EXPOSED TO A RADIATION EVENT. WITH RESPECT TO SAFETY, WE HAVE TAKEN THE SAME APROACH IN THAT, AGAIN LOOK AT GETTING THE SAFETY FROM THE PATIENT POPULATION, PATIENTS WITH CANCER IS CON FLISKTED BECAUSE OF UNDERLYING KAREN. THE OTHER THING IS SAFETY ASSESSMENT SCALE, ADVERSE REACTION SCALES THAT ARE USED IN THE CANCER PATIENT ALLOW LOT MORE SERIOUS REACTIONS TO OCCUR. BECAUSE OF POTENTIAL BENEFIT THE PATIENTS MAY RECEIVE FOR THEIR UNS LYING DISEASE. -- UNDERLYING DISEASE. SO WE ARE ASKING AT THE PRESENT TIME THE SAFETY DATA BE OBTAINED IN HEALTHY VOLUNTEERS. HOWEVER, WE HAVE SOME CASES WHERE THAT IS A SIGNIFICANT CHALLENGE BECAUSE THE HUMAN -- THE HEALTHY VOLUNTEER DOESN'T HAVE THE CYTOKINE RESPONSE GOING ON THAT THE PATIENT THAT'S BEEN EXPOSED TO A RED NUKE THREAT HAS GOING ON SO IT'S MAKING IT VERY DIFFICULT TO SURFACE SOME OF THESE STUDIES. SO THERE'S RENEWED TALK ABOUT THE SAFETY POPULATION THAT WE CAN USE. WE'RE LEARNING AN TRYING TO ADJUST AS NEW INFORMATION IS DEVELOPED. THANK YOU. >> THANK YOU. (OFF MIC) >> LET ME SEE IF I CAN LEARN HOW TO WORK THIS STUFF HERE. HI. LET'S TALK QUALIFICATION PROGRAM. I'M GOING TO GIVE IT TO YOU IN OVERVIEW. I WON'T GIVE ALL THE DETAILS BECAUSE WE DONE HAVE ENOUGH TIME. BUT AN OVERVIEW HOW WE LOOK AT QUALIFICATION NOW, WHERE WE'RE AT IN IT AND WHAT WE HOPE TO SEE IN THE FUTURE. THIS IS MY DISCLAIMER WHICH IS THE -- EVERYBODY ELSE, THIS IS MY VIEWS, NOT NECESSARILY THE FDA OR PURDUE UNIVERSITY WHO I REALLY WORK FOR. SO WHAT I WANT TO COVER IS QUALITY -- THE QUALIFICATION PROCESS AS DEFINITION OF ANIMAL MODEL, WHAT'S IT PURPOSES? CHALLENGES IN THE INTERPRETATION OF THE ANIMAL RULE AND WHY IT LED TO QUALIFICATION. MOST OF THAT YOU HAVE ALREADY HEARD. FEATURES ANIMAL MODEL QUALIFICATION PROGRAM. WHAT CAN YOU DO WITH ANIMAL MODEL WHEN YOU HAVE IT. REMAINS AN ISSUE, BOTH A SUM RATION OF WHAT YOU HAVE ALREADY HEARD AND WHAT YOU'RE GOING TO HEAR ELSEWHERE TODAY. BECAUSE IT KEEPS COMING UP OVER AN OVER AGAIN. I'M GIVING YOU THESE ISSUES IN TERMS OF QUALIFICATION, NOT NECESSARILY PRODUCT APPROVAL OR ANYTHING ELSE. SO WHEN I TALK ABOUT AN ANIMAL MODEL IN TERMS OF QUALIFICATION, WHAT AM I LOOKING FOR IS THE SPECIFIC COMPLY BINATION OF AMENABLE SPECIES, A CHALLENGE AGENT AND A ROUTE OF ADMINISTRATION. THAT PRODUCES A DISEASE PROCESS OR PATHOLOGICAL CONDITION THAT IN SOME IMPORTANT ASPECTS CORRESPONDS TO A HUMAN DISEASE OR CONDITION OF INTEREST. THAT'S ALL I'M TRYING TO SAY WHEN I TALK ANIMAL MODEL. THE PURPOSE OF THIS ANIMAL MODEL IS TO PROVIDE ANIMAL SURROGATES FOR HUMAN SUBJECTS AN EFFICACY STUDIES THAT ARE DONE UNDER THE ANIMAL RULE. ROSE MARY MENTIONED THOSE AND SEVERAL OTHER PEOPLE BUT WHAT ARE THE CHALLENGE? WHY NOT GO FOR QUALIFICATION? PART IS THERE'S A LACK OF PUBLICLY AVAILABLE ANIMAL MODELS WE TALKED ABOUT THAT. WELL CHARACTERIZED MODELS, IN QUOTE BECAUSE I'M STILL NOT SURE WHAT A WELL CHARACTERIZED MODEL IS, NOT READILY AVAILABLE. AND IS NOT A LOT OF PRODUCT INDEPENDENT ANIMAL MODEL THAT ARE ON RECORD. THE DRUG DWOBMENT TOOLS CONCEPTS WHICH ARE DRUG DEVELOPMENT RULES -- IF YOU HAD A DRUG DEVELOPMENTMENT TOOL QUALIFIED AND ANALYTICALLY VALID MEASUREMENT YOU CAN RELY ON IT TO HAVE A SPECIFIC USE IN DRUG DEVELOPMENT REGULATORY AND QUALIFY DDTs WOULD BE AVAILABLE. KEY THING TO REMEMBER, STARTING FROM THE BEGINNING OF THE DRUG DEVELOPMENT TOOLS, IT'S RECOGNIZED INTELLECTUAL PROPERTY RIGHTS MAYBE RETAINED THOUGH PUBLICLY AVAILABLE. THE REGULATORY IMPLICATION IS A TWOOPER RELIES ON USE OF DRUG DEVELOPMENT TOOL FOR QUALIFIED PURPOSE DURING DRUG DEVELOPMENT AND FDA WILL ACCEPT IT UNDER THOSE CIRCUMSTANCES. FINALLY, THE DRUG DEVELOPMENT TOOL PROGRAM AND ANIMAL MODEL QUALIFICATION PROGRAM ARE VOLUNTARILY. YOU DON'T HAVE TO DO THAT IT. THERE ARE THREE QUALIFICATION PROGRAMS UNDER THE DRUG DEVELOPMENT UMBRELLA, ONE IS BIOMARKERS, ONE IS CLINICAL OUTCOME ASSESSMENT, AND THEY'RE BOTH SEVERAL YEARS OLDER THAN THE ANIMAL RULES FOR PRODUCT DEVELOPMENT P UNDER THE ANIMAL RULE. WE'RE THE BABY. OF THE BLOCK. WE HAVE ONLY BEEN AROUND A LITTLE OVER TWO YEARS. IT IS A SUPER AND CDER JOINT PROGRAM. SO AT LEAST TWO CENTERS IN THE FDA ARE WORKING TOGETHER IN DEVELOPING THIS QUALIFICATION PROGRAM. WHAT ARE THE GOALS OF THE DRUG DEVELOPMENT PROGRAM? WE WANT TO SUPPORT STAKEHOLDERS WHO ARE COMING UP WITH A DRUG DEVELOPMENT TOOL, PROVIDES ORGANIZED STRUCTURE AND PROCESS TO INTERACT WITH THE FDA IN A CONSISTENT RESPONSIVE MANNER IN DEVELOPING THESE TOOLS. THAT IS ONE OF THE BENEFITS THAT I THINK YOU NEED TO KEEP IN MIND WHEN THINKING QUALIFICATION. YOU DON'T OFTEN GET THE CHANCE TO GO ONE ON ONE WITH THE FDA AND GET ADVICE. FOR THE ANIMAL MODELS AS A VETERINARIAN THIS IS ELECTRONIC I'M INTERESTED IN IT, THE GOAL IS TO REDUCE USE OF RESOURCES AND ANIMALS ABOUT DECREASE DEVELOPMENT TIME FOR MEDICAL COUNTER MEASURES. WHAT IS QUALIFICATION? CONCLUSION WITHIN THE STATED CONTEXT WHICH I'LL COME BACK TO LATER, CONTEXT OF USE IS A NEW TERM, THE RESULTS OF ASSESSMENT WITH A DRUG DEVELOPMENT TOOL MET (INAUDIBLE) STANDARDS AND CAN BE RELY ON TO HAVE A SPECIFIC INTERPRETATIONEN APPLICATION AND DRUG DEVELOPMENT AND REGULATORY DECISION MAKING PROVIDED THAT THERE ARE NO SERIOUS STUDY FALLS, NO DDT OUTSIDE USE, NO CONFLICTING SCIENTIFIC FACTS. THAT HANG IT IS WHOLE GAME F. THE SCIENCE CHANGE, THE QUALIFICATION CHANGES. WHAT IS THE CONTEXT -- THAT'S INTERESTING. I AM SORRY, FOLKS. I CAN'T GET IT TO CHANGE. I SHOULD BE ON THE SLIDE THAT SAY WHAT IS IS CONTEXT OF USE. I HAVE GOT IT HERE. I SEE IT, ANYBODY GOT A CLUE ON WHAT TO DO? I WILL TRY TO GETCH THE SLIDES, SLIDES CATCH UP TO ME. I'M SORRY ABOUT THAT. THE QUALIFIED CONTEXT OF USE DEFINES BOUNDRIES WHICH THE DATA AVAILABLE AT THE TIME OF INITIAL QUALIFICATION JUSTIFIES ITS USE. IS'S A COMPREHENSIVE DESCRIPTION THAT FULLY AND CLEARLY DELINEATES THE LIMBS OF THE FDA'S QUALIFICATION DECISION IN THE TERMS OF MEARN AN PURPOSE OF USE THAT'S THE OVERALL DRUG DEVELOPMENT DEFINITION. OURS IS A LOT SIMPLER. WHEN YOU TALK ANIMAL MODELS WE WANT TO KNOW TWO THINGS DIRECTLY THAT ARE HARD TO FILL. ONE HOW ARE YOU USING THIS MODEL IN DRUG DEVELOPMENT? AND TWO, HOW ARE YOU GOING TO REPLICATE THE MODEL? THAT'S ALL WE'RE ASKING FOR. IF WE TALK ABOUT WE ALREADY KNOW WHAT THE MODEL WILL BE USED FOR, IT WILL BE USED TO SUPPORT STUDIES FOR PRODUCTS BEING DEVELOPED UNDER THE ANIMAL RULE. THE MODEL SHOULD SUPPORT PRODUCT DEVELOPMENT FOR ONE OF THE FOLLOWING INDICATIONS PRE-OR POST EXPOSURE OR FOR TREATMENT. THAT'S HOW YOU'RE GOING TO USE THE MODEL IN DRUG DEVELOPMENT. THE DETAILS NECESSARY TO REPLACATE THIS MODEL ARE A LITTLE MORE COMPLICATED. WE WANT YOU TO BE ABLE TO CHARACTERIZE THE ANIMALS THAT YOU ARE USING IN THE MODEL INCLUDING SPECIES, AGE, GENDER SCREENING ASSAYS, EXCLUSION CRY TIERIA. WE WANT TO GET ANOTHER SOURCE OF ANIMALS THAT LOOK LIKE THIS SOURCE OF ANIMALS AN MORE IMPORTANTLY THE UPONSORS GET ANIMALS THAT LOOK LIKE ONES SUBMITTERS PUT IN TO DO THE DRUG STUDIES IN. YOU HAVE TO CHARACTERIZE AND TELL US HOW YOU PREPARE THE CHALLENGE AGENT. NOT ALL CHALLENGE AGENTS ARE ALIKE. YOU HAVE TO SPECIFY THE CHALLENGE AGENT. YOU HAVE TO GIVE US ALL THE DNA, ALL THINGS NECESSARY TO CHARACTERIZE YOUR PARTICULAR CHALLENGE AGENT WHICH IS DIFFERENT IF YOU'RE CHARACTERIZING RADIATION VERSUS INFECTIOUS DISEASE VERSUS CHEMICAL. IT HAS TO BE SPECIFIC FOR TYPE OF AGENT YOU'RE TALKING ABOUT. WE WANT TO KNOW HOW YOU EXPOSE. SPECIFIC FOR SOME, IN AN IV STICK. IT CAN BE DIFFICULT TO ADEQUATE THRI CHARACTERIZE AN AEROSOL EXPOSURE. ANYBODY WHO HAS DONE IT KNOWS CHARACTERIZATION OF AEROSOLS TAKE AS LOT OF BIT OF INFORMATION YOU HAVE TO TRANSMIT. WE ALSO WANT YOU TO IDENTIFY END POINTS AND TREATMENT TRIGGERS. A MODEL DOESN'T DO ANY GOOD UNLESS IT CAN BE USED IN DRUG DEVELOPMENT, THAT MEANS WE NEED END POINTS IN TREATMENT TRIGGERS. WE WANT ALSO TO PUT IN CONTEXT OF USE, QUALITY CONTROL DATA, THAT IS NECESSARY TO CONFIRM THAT THE MODEL IS PERFORMING. IN OTHER WORDS, AFTER I GET THROUGH WITH A QUALIFIED ANIMAL MODEL, AND A SPONSOR COMES IN AND USES IT HIS CONTROLS OR HIS EFFICACY STUDIES SHOULD FIT IN THE PARAMETERS OF THAT ORIGINAL MODEL. IT SHOULD BE WORKING THE SAME WAY P THE SPONSOR AS IT DID FOR THE SUBMITTER I ALREADY SAID SOME OF THIS BUT IT'S LIMITED TO MOALTS USED IN PRODUCT DEVELOPMENT UNDER THE ANIMAL RULE, IT IS VOLUNTARY, IT IS INTENDED FOR THE DEVELOPMENT OF PRODUCT INDEPENDENT MODELS. THEREFORE WE REQUEST AND THINK THAT THE NATURAL HISTORY MODEL IS THE LOGICAL STARTING POINT. I KNOW SOME PEOPLE DON'T LIKE NATURAL HISTORY MODEL AS THE PIPE AND THEY WANT TO CALL IT EXPOSURE MODELS OR WHATEVER. WE PICK NATURAL HISTORY MODELS BECAUSE IT WORKFORCE DRUGS, IT WORKS FOR RADIATION AN INFECTIOUS AGENTS. WHATEVER YOU WANT TO CALL IT, THAT'S WHAT WE'RE TALKING ABOUT, WHAT HAPPENS WHEN YOU DO THAT. BECAUSE WE COME BACK TO WHAT I SAID WAS DEFINITION OF ANIMAL MODEL. QUALIFICATION IMPLIES IF A PARTICULAR SPECIES OF ANIMALS GIVEN A PARTICULAR THREAT AGENT BY A PARTICULAR ROUTE IS ADEQUATE REPRESENTATION OF THE HUMAN DISEASE OR CONDITION, CAN BE USED FOR DEVELOPMENT OF DRUGS OF BIOLOGICS UNDER THE ANIMAL RULE. WHEN SHOULD YOU DO THIS? IF YOU HAVE ONE PRODUCT OR ONE INDICATION OR ONE THREAT YOU PROBABLY NEED TO GO UNDER QUALIFICATION. IT'S MOST LIKELY BENEFICIAL WHEN YOU HAVE MULTIPLE PRODUCTS YOU'RE DEVELOPING FOR THE SAME IT LOGIC AGENTS. THIS COULD BE SAME INDICATION FOR TREATMENT OF PROPHYLAXIS OR ONE PRODUCT DEVELOPED FOR THE SAME INDICATION. I MENTIONED THIS EARLIER, I HINTED AT IT. ANOTHER REASON TO THINK ABOUT QUALIFICATION IS THAT YOU HAVE THE ADVANTAGE OF PROCESS WITH THE FDA DURING THE CONSULTATION AND ADVICE STAGE. ONE THING I THINK IS MISSING OR SOMETIMES FORGOTTEN WHEN WE TALK QUALIFICATION IS THAT WHEN YOU USE THE MODEL IN DRUG OR PRODUCT DEVELOPMENT YOU HAVE TO PROVE DEMONSTRATE THAT THE MODEL CHOSEN WHETHER QUALIFIED OR NOT WORK WTS YOUR INVESTIGATIONAL PRODUCT. THAT'S THE REASON THAT NON-HUMAN PRIMATES ARE NOT A REAL GOOD MODEL FOR CHIMERICS STUDIES. HERE IS THE OUTLINE OF THE PATHWAYS. WE HAVE A PLANNING PHASE, A CONSULTATION AND ADVICE PHASE, THEN WE REVIEW THE MODEL THEN HOPEFULLY IT GETS TO GREATER EFFICACY AND IS MADE PUBLIC I. LET'S LOOK AT THESE PHASES A LITTLE BIT IN DETAIL SO YOU KNOW WHAT WE EXPECT AT EACH ONE. THE PLANNING PHASE IS INFORMAL DISCUSSION. WITH THE ANIMAL MODEL QUALIFICATION PROGRAM THEME PRIOR TO THE SUBMISSION. IT IS STRONGLY ENCOURAGED THAT YOU DO THAT. WE WILL TALK TO YOU WHETHER YOU HAVE GOT NOTHING MORE THAN A GLEAM IN YOUR EYE OR WHETHER YOU HAVE 50,000 RMS A DAY. EITHER ONE WORKS FOR US. WHAT WE'RE TRYING TO DO THERE IS GUIDEZ YOU ON WHAT WE WANT IN TERMS OF QUALIFICATION PROCESS. AFTER -- AND WE HAVE ABOUT I THINK 8 TO 10 PRODUCTS OR TEN SUBMITTERS RIGHT NOW LOOKING AT DIFFERENT ANIMAL MODELS, NOT THAT MANY SUBMITTERS BUT THAT MANY ANIMAL MODELS, BETWEEN L TO 10 ALL IN INFORMAL DISCUSSION PHASE. THEN AFTER WE REACH THROUGH THAT, WE HAVE ALL COME TO AGREEMENT THIS WOULD BE A GOOD IDEAL, THE SUBMITTER PROVIDES US U WITH A LETTER OF INTENT. NOW, SEVERAL THINGS WE NEED TO TALK ABOUT ON A LETTER OF INTENT. WE HAVE TWO PEOPLE THAT APPLIED -- GIVEN US A LETTER OF INTENT CURRENTLY. ONE IS PAST THAT, ONE WE JUST GOT THE LETTER OF INTENT SO WE HAVE NOT RESPONDED YET. BUT HERE IS THE THING TO THINK ABOUT. EACH MODEL, EACH SPECIES AGENT METHOD OF DELIVERY I TALKED ABOUT WILL BE REVIEWED SEPARATELY. YOU CAN SEND THEM TO US AND -- MORE THAN ONE AT TIME BUT WE'LL REVIEW THEM SEPARATELY. WE'RE GOING TO LOOK AT NATURAL HISTORY MODELS BEFORE WE LOOK AT EFFICACY MODELS. IF NATURAL HISTORY DOESN'T MAKE SENSE THE EFFICACY CAN'T YOU MAY REQUEST QUALIFICATION FOR MORE THAN ONE INDICATION. PRE-EXPOSURE PROPHYLAXIS POST EXPOSURE PROPHYLAXIS AND TREATMENT. BUT YOU HAVE TO PROVIDE DATA THAT SUPPORTS EACH INDICATION. WHEN WE GET THE LOI WE EVALUATE IT AN ANIMAL MODEL QUALIFICATION PROGRAM TEAM WHICH IS WHERE ONE OF OUR APPLICATIONS IS. AND WE PUT TOGETHER AN INTERDISCIPLINARY QUALIFICATION TEAM. IT'S ASSEMBLED WITHIN CEDR AND OTHER COMPONENTS OF FDA AS APPROPRIATE. WE HAVE CDER REPRESENTATIVES ON THE TEAM. THESE ARE SUBJECT MATTER EXPERTS FROM THE REVIEW DIVISIONS EXPECTED TO BE IMPACTED BY MODEL DEVELOPMENT AND QUALIFICATION. IN OTHER WORDS, THEY COOM FROM THE -- COME FROM THE SAME REVIEW DIVISION AS WE EXPECT TO SEE PRODUCT DEVELOPMENT. FINALLY YOU SUBMIT INITIAL BRIEF DOCUMENTS. WHEN THAT COMES IN WE'RE IN CONSULTATION AND ADVICE PHASE. THIS IS ANARY TIFER PROCESS, THAT MEANS THE QRT AND THE MODELK WE TALK, WE TALK A LO. WE ASSESS THE DATA AND HAVE FACE TO FACE MEETINGS. THIS GOES ON UNTIL ALL OF US ARE HAPPY THAT WE HAVE TALKED THE PROBLEM THROUGH AND WE HAVE LOOKED AT THE ANGLES AND ALL GAPS HAVE BEEN FILLED. IT'S A COLLABORATIVE EFFORT TO IDENTIFY THE SCIENTIFIC GAPS, TO DISCOVER ADDITIONAL DATA AND TO DEFINE THAT CONTEXT THAT WE WERE TALKING ABOUT EARLIER. AFTER THAT, SINCE THE REVIEW PHASE, WHEN BOTH SUBMITTER AND FDA THINKS THE DATA SUFFICIENTLY COMPLETE AND ADEQUATE. AT THAT TIME WE WILL WANT A COMPLETE DATA PACKAGE, THAT DATA PACKAGE WILL REQUIRE FINAL STUDY REPORTS, IT WILL ALSO NEED TO HAVE ALL THE PRIMARY DATA AND WE WANT ALL ANIMAL MEDICAL RECORDS. THE QRT WILL THEN REVIEW THAT COMPLETE DATA PACKAGE AND MAKE THE QUALIFICATION RECOMMENDATION. IN CDER THERE WILL BE A REGULATORY BRIEFING WHICH INCLUDES OFFICE DIRECTORS. THE FINAL SIGN OFF IS BY CENTER DIRECTOR. THEN THE SUBMITTER GETS NOTIFICATION OF THE QUALIFICATION RENGS AND THE RECOMMENDATION IS MADE PUBLICLY AVAILABLE AND ANNOUNCED IN THE FEDERAL REGISTER AS A GUIDANCE. WHAT CAN YOU DO WITH YOUR QUALIFIED MODEL? YOU CAN REFERENCE IT IN YOUR IND, ND ARNTION BLA SUBMISSIONS PROVIDE. THERE'S STUDY FLAWS. WHAT ARE POTENTIAL STUDY FLAW? UNVE FIEBL DATA. IMPROPER PERFORMANCE OF ASSAYS. ASSAYS NOT VALIDATED. NEGATIVE CONTROLS. IF YOUR ANIMALS DIDN'T GET THE PRODUCT DON'T FALL WITHIN THE CALL FEWCATION RANGES WE HAVE A PROBLEM WITH THAT DATA. THERE IS NO ATTEMPT TO USE THE DATA OUTSIDE THE QUALITATIVE CONTEXT OF USE. IN OTHER WORDS YOU HAVE TO USE IT FOR QUALIFIED INDICATION. YOU CAN'T SWITCH CHALLENGE AGENTS, YOU HAVE TO USE IT WITH A CHALLENGE AGENT THAT YOU DEFINE. AND ONCE AGAIN, NO NEW CONFOUNDING SCIENTIFIC FACTS THAT WERE NOT KNOWN. QUALIFICATIONS DON'T SOLVE ALL ISSUES INVOLVED WITH THE ANIMAL RULE AND WE'RE NOT ALL THE ANSWERS FOR THE QUALIFICATION PROGRAM. HERE IS REMAINING ISSUES WITH EAR STRUGGLING WITH. INCOMPLETE DATA ON THE PATHOPHYSIOLOGIC MECHANISM IN REGARDS TO HUMAN, THINK WE HEARD THAT TODAY. SUPPORTIVE CARE, WE HEARD THAT TODAY. AND DATA VERIFICATION. LET ME GIVE YOU QUALIFICATION PROGRAMS TAKE ON THESE. WHAT WE LOOK FOR IN QUALIFICATION IS POINT BY POINT COMPARISON IN HUMAN DISEASE CONDITION IN THE MODEL. CRITICAL FEATURES WITH THE DISEASE OR CONDITION ARE NOT ALL GOING TO BE SAME THERE'S NO WAY CRITICAL FEATURE FOR INFECTIOUS DISEASE ARE THE SAME Z CRITICAL FEATURE FOR RADIATION EXPOSURE. WE'RE LOOKING FOR THE IT OWE LOGICAL AGENT, ROUTE OF SUBMISSION, SIGNS AND SYMPTOMS, TIME COURSE, PATHOPHYSIOLOGICAL MECHANISMS, CRITICAL DIAGNOSTIC TESTS AND TYPICAL GROWTH OF MICROSCOPIC LESION AND WE UNDERSTAND YOU MAY NOT HAVE ALL OF THAT. WHAT ARE THE CRITICAL FEATURE OS THIS DISEASE WE CAN AGREE ON. AND YOU NEED TO MEET THOSE FEATURE WHENCE DEVELOPING A MODEL. IT'S ALSO IMPORTANT TO TELL US AND HAVE DISCUSSION WHAT FEATURES DIFFER BETWEEN HUMAN DISEASE AN MODEL. THAT IS MAYBE AS INTERRING OR MAYBE AS IMPORTANT SCIENTIFICALLY. SUPPORTIVE CARE. WHAT IS THOUGHTS ON SUPPORTIVE CARE? IT'S AN IMPROVISED -- IMPRECISE TERM. WE USE THE SAME WORD SUPPORTIVE CARE FOR AT LEAST THREE INTERVENTIONS AND RESEARCH. ONE WE TALK ABOUT ADEQUATE VERTNARY CARE. THAT IS A REQUIREMENT OF ANIMAL WELL CARE ACT, IT DOESN'T CHANGE. THAT'S UP TO THE IAKUK, THE ATTENDING VETERINARIAN AND CONSULTATION WITH FDA ON WHAT IT IS. YOU ALSO HAVE INTERVENTIONS THAT ARE NECESSARY TO ACTUALLY CAUSE THE MODEL TO OCCUR. FOR FOR EXAMPLE YOU TAKE INTO IT A GI MODEL OF ACUTE RADIATION SYNDROME UNLESS YOU DO SOMEBODY TO DEAL WITH THE HEMOTO LOGICAL PROBLEMS. THAT'S PARTIAL SHIELDING, IT COULD BE OTHER MECHANISMS. IT COULD BE BONE HAIR ROW TRANSPLANTATION. FINAL THING, INTERVENTIONS THAT ARE DESIGNED TO MIMIC HUMAN CLINICAL CARE. TELL US WHAT YOUR INTERVENTIONS ARE GOING TO BE, PROVIDE RATIONALES FOR THE PLAN INTERVENTIONS OF THE STUDY PROTOCOLS. THEN WE GO INTO THEIR -- ITERATIVE PHASE TO DECIDE ON WHETHER THOSE ARE REASONABLE OR NOT THAT'S THE STARTING PLACE. DATA VERIFICATION. LIKE ROSE MARY SAID. WE ENCOURAGE PEOPLE TO CONDUCT ANIMAL STUDIES FOR QUALIFICATION IN ACOR ACCORDANCE WITH THE GLP REGULATIONS. THERE MAYBE PROBLEMS WITH THAT SPECIFICALLY DEALING WITH CHALLENGE AGENTS OF BSL-4 CONFINEMENT. SO WHAT E WE REALLY WILL BE INS IS TENT UPON OR STRONGLY ON IS TELL US WHERE YOU DEVIATEED FROM THE GLP REGULATIONS, EXPLAIN WHY AND DISCUSSION OF THE PROBABLE IMPACT OF THOSE DEVIATIONS ON STUDY RESULTS. AND THE CONCLUSIONS THAT WILL BE SUBMITTED FOR REVIEW. THIS IS SOME OF THE RESOURCES, WE HAVE A FEW MORE RESOURCES THERE. AND IF INTERESTED CONTACT ROSE MARY OR CYNTHIA. THANK YOU. QUESTIONS. [APPLAUSE] >> JERRY, YOU MENTIONED SEVERAL TIMES NATURAL HISTORY STUDIES, I PRESUME LD STUDIES PATHOGENESIS (INAUDIBLE) STUDIES (INAUDIBLE)? >> ANYTHING IT TAKES TO CONVINCE ME OR REVIEWERS OVERALL THAT THE ANIMAL MODEL IS MIMICKING THE HUMAN DISEASE CONDITIONS THAT MAY INCLUDE DOSE RESPONSE STUDIES, LD-50 STUDY, MAYBE KILL SACRIFICE TIME STUDIES, WHATEVER IT TAKES AND THAT WILL VARY ON THE AGENT THAT YOU'RE TRYING TO STUDY AND THE MODEL YOU'RE TRYING TO DEVELOP. BUT IT COVER IT IS WHOLE GAMUT. >> I HAVE GOT A QUESTION BECAUSE OBVIOUSLY I THINK ANIMAL MODEL QUALIFICATIONS ABSOLUTELY FUNDAMENTAL TO THE WORK THAT WE DO. IT'S MORE A SCENARIO WITH NHP STUDIES. SO AS AN EXAMPLE, IF WE HAVE AN AGENT WELL CHARACTERIZED, WE HAVE SPECIESES THAT ARE WELL CHARACTERIZED, WE'RE USING THE SAME GENDER, WEIGHT, AGE, ET CETERA, ET CETERA, WE HAVE GOT A ROBUST DELIVERY SYSTEM, FIT FOR ITS PURPOSE, WHAT HAPPENS WHEN WE GET SURVIVORS YOU ALLUDED WHAT HAPPENS WHEN YOU GET SURVIVORS IN A CHALLENGED NON-TREATED GROUP? IT'S REPEATABLE. DO YOU STILL DO IT AGAIN? DO YOU GET SURVIVOR HOW DO YOU MOVE ON TO TEST YOUR PRODUCT? YOU'LL NEVER KNOW THAT THE PRODUCT -- THAT THAT ANIMAL THAT SURVIVED THAT WAS GIVEN THE PRODUCT, WHEN -- GIVEN THE PRODUCT? >> LET ME MAKE SURE I GOT THE QUESTION RIGHT. IF YOU ASK WHAT HAPPENS WHEN YOU DEFINE YOUR ANIMALS AND SOME STILL GO THROUGH THE EXPOSURE. HOPEFULLY THAT PERCENTAGE IS KNOWN AND IS CONSTANT. >> YEAH. >> WHAT I MEANS (OVERLAPPING SPEAKERS) >> IF YOU DON'T HAVE 100% DEATH SURVIVAL, THERE ARE A NUMBER OF ANIMALS THAT IS IN EACH OF YOUR EMPERIMENTAL GROUPS TO ACHIEVE STATISTICAL SIGNIFICANCE MUST GO UP SO IF YOU'RE RUNNING AT A 90% INSTEAD OF 100 YOU HAVE TO ADD A FEW MORE ANIMALS TO YOUR GROUPS. WHAT YOU'RE LOCKING FOR, YOU HAVE 90% DEATH VERSUS 45% DEATH IN THE TREATED GROUPS OR SOMETHING LIKE THAT. YOU HAVE TO BE ABLE TO SHOW STATISTICAL SIGNIFICANCE IN THE PERCENTAGE AFFECTED. >> SO JUST TO BE CLEAR, YOU CAN SAY THAT IT'S STILL ACCEPTABLE TO HAVE SURVIVORS AS LONG AS IT'S SIGNIFICANTLY DIFFERENCE. >> I DIDN'T CATCH THAT. >> IT'S STILL ACCEPTABLE TO HAVE SURVIVORS IN YOUR NON-TREATED -- >> WE PREFER YOU DIDN'T. >> IF IT'S SIGNIFICANTLY DIFFERENT. >> WHAT IT IS, THAT MAY HAVE HAPPENED. IT DEPENDS ON THE ETIOLOGICAL AGENTS THAT YOU'RE WORKING WITH IN A SPECIES YOU MAYBE ABLE TO WORK WITH US ON QUALIFICATION AND CHANGE THE PROTOCOLS TO GET A BETTER PERCENT DEATH. WE MAY NOT. BUT WHAT HAPPENS IS, AS FAR AS I'M CONCERNED IN QUALIFICATION, THAT ENDS UP BEING A PART OF THE CONTEXT OF USE STATEMENT, THAT WE EXPECT THIS PERCENTAGE OF DEATH IN ANIMAL MODEL. TO USE THIS YOU HAVE TO BE ABLE TO SHOW STATISTICAL COMAING FROM THAT -- CHANGE FROM THAT NUMBER. DOES THAT HELP? >> YES. THANK YOU. >> OKAY. ANY OTHER QUESTIONS? >> I HAVE A PROCEDURAL QUESTION ABOUT QUALIFICATION. FROM YOUR PRESENTATION IT SOUNDED LIKE YOU WOULDN'T NEED TO GET ANIMAL STUDY REPORTS UNTIL THE EN, THE REVIEW PHASE. >> WE DON'T HAVE TO HAVE THE FINAL STUDY REPORT YOU HAVE TO TELL US SOMETHING ABOUT WHAT YOU EAR DOING DURING THE CONSULTATION AND ADVICE STAGE. WE ALSO REALIZE IN PRODUCT DEVELOPMENT AND MODEL DEVELOPMENT YOU MAY HAVE INTERIM REPORTS THAT YOU DON'T HAVE THE FINAL PATCH STUDY SO WE'RE WILLING TO WORK WITH YOU IN THE CONSULTATION AND ADVICE STAGE BASED ON WHAT WE HAVE GOT. ONE OF THE THINGS THAT YOU WILL SEE, THE REVIEW THAT I WRITE, I ASSUME OTHERS, I'M GOING TO TELL YOU IN MY INTERIM REVIEWS, IN MY INTERIM CONVERSATIONS WITH YOU, WHAT I DON'T SEE THAT I WANT TO SEE. SO WHEN IT COMES TO THE REVIEW PHASE EVERYTHING WE TOLD YOU WE WANT TO SEE WE WANT TO SEE. >> UNDERSTOOD. SECOND PART OF HI QUESTION, I REALIZED YOU MAY NOT BE ABLE TO I DRESS BASED ON EXPERIENCE BUT WONDER IF YOU COULD COMMENT ON OVERLAP BETWEEN REVIEWERS -- (LOST AUDIO) (LOST AUDIO) DEPARTMENT OF HEALTH AND HUMAN SERVICES. HE'S GOING TO TALK TO US ABOUT COLLABORATION BETWEEN GOVERNMENT AGENCIES REGARDING ANIMAL MODEL DEVELOPMENT. >> GOOD MORNING, EVERYBODY. SO WE'RE GOING TO TAKE A STEP BACK HERE FROM THE GREAT DISCUSSION THAT'S TAKING PLACE REGARDING QUALIFICATION OF ANIMAL MODEL TO TALK MORE ABOUT INTERAGENCY COLLABORATION, THE MEDICAL COUNTER MEASURE ENTERPRISE AND WHY WE'RE ALL HERE AND WHAT WE'RE DOING AS US GOVERNMENT TO FACILITATE ROBUST INTERAGENCY COLLABORATION AND OTHER THINGS WE CAN DO TO ENHANCE OUR COLLECTIVE ABILITY TO PRODUCE NEW MEDICAL COUNTER MEASURES. SO I THINK IT WILL BE A GREAT TALK, HOPEFULLY IT WILL BE MORE INTERESTING THAN PONDING ARE WHETHER TO GET SOUP AND SALAD AND I KNOW I'M THE LAST PERSON BEFORE LUNCH BUT I THINK IT WILL BE A GOOD TALK AND IT PUTS THINGS WE'RE GOING INTO -- DOING INTO CONTEXT. SO BRIEFLY WHAT WE'RE GOING TO TALK ABOUT TODAY ARE A NUMBER OF THINGS. ONE IS THE PUBLIC HEALTH EMERGENCY MEDICAL COUNTER MEASURES ENTERPRISE. WHICH MANY OF YOU SURE ARE FAMILIAR WITH. ALSO WHAT MANY PRODUCTS FAMILIAR WITH ARE INTEGRATED PORTFOLIO FOR CBER MEDICAL COUNTER MEASURES SPECIFICALLY THE PACK. FOR MISSION OF ANIMAL MODEL DEVELOPMENT COORDINATION WORKING GROUP AND IF ANYBODY HAS GOT A BETTER IDEA FOR AN ACRONYM SHOUT IT OUT BECAUSE THERE'S A MOUTHFUL. WHAT ARE THE GOALS OF THIS. AND ALSO IN THE LARGER CONTEXT, OTHER INITIATIVES. THIS IS ONE OF A NUMBER OF INITIATIVES USING TO REALLY HELP TO BRING COHESIVE ELEMENT OF INTERAGENCY COLLABORATION TO THE ENTERPRISE. THIS IS ONE OF THE WAYS WE DO THAT. LASTLY, AN EXAMPLE HOW THIS CHARTER -- HOW THIS WORKING GROUP IS ACTUALLY HOPING TO FUNCTION IN TERMS OF ANIMAL MODEL QUALIFICATION. BECAUSE THIS IS A NEW ANIMAL MODEL GROUP. AND THERE'S BEEN A NUMBER OF THEM OVER THE YEARS AS MANY OF YOU KNOW. BEFORE I JUMP INTO MEDICAL COUNTER MEASURE ENTERPRISE SPECIFICALLY, I WANT TO SHOW EVERYBODY THIS SLIDE. IT BEGINS TO PUT INTO CONTEXT WHAT OUR REALITY IS HERE. AND FOR THOSE WHO ARE DEEPLY ENGROSSED IN THE PROCESS OF BRIP BRINGING MEDICAL COUNTER MEASURE TO LICENSURE YOU'RE GOING TO BE FAMILIAR WITH THIS. FOR THOSE WHO MAYBE DON'T WORK IN THIS SPACE DAY TO DAY, THIS IS SOMETHING THAT'S VERY IMPORTANT AND SHAPES ALL OF OUR COLLECTIVE REALITIES. MEDICAL COUNTER MEASURES OR DRUGS WHETHER COMMERCIAL OR WHAT WE'RE TRYING TO DO, THEY'RE EXTENSIVE, THEY TAKE A REALLY LONG TIME TO DEVELOP AND C, THERE'S A LOT OF FAILURE. MUCH MORE SO THAN IN OTHER INDUSTRIESCH THIS IS SOMETHING THAT IS A UNIQUE CHALLENGE TO US. NOT ONLY SWIMMING UPSTREAM AGAINST, EVERYONE ACUTELY AWARE THE SEMITRACTABLE REGULATORY PROCESSES IN PLACE FOR MOST COMMERCIAL INDICATIONS ARE A REALITY. WE HAVE A LOT OF OTHER THINGS THAT WE TBHEED TO CONSIDER. BIG ONE BEING ANIMAL ROLE WHICH IS WHY WE'RE HERE TODAY. I WANT EVERYBODY TO CEET THIS IN THE BACK OF THEIR MIND WAS WE MOVE THROUGH THE SLIDES BECAUSE THIS IS THE CENTRAL GOAL FOR WHAT WE'RE TRYING AS INTERAGENCY GROUP TO ADDRESS. WE'RE TRYING TO LOWER THE INITIAL BARRIERS TO PROGRESS AND ENHANCE SYNERGY FROM COLLECTIVE EFFORTS. SO MOVING TO THE ENTERPRISE. 2009, 2010 SECRETARY SEBELIUS ASKED FOR A COMPREHENSIVE MEDICAL REVIEW. SHE WANTED US TO TAKE STOCK OF THE CURRENT STATE OF PUBLIC HEALTH EMERGENCY COUNTER MEASURES ENTERPRISE, WHAT ARE WE DOING WELL, WHAT CAN WE DO BETTER. FROM THAT A NUMBER OF THINGS CAME OUT, MOST IMPORTANT TO THIS GROUP WE HAD A VISION ARTICULATED BY THE SEC. A NATION MUST HAVE A NIMBLE FLEXIBLE CAPACITY TO DO COUNTER MEASURES AGAINST A THREAT KNOWN OR UNKNOWN INCLUDING PREVIOUSLY UNRECOGNIZED NATURALLY OCCURRING INFECTIOUS DISEASE. THAT'S A LOFTY GOAL. HOW? THERE'S NUMBER OF TRYING TO I CHEEF THIS GOAL WHICH IS A LAUDABLE GOAL. AND ATTAINABLE GOAL IF WE WORK HARD ENOUGH. THERE'S NUMBER OF REALITIES WE ARE FACING FIRST, GIVEN THE PUBLIC HEALTH FOCUS WE HAVE A LOT OF COORDINATION AGAINST THE PUBLIC HEALTH ENTITIES. AS MANY OF YOU WE ARE UNIFORM THIS IS THIS BUILDING AND YOU'RE MILITARY LAB ALUMS PRESENTLY WORKING AT KNOW, THE DOD HAS A MATURE ROBUST LONG STANDING CAPABILITY IN THIS SPACE THAT FOCUS ON A NUMBER OF SAME AGENTS OF PUBLIC HEALTH CONCERN. CAN WE WORKING TO AND DERIVE SYNERGY. BUT AS EVERYTHING IN GOVERNMENT WE HAVE TO MAKE IT MORE COMPLICATED. SO HOW DO WE DO THAT? THIS IS OUR REALITY. THIS IS THE MEDICAL COUNTER MEASURE ENTERPRISE PUBLIC HEALTH SIDE AND MILITARY SIDE. SO AS YOU CAN SEE MOVING FROM BASIC RESEARCH, I'M NOT GOING TO TOUCH THESE BUTTONS, BUT MOVING FROM THE LEFT TO THE RIGHT WE HAVE BASIC RESEARCH AND MOVE TO READINESS AND STOCK PILING. ALONG THAT P CONTINUUM WE HAVE AGENCY OPS THE PUB HEALTH SIDE, ASP,R, CEC AND MILITARY SIDE WE HAVE DARPA, CHEM BIODEFENSE PROGRAM AT PENTAGON, DEFENSE THREAT REDUCTION AGENCIES, JOINT TECHNOLOGY OFFICE. SO YOU HAVE BASIC RESEARCH, JPM, CBMS AND CMC WORKING SO ALL THESE FOLK VERSUS THEIR OWN MISSIONS, THEIR OWN BUDGETS. THEY ARE ENGAGED IN THINGS THAT ARE NOT NECESSARILY DEVELOPING A MEDICAL COUNTER MEASURE. SO HOW DO WE COORDINATE IN A WAY TO TAKE DISPARATE GROUPS OF FOLK AND DEVELOP A COHESIVE APPROACH TO MEDICAL COUNTER MEASURE DEVELOPMENT. THAT'S NO SMALL TASK. COUPLE THAT, AGAIN THERE ARE SIMILARITIES WE CAN START TO DEFINE. SO IF WE LOOK AT WHAT THE FOLKS -- THE FOCUS IS FOR ADVANCED RESEARCH AND DEVELOPMENT AMONGST THE DOD AN HHS ONE NICE THING IS THERE'S COMMONALITY. AS YOU'LL SEE IN THE MIDDLE OF SLIDE HERE THERE'S ANTHRAX, SMALLPOX, EBOLA, WE'RE LOOKING AT COMMON THREATS. HOWEVER THERE, A FUNDAMENTAL DIFFERENCE. AMONG OTHERS IS THAT WHEN WE PREPARE A WAR FIGHTER WE KNOW THEY WILL BE ENTERING THIS ENVIRONMENT. WE CAN PROTECT AND VACCINATE THEM. WE HAVE COLLECTIVE PROTECTION. HOW FAR, FOR A PUBLIC HEALTH FOCUS. WE WILL BE DEALING WITH A SITUATION AFTER IT OCCURRED SO WE HAVE TO FIND OUT WHAT HAPPENED, FIND OUT WHAT WE'RE DEALING WITH, AND THEN TREAT. SO EVEN THOUGH WE'RE DEALING WITH MANY OF THE SAME THREAT AGENTS THE CON OPS ARE GOING TO BE SIGNIFICANTLY DIFFERENT WHICH HAD DUPLICATIONS INTO ANIMAL MODEL DEVELOPMENT BECAUSE IT HAS IMPLICATIONS HOW YOU'RE GOING TO LICENSE A PRODUCT FOR WHAT INDICATIONS. THAT'S A VERY KEY. THAT IS A CONFOUNDING FACTOR THAT NEEDS -- THAT NEEDS TO BE ADDRESSED. AS ALWAYS IN OUR COLLECTIVE MINDS WITHIN THE AGENCY. SO WE HAVE COMMONALITY HERE. OVER YEARS DR. LYNDON, CAD LICK AND GALLOWAY WERE CONVENING A NUMBER OF MEETINGS, FROM MY UNDERSTANDING HOW I'M TAUGHT, THIS IS BEFORE MY TIME OBVIOUSLY, EVERYBODY CAME TOGETHER AND REALIZED AT THE SAME TIME THERE'S A LOT OF WORK GOING ON ARTICULATED THAT WE CAN DERIVE A FAIR AMOUNT OF SYNERGY FROM. SO FOLKS GOT TOGETHER AND STARTED HAVING MEETINGS. SO AGAIN, HHS, DOD GOT TOGETHER, THE FIRST CONCEPT FOR COMBINED INTEGRATED MEDICAL COUNTER MEASURES PORTFOLIO WAS ARTICULATED. NIAID, BARTA, CPDP, CDMS AND JSGO. THEN A SERIES OF WORKING MEETINGS CONDUCTED WITH HOMELAND SECURITY COUNCIL OVER SUMMER OF 2008. AGAIN, WE'RE ARTICULATING ISSUES THAT I HAVE MENTIONED FOR YOU FOLKS HERE, TRYING TO FIGURE A STRUCTURE IN PLACE TO FE GIN TO IN A REPRODUCIBLE AND TRACTABLE MANNER ADDRESS INTERAGENCY ISSUES. INTEGRATED PORTFOLIO. MEETINGS TAKE PLACE 2008, THE GROUP MET FROM 2008, TWINE, 2010 WE GOT THE FIRST CHARTER. IN 2011 WE UPDATED. THIS IS IMPORTANT SO THIS IS THE INTERAGENCY GROUP GOALS. THE MISSION IS TO MAXIMIZE NATURAL PRE-- NATIONAL PREPAREDNESS BY ALIGNING AVAILABLE PROGRAMS BETWEEN DOD AND DHS. PROVIDING COMPREHENSIVE VIEW OF USG EFFORTS AND ENHANCING INTRAAND INTERDEPARTMENTAL COLLABORATION. WE DO THAT SPECIFICALLY IN FOUR WAYS, FOUR SPECIFIC TASKS WE SUPPORT FOR THE ENTERPRISE. PORTFOLIO ANALYSIS, COORDINATION OF MEDICAL COUNTER MEASURE PROGRAMS, SUPPORTING INFRASTRUCTURE ANALYSIS. AND STRATEGIC COMMUNICATION. AND WHEN WE MOVE INTO THE ANIMAL MODEL WORKING GROUP, THAT IS IN SUPPORT OF BULLETS 2 AND 3. THAT'S WHERE I THINK THE RELEVANCE OF THIS GROUP COMES IN. TO SHOW YOU WE'RE NOT A WORKING GROUP SITTING IN THE EITHER AND DON'T HAVE A LINE DECISION OF POLICY MAKERS THIS IS HOW THE ENTERPRISE IS STRAWRD. SO WITHIN THE PUBLIC HEALTH EMERGENCY MEDICAL COUNTER MEASURES ENTERPRISE WE HAVE ESC AT THE TOP WHICH ARE THE PRINCIPLES, DR. FAUCI, HAMBERG, LIEU WHICH, FREEDON, SENIOR PRINCIPLES FOR EACH OF THESE GROUPS. THEN THAT'S POLICY AND STRATEGY. WITHIN THAT WE HAVE THE EES, WHICH FEEDS INTO THE ESC, THOSE ARE THE PROGRAMATIC LEADS ACROSS INTERAGENCY, AS I MENTIONED AT THE ESC LEVEL WE HAVE DOD REPRESENTATION. BUT IT IS A LITTLE BIT MORE HHS CENTRIC. MOVING DOWN THE POINT THAT'S IMPORTANT HERE IS THE PACKAGE IS DOD AND HHS COME TOGETHER IN A VERY ROBUST INTEGRATIVE FASHION. ALL THE PROGRAM LEADS FROM ACROSS DOD AND HHS COME TOGETHER ONCE A MONTH, IN FACT THIS FRIDAY IS THE MONTHLY MEETING AND WE HAVE A MEETING EVERY WEEK. THIS IS REALLY SO THAT ALL OF OUR PROGRAMS WHERE WE HAVE OVERLAP AND AREAS WE DON'T AND WE OTHER LOOKING FOR MORE WE CAN HAVE THESE DISCUSSIONSCH THIS IS A ROBUST GROUP WITH ROBUST ACTIVITIES AND TAKES PLACE IN A MONTHLY BASIS SO JUST WANTED TO LET EVERYBODY KNOW THIS IS TIED INTO HOW THE OVERALL ENTERPRISE WORKSCH AS WE CONTINUE TO GO FORWARD ONE GREAT THING THAT'S COME OUT OF THIS EFFORT HAS BEEN A MUCH BETTER ABILITY TO ARTICULATE DOD AND HHS MEDICAL COUNTER MEASURES ENTERPRISES AREN'T SEPARATE. THEY REPRESENT AN INTEGRATED NATIONAL SECURITY NATIONAL DEFENSE CAPABILITY. WE HAVE HAD A LOT OF SUCCESS DRIVING SYNERGY OUT OF OUR PROGRAM SO IT IS A NATIONAL SECURITY CAPABILITY RATHER THAN HHS AND DOD. SO WITH THAT, THAT'S THE OVERVIEW, THAT'S THE BIG PICTURE. WE SUPPORT A NUMBER OF INITIATIVES THAT INCLUDE COST MODEL DEVELOPMENT, PORTFOLIO TRACKING, CAPABILITY, ANIMAL MODEL COORDINATION WHICH IS WHY I'M HERE AND YOU FOLKS ARE HERE. THIS IS ONE OF THE INITIATIVES WE HAVE UNDERTAKEN TO ENHANCE ABILITY TO DI DE RIEF SYNERGY FROM THE WORK BEING DONE. THE BIGGEST QUESTION, WHY DO WE NEED ANOTHER ANIMAL MODEL WORKING GROUP? THERE'S PLENTY OF WORKING GROUPS AN COLLECTIVE KNOWLEDGE SO WHY ANOTHER MEETING ON CALENDARS? I THINK THERE'S THREE GOOD REASONS. ONE IS AS ALL ARE AWARE, MULTIPLE AGENCIES ARE ENGAGED IN ANIMAL MODEL DEVELOPMENT DEDICATED PROGRAMS AND ALSO PART OF PRODUCT DEVELOPMENT PROGRAMS SO WE HAVE ANIMAL MODELS DEVELOPED FOR USE, THEN ANIMAL MODELS SUPPORTING COMMERCIALIZATION DEVELOPMENT PROGRAMS FOR MEDICAL COUNTER MEASURES. ENTERPRISE DOESN'T NEED OR WANT WORKND PEN DEN OF ONE ANOTHER. AN FDA MODEL SHOULDN'T BE DIFFERENCE THAN A STANDARD MODEL. WE SHOULD HAVE ONE ENTERPRISE MODEL. I THINK THAT'S PROBABLY RESONATES A LOT OF FOLK IN THIS ROOM. WHY DO WE NEED ANOTHER ANIMAL MODEL OVER TIME. THIS SLIDE IS I THINK TO ARTICULATE THE EVOLUTION WE HAVE SEEN OVER THE YEARS IN TERMS OF ANIMAL MODEL WORKING GROUPS AND HOW THEY EVOLVE TO SUPPORT THE NEEDS OF THE INTERAGENCY AND WHERE WE'RE AT -- WHERE WE HAVE BEEN AND WHERE WE'RE GOING. FIRST IS WEAPONS OF MASS DESTRUCTION EXISTING SUBGROUP, PUT TOGETHER TO FIGURE OUT WHEN ENTERPRISE IS STOOD UP, DO WE HAVE ANIMAL MODELS TO USE? WE HAVE TO FIND SOME WAY TO DEMONSTRATE SAFETY AND EFFICACY. DO WE HAVE ANIMAL MODELS TO DO THIS? THAT WAS THE FIRST ANIMAL MODEL WORKING GROUP. THAT WAS FOLLOWED BY WMD TOOLS WORKING GROUP. WE HAVE THE ANIMAL MODELS. DO WE HAVE THE TOOLS WE NEED, THE CHALLENGE MATERIALS AGREEMENT ON WHAT CHALLENGE MATERIALS WE'LL USE? THAT WAS THE THRUST OF THIS GROUP. THEN IT EVOLVED IN 2009, 2010, WAS SOMETHING CALLED THE ANIMAL STUDY Q EVALUATIONS UPONSORS FOR THE PACK. WHO IS FUNDING ANIMAL MODEL STUDIES, HOW ARE THEY BORDER AND BOTTLENECKS WE CAN AVOID TO HELP DEVELOPERS SPEED THEIR PROGRESS ALONG. AND OTHER WAYS TO DRIVE SYNERGY AND EFFICIENCY OUT OF WHAT WE'RE INVESTING IN. THAT WAS THE ASQE. ASQE SUN SETTED EARLY THIS YEAR, LATE LAST YEAR. ABOUT TWO TO THREE MONTHS AGO WE CHARTERED THIS THING. ANIMAL MODEL DEVELOPMENT QUALIFICATION AND WORKING GROUP. AMD QCWG. IT'S GETTING START AND TO HELP IN TERMS OF WHO IS DEVELOPING QUALIFIED MODELS, WHAT DATA IS GENERATED HOW IS THE DATA VETTED AND OTHER WAYS TO COMBINE DATA AND KEEP IT IN A COMMON REPOSITORY AND SHARE INFORMATION AND LESSONS LEARNED SO WE CAN BEGIN TO TRY AND MUCH AS POSSIBLE STANDARDIZE THIS AND LOWER BARRIERS TO GETTING MODELS QUALIFIED WHERE WE CAN. IT'S SYNERGY, EFFICIENCY AND MUCH PROGRESS AS WE CAN FOR THE AMOUNT OF WORK BEING PUT IN. SO THIS IS HISTORY. NEXT SLIDE IS HOW WE GET TO THIS POINT. WE CHARTERED THE ASQE AND IT WAS CHARTERED WITH MONITORING THE Q OF CBER ANIMAL STUDIES. THE Q SUBSIDED IN 2010 DUE TO DECREASES IN BUDGETS AND REALIZATION THERE WAS INCREASED UNCERTAINTY REGARDING REGULATORY PATH WAYS SO A NUMBER OF CHALLENGES WE WERE SEEING. WE DIDN'T SEE A CLEAR PATH FORWARD FOR US TO BE ABLE TO DELIVER VALUE AND MAKE AN IMPACT SO DECISION WAS MADE THAT WE WOULD SUN SET THE ASQE. ABOUT THIS TIME, INCEPTION OF ANIMAL MODEL QUALIFICATION, THAT WAS THE LAND MARK EVENT THAT GENERATED THE SHIFT FROM THE SAQE TO THE NEW WORKING GROUP. SO THAT TOOK PLACE, IN 201 NIAID HAD A WHITE PAPER AND A DISCUSSION ON NEW MISSION WHERE Q MOVED FROM Q TO QUALIFICATION. IS THERE A ROLE WE CAN PLAY IN THE QUALIFICATION PROCESS AND BRING THE ENTERAGENCY TOGETHER FOR A COMMON COLLECTIVE GOOD IN DERIVING SYNERGY IN TERMS OF ALL EFFORTS. THAT DECISION WAS YES, YES WE CAN. SO WHAT HAPPENED NEXT WAS A SMALLER GROUP OF AGENCY SETTLED ON A SCOPE THAT BECAME DEVELOPMENT, QUALIFICATION, COORDINATION. THROUGH A SERIES OF MEETINGS TO SOLIDIFY WORK GROUP AGREEMENT WAS MADE ON INTERAGENCY ROLES AN MISSION AND VISION OF THE WORKING GROUP WOULD BE. I THINK PROBABLY SEPTEMBER, JULYISH WE SIGNED A CHARTER FORMATION OF THE GROUP IS NOW IN PROGRESS. SO WHAT IS THE MISSION OF THIS WORKING GROUP? WE'RE TRYING TO FIGURE OUT HOW WE CAN HELP. NOT DEFINING HOW FOLKS DO THE WORK BUT ACTING AS REPOSITORY FOR INFORMATION FOR LESSONED LEARNED AND BEING A RESOURCE FOR FOLKS ENGAGED IN ANIMAL MODEL QUALIFICATION COORDINATION AND DEVELOPMENT. TO THAT END THE GOAL IS REALLY SIMPLE, SHARING MODEL ANIMAL ACTIVITIES. WHAT WE'RE DOING WHO IS DOING IT WHO NEEDS IT. ANALYZING SOURCE REQUIREMENTS FOR QUALIFICATION. HOW MUCH DOES IT TAKE AND HOW MUCH DOES IT COST HOW DO WE BENCHMARK WHAT WE DO. SHARING SIGN TICHIC AND REGULATORY LESSONS LEARNED. EVERYBODY IS MOVING TO A NEW TERRITORY HERE. HOW DO WE SHARE WHAT LESSONS WE LEARNED SO FOLKS DON'T HAVE TO SUFFER THROUGH THE LEARNING CURVE AND WE CAN TRY TO ACCELERATE THE PROCESS TO MAKE IT EASIER FOR FOLKS. HOW DO WE TRANSLATE EXPERIENCE ACROSS AGENCIES THAT FULLY INTEGRATED MEDICAL COUNTER MEASURE ENTERPRISE CAPABILITY. THOSE ARE THE BIG GOALS. IN TERMS OF WHERE THE WORKING GROUP VORTING, IT REPORTS INTO THE PATH WHICH ED SHOWED BEFORE, REPORTS DIRECTLY INTO THE EEK AND IS KEY PART OF THE MEDICAL COUNTER MEASURE ENTERPRISE SO WE HAVE COMMUNICATION UP THE CHAIN OF COMMAND, DOWN THE CHAIN OF COMMAND. LASTLY IN SPIRIT THE INTERAGENCY WE HAD THREE LEADS, THERE ARE THREE CHAIRS TO THIS GROUP, HHS, DOD AND FDA SO YOU HAVE ROBUST PARTICIPATION YOU HAVE THE VIRIOUS PERSPECTIVES BEING INVOLVED SO IT'S INTENDED TO DO HOLISTIC VIEW OF WHERE THIS WORKING GROUP IS GOING AND WHAT IT'S TRYING TO DO SO NO ONE IS OPERATENING A VACUUM LASTLY AN EXAMPLE HOW THIS IS USED. BEFORE I GO FURTHER ON THE SLIDE I'M GOING TO POINT OUT THE LAST BULLET, NO IMPACT ON CURRENT SPECIFIC PRODUCT REGULATORY SUBMISSIONS SO THOSE INVOLVED IN THIS SPACE, NO IMPACT ON WHETHER U YOU'RE DOING. BUT THIS IS A MODEL HOW WE OUTLYZE THIS WORKING GROUP GOING FORWARD IN WORK WE'RE ANTICIPATING DOING BEING ABLE TO DO. SO BARTA AND I WILL WORK TOGETHER ON AN ANIMAL MODEL QUALIFICATION FOR THERAPEUTICS. THEY WILL SUBMIT MATERIALS TO THE FDA, COMPRISED OF NIAID AND BARTA DATA WHICH COOL. THEY JOINTLY DEVELOP THE PACKAGES ATTEND MEETINGS AND POND TO QUESTIONS SO IT'S DEVELOPING AN INTEGRATED ENTERPRISE APPROACH TO ANIMAL MODEL QUALIFICATIONS. THAT'S THE INTENT. THE WORK IS STOOD UP NOW, THEY'RE GETTING THEIR STRIDE SO EXPECT MORE COMMUNICATIONS, EXPECT AN EVOLUTION BUT THIS IS AN EXAMPLE OF THE TYPE OF WORK THAT THIS GROUP IS CHARGED WITH AND WILL BE DOING. WITH THAT, I WANT TO TRY TO GET EVERYBODY TO LUNCH AS QUICKLY AS POSSIBLE SO ANY QUESTIONS THAT YOU HAVE I WOULD BE HAPPY TO DO MY BEST TO ANSWER. [APPLAUSE] ALL RIGHT. ENJOY YOUR LUNCH EVERYBODY, THANK YOU. >> THAT CREATES A PROBLEM FOR STANDARDIZATION AND REPRODUCIBILITY, STANDARD SITION ACROSS LABS SO HOPEFULLY WE'LL -- WE MIGHT GET INTO THAT SOME AND HEAR SOLUTIONS FOR THAT. THANK YOU. GOOD AFTERNOON, WELCOME BACK TO THE AFTERNOON SESSION OF ANIMAL MODELS WORKSHOP. I'M SAM CHAMBERLAIN, CO-MODERATING THIS SESSION. I'M WITH THE FDA OFFICE OF COUNTER COUNTER-TERRORISM AND EMERGING THREATS A VETERINARY MEDICAL OFFICER SUPPORTING THE REGULATORY SCIENCE TEAM IN THAT OFFICE. I'M ALSO THE INSTITUTIONAL OFFICIAL FOR THE WHITE OAK CAMPUS ANIMAL PROGRAM. THE ROLE OF ANIMAL CARE AND STUDIES NEAR AND DEAR TO MY HEART AND I APPRECIATE AND THANK THE WORKSHOP ORGANIZERS FOR INVITING ME TO ORGANIZE THIS SESSION. WITHOUT FURTHER ADIEU I WOULD LIKE TO INTRODUCE THIS AFTERNOON'S FIRST SPEAKER, THAT'S CAPTAIN ESTELLA JONES, CURNSLY SERVE AS SENIOR SCIENCE AD VIER AND REGULATORY VETERINARIAN WITH FDA OFFICE OF COMMISSIONER OFFICE OF CHIEF SCIENTIST AND COUNTER-TERRORISM AND EMERGING THREATS. SHE ALSO REPRESENTS SURGEON GENERAL'S OFFICE ON THE SUBCOMMITTEE FOR DISASTER REDUCTION FOR THE EXECUTIVE FIS OF THE PRESIDENT OF THE UNITED STATES. DR. JONES THIS AFTERNOON WILL BE PRESENTING CONSISTENT EUTHANASIA CRITERIA. DR. JONES. >> GOOD AFTERNOON. >> GOOD AFTERNOON. >> I'M SO LUCKY TO BE THE FIRST SPEAKER AFTER LUNCH SO I HAVE -- I FEEL LIKE I HAVE TO KEEP YOU ENTERTAINED AND I DO WANT TO THANK THIS TEAM THAT'S BEEN WORKING SO HARD TO GET THE SLIDES UP, BACK UP AND RUNNING. SO I KNOW I HAVE TO SAY NEXT SLIDE WHEN I'M READY. NEXT SLIDE. MY TOPIC IS CONSISTENT EUTHANASIA CRITERIA. THIS IS SOMETHING THAT'S ACTUALLY VERY DEAR TO MY HEART BECAUSE I'M ALSO A PRACTICING VETERINARIAN AND PRACTICE FOR THE LAST OVER THE LAST 20 YEARS, I CAN'T SAY REALLY HOW LONG BECAUSE I WOULD BE TELLING MY AGE. BUT IT IS ALWAYS A CONCERN WHEN YOU COME TO THE END OF ANY LIFE AND THERE IS LOT OF TOPICS OUT THERE CONCERNING EUTHANASIA IN HUMANS, IT'S A VERY CONTROVERSIAL TOPIC. SO WE'RE GOING TO EXPLORE SOME OF THE PROBLEMS AND ENCOUNTERS AND OFFER A FEW SOLUTIONS TO HELP WORK THROUGH THIS AS A TEAM. I'M GOING TO START WITH POLICIES, WHICH CAN BE A BORING SUBJECT SO WE SEAL IF WE CAN KEEP IT INTERESTING BECAUSE YOU HAVE TO HAVE BASIC KNOWLEDGE BEFORE YOU APPLY THESE PRINCIPLES. NEXT SLIDE PLEASE. FIRST THING I WANT TO DO IS DEFINE EUTHANASIA. IT CAME FROM THE GREEK WORD MEANING GOOD AND DEATH. SO GOOD DEATH IS DEATH THAT INVOLVES MINIMAL PAIN, DISTRESS AND WITH HUMANENESS, VETERINARIANS ARE FACED WITH THIS CHALLENGE ALL THE TIME ESPECIALLY PRACTICING VETERINARIANS. YOU COME TO A POINT WHERE YOU HAVE TO DECIDE IF THIS IS GOING TO BE A GOOD DEATH OR A NOT SO GOOD DEATH. THAT'S WHAT I WOULD SPEAK FOR EVERYONE IN THIS ROOM TO SAY NO ONE IS IMMORTAL AND WE ALL THREE HOPE FOR A GOOD DEATH, A PAINLESS L OR MINIMALLY PAINLESS DEATH. SO THE PROBLEM IN VETERINARY MEDICINE AND INTERPRETING SOME OF THE DATA WHEN WE LOOK AT THE END OF AN MANL'S LIFE IS WE HAVE TO BE ABLE TO RECOGNIZE PAIN IN EACH SPECIES AND THERE'S SO MANY DIFFERENT WAYS THAT PAIN MANIFESTS ITSELF OR IT SHOWS UP. SO WHEN YOU COMPARE ANIMAL PAIN TO HUMAN PAIN HUMAN VIEWS A LOT OF WORDS LIKE SYMPTOMS. IN VETERINARY MEDICINES ANIMALS DONE HAVE SYMPTOMS. A SYMPTOM IS I HAVE A HEADACHE. I'M NOT FEELING SO WELL TODAY. THAT'S A SYMPTOM. A SIGN IS A AN OBJECTIVE THING. OFF FEVER, SOMETHING MEASURABLE THAT YOU CAN TAKE. SO WHEN YOU TALK ABOUT SIGNS IN ANIMALS, ANIMALS DON'T HAVE SYMPTOMS THAT'S REALLY A HUMAN TERMINOLOGY. SO THEN YOU HAVE TO BE ABLE TO EXTRAPOLATE WHAT IS PAIN? PAIN ISh ESPECIALLY IN HUMAN MEDICINE. IF YOU LOOK AT THE VETERINARY TEXT, THEN PAIN IS ALSO NOW BEING CONSIDERED A FIT, SOMETIMES FOURTH CYCLE BECAUSE EVERYBODY DOESN'T MEASURE BLOOD PRESSURE. SO WHEN YOU TALK VITAL SIGNS AND LOOK AT CLINICAL CASE SHEETS, I I WANT TO ENCOURAGE YOU TO PICK UP A COPY OF DR. SIMON MARDELL'S CASE SHEET, FOR HUMAN, YOU CAN HEAR ME DISTINGUISH BETWEEN HUMANS AND NON-HUMANS A LOT BECAUSE THIS IS A CASE HISTORY REPORT THAT THEY'RE USING IN THE UK. I THINK IT'S DONE REALLY NICELY AND HE DID ALLUDE TO THE FACT THAT ALL THE HOSPITALS IN THE UK ARE NOW USING THIS. OUR GOAL IS TO DEVELOP SOMETHING LIKE THIS. SO THAT IF YOU LOOK AT THIS SHEET PAIN IS A MEASURABLE SCORED ITEM SO WHEN YOU ASSESS PAIN YOU HAVE TO TAKE THAT INTO ACCOUNT BECAUSE IT IS CONSIDERED VITAL SIGN, RIGHT THERE WITH RESPIRATORY RATE, HEART RATE RESPIRATORY RATE, HEART RATE, PULSE AND BLOOD PRESSURE AND FIVE IS PAIN SCORE. NEXT SLIDE, PLEASE. SO FOR LAWS AND P POLICIES I COULDN'T LIST ALL BECAUSE THERE'S SO MANY SO I LISTED ONES PERTINENT ESPECIALLY TO MEDICAL COUNTER MEASURES AND ONES YOU'LL SEE OVER AND OVER AGAIN. SO YOU REALLY NEED TO BECOME AN EXPERT AT WHAT THESE LAWS AND POLICIES SAY. MOST OF YOU ALREADY HEARD ABOUT THE ANIMAL WELFARE ACT DR. ROBERTS TALKED ABOUT IT. DR. DAVIS, JERRY DAVIS TALKED ABOUT IT IN EARLIER PRESENTATIONS. IT IS A LAW THAT WAS ENACTED IN 1966 NOTICE THE COMMON THEME AS I GO THROUGH MY SLIDE. THERE'S A LAW THAT DEVELOPS IN RESPONSE TO A TRAGIC INCIDENT. SO I'LL GO THROUGH THESE AND WHY THEY'RE IMPORTANT. I DREW IS CIRCLES SO YOU KNOW HOW THE LAWS INTERFACE. PHS POLICY IS INSEPARABLE FROM THE GUIDE AND U.S. PRINCIPLE, THAT'S WHY I LISTED THEM TOGETHER. THE FEDERAL FOOD AND DRUG COSMETIC ACT IS ANOTHER ONE THAT INTERTWINES WITH THESE. ANIMAL WELFARE ACT, I GOT TO TELL A STORY BECAUSE IT'S AFTER LUNCH AND I WANT YOU TO STAY AWAY. THE STORY OF PEPPER THE DALMATION RESULTED IN THE ANIMAL WELFARE ACT OF 1966 IN 1965 PEPPER THE FAMILY DOG WAS STOLEN FROM HIS BACKYARD AND SOLD ILLEGALLY INTO RESEARCH SO THE FAMILY WAS PROACTIVE BUT BY TIME THEY GET A CONGRESSMAN INVOLVED IT WAS TOO LATE, PEPPER DIED IN A STUDY IN A NEW YORK HOSPITAL ON THE SURGERY TABLE. SO THIS DOG'S FACE APPEARED ON TIME MAGAZINE, LIFE, SPORTS ILLUSTRATED. SEVERAL MAGAZINE COVERS ABOUT THE ATROCITIES OF STOLEN ANIMALS SOLD TO RESEARCH. SO AS A RESULT CONGRESS PASSED THE ANIMAL WELFARE ACT, WE CALL IT AWA IN 1966, YOU CAN SEE IT'S BEEN STRENGTHENED AND AMENDED MANY TIMES. IT WILL CONTINUE TO BE AMENDED I'M SURE IN THE FUTURE BECAUSE THERE'S A LOT OF THINGS THAT IT STILL IS STRUGGLING TO ADDRESS. NUMBER ONE, THE USE OF RODENTS, COUNTING RODENTS UNDER THE ANIMAL WELFARE ACT. IN OUR CASE FOR DISCUSSION PURPOSES WE KNOW THEY'RE INCLUDED IN THS POLICY SO IF YOU RECEIVE ANY PHS FUNDING OR IF IT'S A CONTRACTEDDED STUDY THAT'S RECEIVING PHS FUNDING YOU EAR DOWN TO THOSE SAME POLICIES AND LAW. SO AWAS ESTABLISH MINIMUM STANDARDS FOR BASIC VETERINARY CARE AND YOU CAN'T DUPLICATE EXPERIMENTS, IT ALSO SAYS AN IAKUK, INSTITUTIONAL ANIMAL CARE AND USE COMMITTEE IS RESPONSIBLE FOR OVERSEEING THE USE AND EXPERIMENTS ANIMAL EXPERIMENTS, AND RESEARCH FACILITIES HAVE TO BE LICENSED. NEXT SLIDE, PLEASE. I PUT THIS HERE TO SHOW NINE GOVERNMENT PRINCIPLES NOT TO SITE THE PRINCIPLES TO YOU, THIS WAS ENACTED IN 1985 AND PHS -- IN '86 BUT IF YOU NOTICE HOW MANY TIMES THE WORDS PAIN, DISTRESS, SEDATION, ANESTHESIA, ANAL ANALGESIA, ARE MENTIONED AND PAINLESSLY KILLED AT THE END OF THE PROCEDURE, IT IS A BIG DEAL. ICE MENTIONED IN -- IT'S MENTIONED IN 4, 5, AND 6 OF THE NINE GOVERNMENT PRINCIPLES. SO IT'S A VERY HOT TOPIC RIGHT NOW AND WE DO HAVE TO COME TO A LOT OF SOLUTIONS AND DECISIONS IN THE PLANNING PHASE OF PROTOCOLS. NEXT SLIDE, PLEASE. SO PHS POLICY, IT GOES HAND IN HAND WITH THE GUIDE IT GOES HAND IN HAND WITH U.S. PRINCIPLES. IT STATES THAT YOU SHOULD AVOID OR MINIMIZE PAIN, THERE'S THE WOR PAIN AGAIN, DISTRESS. WE ALSO NEED TO RECOGNIZE THAT SOMETIMES ANIMALS ARE DISTRESSED, IT'S NOT NECESSARILY PAINFUL BUT IT'S DISTRESSFUL SO YOU'RE NOT GOING TO GET A GOOD RESULT IF YOU HAVE THAT CONDITION. PROVIDE ADEQUATE VETERINARY CARE AND THERE'S A LOT OF DIFFERENT DEFINITIONS OF WHAT PROVIDING ADEQUATE VETERINARY CARE INVOLVE. IF YOU HAVEN'T SEEN THE ACE EDITION OF THE GUIDE I WOULD ENCOURAGE YOU TO DOWNLOAD IT FROM THE INTERNET. ALL THESE PUBLICATIONS ARE FREE PUBLICATIONS. QUALIFIED TRAINED PERSONNEL, WE'RE GOING TO TOUCH ON THAT. HERE TO THE AMERICAN VETERINARY MEDICAL ASSOCIATION GUIDELINES FOR EUTHANASIA. NEXT SLIDE, PLEASE. SO THE FEDERAL FOOD AND DRUG COSMETIC ACT, AGAIN, WE HAD SOME TRAGEDIES IN HERE, WE HAVE ANOTHER LAW SO THIS CAME INTO PLAY IN 1938. I WASN'T AROUND BACK THEN BUT THERE WAS AN ELIXIR SULFANA ALAMIDE WHERE 100 PEOPLE DIED AFTER A MANUFACTURER TRIED TO MIX DIETHYLENE GLYCOL TO MAKE IT MORE PALATABLE FOR PEOPLE TO TAKE AND IT RESULTED IN DEATH. ETHYLENE GLYCOL POISSONS YOUR KIDNEYS. THEN IT WAS AMENDED TO INCLUDE EFFICACY AND SAFETY TESTENING 1962, THAT WAS AFTER THE THALIDOMIDE TRAGEDY WHERE THE PREGNANT WOMEN CAUSED THE NAUSEA PILL AND IT CAUSED BIRTH DEFECTS. SO THAT'S WHEN ANIMAL STUDIES CAME INTO LAW I WILL SAY AND USING ANIMALS FOR STUDIES THAT COULD BE DANGEROUS TO HUMANS. I WANT TO SAY ANIMAL RESEARCH WAS INCLUDED IN THE ANIMAL RULE BUT IT WAS DESIGNED BECAUSE WE ARE UNDER THE DECLARATION OF HELSINKI AND THE NEURONBERG CODE IN CIVILIZED COUNTRIES. WE DON'T DO THAT KIND OF RESEARCH IN HUMANS. SO I HAVE TO GET THAT OUT THERE. FDA JOINED THE ENTERAGENCY COORDINATING COMMITTEE ON THE VALIDATION OF ALTERNATIVE METHODS, THAT'S CALLED ICSAM, THERE ARE 15 GROUPS INVOLVED AND THEY ARE CHARGED WITH THE THREE Rs. THEY HAVE LOTS OF WAYS OF REDUCING THE NUMBERS OF ANIMALS IN RESEARCH. REDUCING REFINING REPLACEMENT ARE ALL THE THREE Rs THAT REALLY ARE PART OF PUBLIC LAW. NEXT SLIDE SOME WE'RE GOING TO REVIEW CATEGORIES OF PAIN AND DISTRESS. THESE ARE DEFINITIONS. YOU HAVE TO HAVE AN UNDERSTANDING TO CATEGORIZE PAIN TO UNDERSTAND A CONSISTENT EUTHANASIA POINT. NEXT SLIDE. NEXT SLIDE. THESE ARE USDA CATEGORIES SPLIT UP FOR EASE OF READING. THERE'S FOUR CATEGORIES STARTING WITH CATEGORY B. YOU CAN READ THESE YOURS AND IF YOU'RE DOING RESEARCH YOU'RE FAMILIAR WITH THEM. NOTICE IT STARTS WITH B AND B YOU'RE NOT NECESSARILY DOING ANYTHING TO THE MANL. HE'S ARRIVED, HE'S SITTINGzV IN CONSIGNMENT OR QUARANTINE DOES NOT ARRIVE P CATEGORY C DOES NOT INVOLVE WITH PAIN DISTRESS OR USE OF PAIN RELIEVING DRUGS. NEXT SLIDE PLEASE. D AND E ARE PROBABLY THE CATEGORIES THAT YOU'RE MOST FAMILIAR WITH BECAUSE THAT'S REALLY WHEN YOU TALK ABOUT RELIEF, RELIEVING PAIN OR USING TRANQUILIZERS ANESTHETICS, ANALGESICS, THOSE ARE ADDRESSED AT THE SPECIFIC AIM OF RELIEVING PAIN. SO CATEGORY E ARE THOSE TESTS THAT DON'T ALLOW ANY RELIEF OF PAIN OR THE SO-CALLED STUDIES THAT INVOLVE DEATH OF EMPLOYEE WOULD BE CONSIDERED CATEGORY E. THESE CATEGORIES ARE REALLY IMPORTANT TO KNOW BECAUSE USDA COLLECTS ALL THIS DATA AND THEY NEED TO LOOK AT THE TOTAL NUMBER OF ANIMAL USED. A LOT OF ANIMAL RIGHTS GROUPS FEEL IT'S NOT REPRESENTATIVE OF THE REAL DATA BECAUSE IT DOESN'T INCLUDE SMALL RODENTS, MICE, RATS, BIRDS. SO CATEGORY ES ARE SENSITIVE F. YOU'RE USING NON-HUMAN PRIMATES YOU'LL FIND THAT YOU PROBABLY WILL RECEIVE A FREEDOM OF INFORMATION ACT FOR THOSE STUDIES BECAUSE THOSE ARE THE RESEARCHERS THAT ARE TARGETED BY SOME OF THE EXTREMIST GROUPS FOR USING ANIMALS. NEXT SLIDE, PLEASE. SO CATEGORY B, THE NICE THING ABOUT THESE SLIDES, THESE NEXT SLIDES IS MOST OF THE IACUC'S NEIGH WIDE HAVE AGREED AND HAVE DIFFERENT STANDARDS AND THEY TEND TO FALL WITHIN THE DEFINITIONS OF EXAMPLES OF WHAT IS THE CATEGORY B WHAT IS CATEGORY C. IF YOUR ANIMAL ARRIVED AND YOU PUT AN EAR TAG OR TATTOO, THAT'S AUTOMATIC CATEGORY C. BECAUSE YOU HAVE DONE A PROCEDURE NOW. IF IT'S A HUSBANDRY PROCEDURE SOME PEOPLE TATTOO THEIR DOGS. IN RESEARCH THAT'S CONSIDERED A CATEGORY C PROTOCOL. NEXT SLIDE, PLEASE. THESE ARE THE MORE COMPLEX WHEN YOU GET INTO CATEGORY D AN E. NOTICE CATEGORY E IS NOT LIMITED TO SEVERE STUDIES LIKE RADIATION SICKNESS, IT'S ALSO REINFORCEMENT BEHAVIORAL EXPERIENCE BECAUSE THOSE GO ON AS WELL. ANYTHING THAT LEADS TO TISSUE DEATH OR LONG PERIODS OF RESTRAINT ARE CONSIDERED CATEGORY E. NEXT SLIDE. COMMON CHALLENGES NOW THAT WE HAVE THE OTHER THINGS OUT OF THE WAY WE'RE GOING THE ADDRESS WHAT OUR CHALLENGES ARE AND HOPEFULLY SOME SOLUTION SO CHALLENGE ONE, THERE'S SEVERAL CHALLENGES BUT I TRIED TO SIMPLIFY BECAUSE WE DON'T HAVE ENOUGH TIME TO G INTO EVERY CHALLENGE. MULTIPLE STAFF MEMBERS SHOULD AIM FOR CONSISTENT REPRODUCIBLE MEASURES. IN OTHER WORDS, YOU SHOULD HAVE YOUR PROFESSIONAL STAFF TRAINED TO OBSERVE THE SAME THING. THEY NEED A KEEN EYE TO OBSERVE CHANGES IN ANIMALS BECAUSE THEY MASK SIGNS OF PAIN. MOST SPECIES USED IN RESEARCH NON-HUMAN PRIMATES ARE WILE ANIMALS. WILD ANIMALS ARE TAUGHT -- ARE NOT TAUGHT INNATELY MASK PAIN BECAUSE IN THE WILD IT'S DEADLY, IF YOU'RE IN PAIN AND YOU SHOW IT YOU'RE SOMEBODY'S DINNER. SO IN THE WILD EVEN MICE HAVE THE ABILITY TO MASK WHAT WE PERCEIVE AS PAIN. I'LL TALK ABOUT THAT LATER. THERE'S A PAPER PUBLISHED ON THAT. SO YOU ALSO NEED TO HAVE PERSONNEL THAT ARE PRECISION AND NOT JUST RECOGNIZING PAIN BUT WITH THE PAIN MANAGEMENT PLAN. ALL OF THESE THINGS ARE PREEMPTIVE, THIS IS NOT SOMETHING YOU INSTITUTE AS YOU GO ALONG. THESE -- THIS IS SOMETHING THAT FDA LIKES TO SEE UP FRONT IN YOUR PROTOCOL. AND YOUR IACUC IS GOING TO BE A TREMENDOUS HELP IN HELPING YOU CLASSIFY YOUR PROTOCOL AS WELL AS HELPING YOU COME UP WITH A PREYES, MA'AMTIVE PLAN FOR ANALGESICS AN BEING AING BEING ABLE TO LINK SIGNS WITH WHAT YOU'RE SEEING WITH YOUR ANIMAL COLONY. SO I PUT THE KNOWLEDGE EMOTIONAL IMPACT ON EMPLOYEES HERE. BECAUSE I THINK ANY REALLY WELL-RUN PROGRAM HAS AN ASPECT OF STRESS MANAGEMENT. IF YOU HAVE WORKED IN MEDICAL COUNTER MEASURES OR EVEN WORKED IN HIGH CONTAINMENT YOU KNOW IT'S A STRESSFUL ENVIRONMENT. A LOT OF( TIMES YOUR ST AFF IS GOING TO BE AFFECTED BY SOME OF THE EXPERIMENTS YOU'RE DOING TO THE ANIMALS. THEY MAY NOT COME AND TALK TO YOU ABOUT IT BUT IF YOU HAVE A PLAN IN PLACE THAT YOU CAN ADDRESS THESE AT A STAFF MEETING OR HAVE SOME TYPE WHERE THEY CAN TALK TO EACH OTHER ABOUT HOW THEY FEEL, IT ALSO INCREASES YOUR RETENTION. IN THIS FIELD THE RETENTION IS VERY LOW. PEOPLE ARE CONSTANTLY LEAVING. A LOT OF PEOPLE HAVE TROUBLE DEALING WITH THE STRESS AND GRIEF BECAUSE THEY DON'T WORK IN THE FACILITIES BECAUSE THEY HATE ANIMALS THEY WORK BECAUSE THEY LOVE ANIMALS AND WANT TO HELP THEM SO WHEN THEY'RE ON PROTOCOL THAT'S AN EMOTIONAL TIME AT THE END OF THAT PROTOCOL AND THEY HAVE TO SAY GOODBYE TO THAT ANIMAL. BUT THAT'S NOT JUST IN THE RESEARCH ARENA, YOU CAN GO TO ANY POUND IN THE UNITED STATES YOU NEED TO SAY THE SAME THING. WHEN I WAS OOH SENIOR IN VETERINARY SCHOOL, ONE OF OUR DUTIES WAS TO VOLUNTEER TIME AT THE LOCAL POUND. THIS WAS IN THE '80s BEFORE A LOT OF EUTHANASIA METHODS WERE REFINED. IT WASN'T A DAY I DIDN'T COME HOME CRYING BECAUSE OF THE NUMBER OF HEALTHY ANIMALS THAT WE PUT DOWN AND THE ANIMALS THAT WE JUST UNCARED FOR, UNWANTED, ALL A RESULT OF HUMAN IRRESPONSIBILITY. SO WHEN WE TALK ABOUT BEING ABLE TO PROVIDE THESE RESOURCES TO OUR LABBEN LAB ANIMALS THESE ARE HEALTHY ANIMAL, THEY ARE ON STUDY N A LOT OF CASES BONNED WITH YOUR STAFF AND THERE'S NOTHING WRONG WITH THEM BEING ABLE TO HAVE A METHOD OF STRESS REDUCTION AND GOING THROUGH THE STAGES OF GRIEF. IT HAPPENS IN PRACTICE, IF YOU HAD A LOVING PET YOU SAID GOODBYE TO BECAUSE OF TERMINAL DISEASE, YOU STILL GO THROUGH THE FIVE STAGES OF GRIEF. SO A LOT OF PRIVATE PRACTICE CLINICS ARE OFFERING GRIEF COUNSELING, THERE'S ACTUALLY GRIEF GROUPS FOR PEOPLE WHO LOST THEIR LIFETIME COMPANION BE IT A CAT, A DOG, SO THESE ARE NORMAL THINGS. I THINK AN EXCELLENT PROGRAM IS GOING TO ADDRESS THOSE THINGS AND NOT JUST PRETEND LIKE THEY DON'T HAPPEN. SO I WANTED TO TALK ABOUT PROGRAMS THAT HAVE EXCELLENT WAYS FOR STAFF TO REDUCE THEIR GRIEF. NEXT SLIDE PLEASE. THE FDA WANTS TO KNOW BEFORE. DECIDE EARLY WHAT MATTERS MOST IN YOUR CLINICAL END POINT. IF YOUR USING TELEMETRY YOU HAVE TO DECIDE WHICH ORGAN MATTERS MOST, ARE YOU LOOKING AT THE NEURAL SYSTEM T CARDIOVASCULAR SYSTEM, WHEN YOU IMPLEMENT YOUR PROTOCOL AN MEASURE THINGS ARE YOU LOOKING AT TEMPERATURES, IS THE FEVER GOING TO SPIKE AT A CERTAIN POINT. ALL THESE ARE IMPORTANT AND YOU SHOULD DECIDE AHEAD OF TIME. IT SHOULD GO INTO THE PROTOCOL. YOU NEED TO ESTABLISH INTERVENTIONS AND HUMANE END POINTS. THAT'S WHERE THE EXPERTISE HAVING YOUR STAFF TRAIN FOR THAT SPECIES AN KNOWING WHAT THEY'RE DOING COMES IN. PAIN MANAGEMENT IS GOING TO LOOK DIFFERENT IN A MOUSE THAN A RAT AND A HAMSTER AND JOURNAL AND GUINEA PIG AND PRIMATE. IT'S ALL GOING TO BE DIFFERENT. AND WE WILL TALK ABOUT THAT TOO AS WELL. SO ANTICIPATE YOUR PHYSIOLOGIC RESPONSES IF YOU'RE POOLING BLOOD SAMPLES AND YOU KNOW A CREATININE WILL SPIKE AT CERTAIN POINT. IF THERE'S A MAGIC BULLET YOU CAN TIE INTO YOUR END POINT CONSIDERATIONS. THAT'S GOING TO BE BASED ON THE AGENT YOU'RE WORKING WITH AN BASED ON YOUR PROTOCOL. SHE DID A GOOD JOB TOUCHES ON IT WHERE IF YOU COME IN AND YOUR ANIMAL HAS BEEN DEAD 12 HOURS YOU'RE NOT GOING TO GET ANY SAMPLE INTEGRITY OUT OF THAT THEY CAN'T DO ANYTHING WITH YOUR RESULTS. ADEQUATE CONTROLS IN ANIMAL NUMBERS, DECIDING ON YOUR SAMPLE SIZE AND MAKING SURE IT'S RELEVANT. NEXT SLIDE. THESE ARE VALUABLE SOLUTIONS. OF COURSE WE HAVE MORE TO TALK ABOUT WHAT'S REPRESENTED HERE BUT ADEQUATE TRAINING, REDUCES SUBJECTIVE ASSESSMENT. WE TALK ABOUT SUBJECTIVITY OF PAIN AND SYMPTOM VERSUS SIGN. IF YOU HAVE MEASURABLE THINGS THAT YOU KNOW ARE NOT SUBJECTIVE THOSE NEED TO BE CLEARLY STATED IN YOUR PROTOCOL SO PRE-PLAN YOUR INTERVENTION STANDARDS AND A LOT OF LABS HAVE DESIGN SCORING SYSTEMS THAT ARE SPECIFIC TO THE PROTOCOL. SO WE DON'T -- FOR INSTANCE, THIS IS A SCORING SYSTEM FOR HUMANS. SO WHEN YOU DEVELOP THIS, SOMETIMES IT GIVES YOU A CLUE WHERE YOUR EARLY INTERVENTION STAGE SHOWBS BECAUSE IF IF YOU'RE DOING CONSISTENT WORK YOU'RE GOING TO SEE A PATTERN. FOLLOW YOUR IACUC STIPULATED GUIDELINES. I PUT THAT NARRATIVE THERE TO REMIND YOU IT IS LAW TO WRITE A NARRATIVE AND DO A PROPER SEARCH AND WHEN YOU DOING A NARRATIVE IT NEEDS TO INCLUDE DATES OF YOUR SEARCH, THE YEAR THAT YOU COVERED, THE SUBJECT, KEY WORD. IT NEEDS TO BE INCLUDE SIF. -- INCLUSIVE. THAT'S A LOT OF INFORMATION HOW TO DO A SEARCH. WE'RE GOING TO COVER THAT TOPIC, WE HAVE A MEMBER OF USDA COMING TO FDA IN NOVEMBER TO SPEAK ABOUT THE ANIMAL WELFARE ACT AND THEY WILL TOUCH ON HOW TO DO A SEARCH BECAUSE PEOPLE DON'T KNOW HOW DEEP THAT NEEDS TO BE. IF YOU FIND THE WORK HOW YOU NEED TO JUSTIFY IF THERE IS AN ALTERNATIVE AND YOU FIND ONE AND YOU DON'T WANT TO USE IT, IT HAS TO BE STRONGER. YOU HAVE TO SCIENTIFICALLY JUSTIFY WHY YOU DON'T WANT TO USE AN ALTERNATIVE. THAT SEPARATES THE GUEST WORK FROM SCIENCE. IN THE END THAT'S WHAT YOU WANT. YOU DON'T WANT TO DO GUESS WORK BECAUSE YOU WON'T HAVE GOOD INTEGRITY OF YOUR DATA IF IT'S GUESS WORK. THEN YOU TRAIN FOR TECHNIQUES THAT ENSURE CONSISTENT RESULTS. YOU CAN DO THIS A NUMBER OF WAYS. YOU CAN COMPARE ASSESSMENTS BETWEEN EXPERIENCED TECHNICIANS. YOU CAN LOOK AT THE PUBLISHED DATA AND SAY WELL, ARE THE RESULTS CONSISTENT? THE OTHER PEOPLE IN THIS FEEL IF THEY'RE DOING THIS WORK ARE THEY GETTING SIMILAR RESULTS THAT YOU'RE GETTING. YOU CAN'T IGNORE TELEMETRY ESPECIALLY IN A HIGH CONTAINMENT ENVIRONMENT WORKING WITH SOME OF THE MEDICAL COUNTER MEASURES. BECAUSE TELEMETRY RESPONSES ARE GOING TO BE CONSISTENT AIDS. THEN POWER ANALYSIS MAKING SURE YOU DONE HAVE A TYPE 2 ERROR. LASTLY ESTABLISHING A CRITERIA AND VETERINARY MONITORING FOR END POINTS. NEXT SLIDE. WE TALK THE THREE Rs, THE BIG 3R WHERE WE HAVE TO ADDRESS PAIN IS REFINEMENT. SO THESE ARE SHOM SOLUTIONS IF YOU'RE LOOKING FOR REFINEMENT, A LOT OF PREEMPTIVE ANALGESIA IS NUMBER ONE. IF YOU IDENTIFY WHERE THIS IS GOING TO HAPPEN, THEN YOU KNOW WHERE TO INTERVENE. EVEN IN HUMAN HOSPITALS YOU'LL HEAR PHYSICIANS SAY TAKE YOUR PAINKILLER AFTER YOU HAVE THE PROCEDURE BEFORE THE PAIN STARTS BECAUSE IT'S HARD TORE CONTROL AFTER THE PAIN STARTS, THE SAME IS TRUE IN ANIMALS. THIS IS A PAIN ASSESSMENT PAPER WRITTEN BY THE NATIONAL OR SUPPORTED BY THE NATIONAL ACADEMY OF SCIENCE. IT DOES NOT REPRESENT ALL SPECIES BUT IT IS QUITE A SPECIES -- SOMETIMES SWEATING IS A SIGN OF PAIN. NEXT SLIDE. THEN I PUT THIS HERE BECAUSE THIS WAS A SWIFT PAPER THAT WAS RECENTLY DONE TO ASSESS PAIN IN MICE. WHAT THEY DID IS THEY DID VASECTOMIES IN MALE MICE AND THEY HAD A CONTROL GROUP THAT DID NOT RECEIVE ANY PAIN MEDICATION. IT WAS A SIMPLE STUDY THAT USED TWO VERY COMMON PAIN RELIEVING DRUGS. PRETTY MUCH EVERYBODY IS PREDATORS FOR MICE. CATS, EVERYBODY IS OUT TO GET THEM SO SOMETIMES WHEN THE INVESTIGATOR COME MS. THE ROOM, HERE IS THE PREDATOR TO THE MOUSE. THE ONLY WAY THEY SHOW THAT BECAUSE THEY CAN MASK A LOT OF DIFFERENT SIGNS, IS INCREASED HEART RATE WHICH IS A SYMPATHETIC ACTION. SO THIS PAPER USED TELEMETRY TO LOOK AT HEART RATE AND THEY NOTICE THERE WAS NO CHANGE IN HEART RATE WITH ANIMALS THAT RECEIVED THE PAIN RELIEVING MEDICATIONS AD HEAD OF TIME. THE HEART RATE WENT UP IN CONTROL GROUP THAT DIDN'T HAVE THE PAIN MEDICATION TESTIMONY OTHER THING THEY NOTED IS THE CONTROL PAIN GROUP WENT BACK ON THEIR FEED. THERE WAS A THREE DAY LAPSE FOR MICE THAT HAD THE SURGERY THAT DID NOT -- THREE LAY LAPSE FOR EATING SO THEY LOST SOME WEIGHT. NEXT SLIDE. THIS IS AN EXAMPLE OF A SCORING SHEET. THERE'S EXAMPLES OUT THERE. I LIKE THIS ONE BECAUSE I HAD THE CHANCE TO WORK ON THIS WITH HPA, USING THIS FOR SOME OF THEIR POX STUDIES IN NON-HUMAN PRIMATES. I STUCK IT THERE TO SHOW YOU SOME OF THE THINGS THAT YOU CAN ASSESS AND HOW THE READINGS WERE DONE BECAUSE A LOT OF TIMES IF YOU'RE GETTING CONSISTENT READINGS YOU'LL KNOW THIS COULD BE A TRIGGER POINT IN YOUR STUDY. NEXT SLIDE. THIS IS MY LAST SLIDE. ADMA, EVERYBODY HAS TO FOLLOW, IT'S NOT OPTIONAL BECAUSE IT'S PART OF THE PHS POLICY. THE AMERICAN VETERINARY MEDICAL ASSOCIATION GUIDELINES ON EUTHANASIA. IT USED TO BE CALLED THE ADMA PANEL ON EUTHANASIA. ABOUT ONCE EVERY FIVE YEARS A GROUP OF SMART VETERINARIANS AND SIGNTISSINGS GET TOGETHER AND THEY LOOK AT ALL THE CONCERNS SURROUNDING HUMANE EUTHANASIA. IT'S BECOME AN ISSUE BECAUSE CERTAIN GROUPS WANT THEM TO ADDRESS THE USE OF PAIRLYTIC AGENTS USED IN HUMAN EUTHANASIA LIKE PRISONERS, THAT'S WHAT WE CALL HUMAN EUTHANASIA BUT IT'S NOT ADDRESSED IN THE ACT AT ALL. IT REALLY SHOULDN'T BE ADDRESSED HERE BECAUSE THIS DOCUMENT IS FOR VETERINARIANS AFTER VETERINARY USE. WE ARE WAIT FOR A NEW VERSION DUE OUT IN FALL OF 2002, THE COMMENT PERIOD PASSED BUT BAY CLIS IT WAS A 39 PAGE REPORT. I UNDERSTAND THE NEW REPORT IS MORE EXTENSIVE AND THE APPENDICES GIVES YOU AGENT AND ACCEPTABLE METHS OF EUTHANASIA. LAST SLIDE, PLEASE. THIS IS, IF YOU NEED MORE INFORMATION ON OUR MEDICAL COUNTER MEASURES INITIATIVE, PLEASE VISIT OUR WEBSITE, I DO WANT TO SAY THAT WE HAVE STARTED A TRAINING PROGRAM ENTITLED ACADEMIC DEVELOPMENT OF GOOD LABORATORY PRACTICES IN MAXIMUM CONTAINMENT, AND THAT'S GOING TO BE WITH THE UNIVERSITY OF TEXAS MEDICAL BRANCH, OUR KICK OFF COURSE IS OPEN TO ANY ONE DOING MCM RESEARCH APRIL 1st 2013. THANK YOU VERY MUCH FOR YOUR ATTENTION AND I HOPE NOBODY FELL ASLEEP. [APPLAUSE] >> I THINK IN THE INTEREST OF TIME WE'LL KEEP MOVING WITH THE PROGRAM AND FORGO QUESTIONS AT THIS POINT. SO I WOULD LIKE TO INTRODUCE OUR NEXT SPEAKER, DR. JIM SWEARENGEN, A COMPARATIVE MEDICINE VETERINARIAN FOR THE NATIONAL BIODEFENSE ANALYSIS AND COUNTER MEASURES CENTER, AND FORMER SENIOR DIRECTOR FOR ASSESSMENT AND ACCREDITATION OF LABORATORY ANIMAL CARE. ALAC INTERNATIONAL. HIS TALK THIS AFTERNOON IS ON SUPPORTIVE CARE OVERVIEW. LENDING SUPPORT OF CARE CONSIDERATIONS WITH EXPERIMENTAL DESIGN. PLEASE WELCOME DR. SWEARENGEN. >> GOOD AFTERNOON. RECONNECT WITH OLD FRIENDS TODAY, THESE MEETINGS ARE FUN FOR THAT REASON. FIRST I WOULD LIKE TO THANK JUDY VERY MUCH FOR THE OPPORTUNITY TO COME HERE AND TALK ABOUT THIS TOPIC TODAY SINCE MY FIRST YEAR RESIDENCY IN 1990 WHEN I FIRST GOT INVOLVED WITH INFECTIOUS DISEASE RESEARCH, THIS HAS BEEN AN ISSUE, I HAVE ALWAYS FELT PASSIONATE ABOUT AND HAVE TRIED TO MOVE FORWARD AS TIME GOES ON. IT'S REALLY EXCITING TO HEAR SOME OF THIS DISCUSSION HERE TODAY ON THIS TOPIC. I THINK I CAN SAY WITH CONFIDENCE THAT THIS IS HAS SOME REAL TRACTION AND MAKES ME FEEL REALLY GOOD THAT WE'RE MOVING IN THE RIGHT DIRECTION WITH REGARD TO BLENDING SUPPORTIVE CARE WITH EXPERIMENTAL DESIGN ON THESE TYPES OF STUDIES. IT'S BEEN GOOD DISCUSSION. NOT SURE I REALLY NEED TO GIVE MY TALK BUT I'LL DO IT ANYWAY, BRING SOME POINTS UP THAT WILL HELP CONTINUE TO MOVE THIS SUBJECT FORWARD. THIS IS A QUICK SLIDE, YOU HAVE SEEN THIS A NUMBER OF TIMES, THE ONLY THING I'LL MENTION IS THE LINE HIGHLIGHTED IN RED THAT TALKS ABOUT THE AFFECT SHOULD BE CLEAR RELATED TO WHAT THE AFFECT SHOULD BE IN HUMANS AND THE STATEMENT ENHANCEMENT OF SURVIVAL OR PREVENTION OF MAJOR MORBIDITY. THAT'S ALWAYS BEEN A TOUGH THING TO TRY TO INTERPRET. MANY OF YOU DEALING WITH THIS FOR A NUMBER OF YEARS HAVE REALIZED WE HAVE KIND OF GONE FROM A PLACE WHERE THIS WAS TAKEN LITERALLY, TO THE POINT TO WHERE WE NOW REALIZE THIS HAS TO BE INTERPRETED. AND THERE IS -- WE HAVE ROOM TO WORK WITH THIS AND REALLY TO IMPLEMENT INTENT VERSUS RATHER THAN A LITERAL INTERPRETATION. NEXT SLIDE PLEASE. ANOTHER COUPLE OF POINTS TODAY THAT I LIKE SEEING BROKE OUT AND TALKED ABOUT SEPARATELY. THAT'S THE ISSUE OF NATURAL HISTORY STUDIES VERSUS EFFICACY STUDIES. I THINK THIS KIND OF GOT MIXED IN THE MILIEU EARLY ON AND STARTING TO SEPARATE OUT AND PEOPLE RA REALLY STARTING TO UNDERSTAND, I THINK JERRY'S TALK EARLIER REALLY BROUGHT THIS HOME WHEN HE SAID WHEN YOU'RE QUALIFYING THESE MODELS YOU NEED TO QUALIFY THE NATURAL HISTORY MODEL. AND YOU NEED TO QUALIFY THE EFFICACY MOAD. SO THAT WAS REALLY AN IMPORTANT POINT IN MY MIND, TO UNDERSTAND THE DIFFERENCE TWEENS THE TWO TYPES OF STUDIES WITH NATURAL HISTORY BASICALLY COMPARING HUMANS AND IN THIS CASE MANY TYPES MORTALITY IS THE END POINT. ILLUSION OF INTERPRETATION OF CODE OF FEDERAL RESERVATIONS IS THE USE OF PROACTIVELY PROSPECTIVELY DEFINED EUTHANASIA CRITERIA IS BECOMING MORE AND MORE EXPECTATION AND IS THE CURRENT EXPECTATION NOW. EFFICACY IS STRAIGHT FORWARD, MIMICKING THE CLINICAL SCENARIO TO HUMANS, THAT'S PRETTY STRAIGHT FORWARD BUSM I'LL SHOW YOU SLIDES LATER ON THAT WILL MAKE THAT MORE DISCUSSION POINT AND SAYING YEP THAT'S WHAT WE WANT TO DO. AS FAR AS CARE PAYS A ROLE IN MIMICKING THE CLINICAL SCENARIO IN HUMANS. IN THE GUIDANCE FOR INDUSTRY, THERE IS ANOTHER SENTENCE THERE HIGHLIGHTED IN RED. YOU HAVE TO REALIZE IN SOME INTANSES SUPPORTIVE CARE HAS PROVIDED AS PART OF THE STUDY DESIGN. REALIZE STUDIES SHOW THE SUPPORTIVE -- OVER SUPPORTIVE CARE ALONE. I HAVE A COUPLE OF EXAMPLES OF THAT LATER ON IN THE TALK. THE LAST BULLET YOU HEARD IT OVER AND OVER, YOU HAVE TO DO THIS UP FRONT, GET INPUT WITH FDA. WE'RE NOT TALKING DISCOVERY, WE'RE TALKING ABOUT ADVANCE DEVELOPMENT WHEN WE'RE TALKING ABOUT QUALIFYING MODELS, WORKING ON NATURAL HISTORY STUDIES ADVANCED EFFICACY STUDIES AND THINGS LIKE THAT. WHEN YOU GET READY TO DO THOSE KINDS OF THINGS MAKE SURE THERE'S A LOT OF COMMUNICATION WITH THE FDA AND TO HAVE THIS GROUP PUT TOGETHER TO ADDRESS ISSUES AND BEGIN THIS CONVERSATION IS JUST HUGE AND SHOWINGS THE THOUGHT AND PROACTIVE APPROACH THE FDA IS TAKING IN THIS WHOLE ISSUE AND IS A REAL -- VERY NICE TO SEE. NEXT SLIDE, PLEASE. SOILY GO OVER A COUPLE -- SINCE ESTELLA DID A NICE JOB TALKING ABOUT END POINTS I WILL MIX THE TWO AND GIVE YOU YOU EXAMPLES WHERE BE MAYBE NOT AS STRICT FORWARD AND STILL DISCUSSION POINT NEED TO OCCUR ON THIS. SO THE CASE OF RABBIT INHALATIONAL ANTHRAX. THAT'S A COUPLE PAPERS WHERE I PULLED THIS INFORMATION. AND YOUR TYPICAL PROGRESSION IS REALLY VERY QUICK. DAY 2 YOU MIGHT -- YOU USUALLY SEE A FEVER AND SOMETIMES THAT FEVER MAYBE AN HOUR OR TWO BEFORE THE ANIMAL DIES BUT IN DAY 2 AND 3, THAT'S WHEN THE ANIMALS WILL DIE. THERE IS NO OTHER CLINICAL SIGNS UNTIL SHORTLY BEFORE THE DEATH SO QUICK PROGRESSION. NEXT SLIDE, PLEASE. DIFFERENT MODEL, HOMOLOGOUS MACAQUE WITH EBOLA VIRUS. YOU CAN SEE IT'S A MUCH LONGER PROGRESSION. TIME IS A FACTOR AND WE'RE RUNNING LATE BUT FROM DAY 3 THROUGH DAY 6 THERE IS A VERY SPECIFIED KIND OF TYPICAL PROGRESSION OF DISEASE AND REPRODUCIBLE SO YOU HAVE A PERIOD OF TIME WHICH YOU CAN IDENTIFY THESE CLINICAL SIGNS AND DEAL WITH THEM. AND ALSO ALLOW YOU TO DEVELOP YOUR END POINTS. NEXT SLIDE, PLEASE. THIS NEXT SLIDE IS KIND OF JUST TO GIVE AN OVERVIEW WHAT WE'RE TALKING ABOUT. FOR THE RABBIT ANTHRAX MODEL WHAT YOU'RE GOING TO SEE IS FEVER. AGAIN, THERE'S SOME REPORT THAT THERE MAYBE A LITTLE HYPERACTIVITY ASSOCIATED RIGHT BEFORE DEATH ORENING LIKE THAT. I HAVE SEEN THAT OCCASIONALLY BUT NOT CONSISTENTLY IN RABBITS. BUT IT'S A RABBIT DISEASE PROGRESSION VERY FEW CLINICAL SIGNS, FEW OPPORTUNITIES FOR SUPPORTIVE CARE ACTUALLY AND CLINICAL SCORE CHECKLISTS ARE PRETTY MUCH INEFFECTIVE. A REAL LIFE EXAMPLE YOU SAW THE PROGRESSION OF DISEASE BUT SOME IDEA HOW FAST IT GOES, IT WAS ABOUT TWO MONTHS AGO. AND WE WORKING WITH ANTHRAX RABBIT MODEL. WE'RE DOING FOUR TIME DAY CHECKS ON THEM. I WENT INTO DO THE EARLY MORNING CHECKS AND CAME UP ON ONE RABBIT AND WAS MONITORING AND WATCHING THE CLINICAL SIGNS. YOU STAY AT THE BACK OF THE CAGE A BIT, MOST WILL HOP AROUND AS YOU OPEN THE DOOR OR COME UP TO THE FRONT. THESE WERE ISOLATION PRIMARY ISOLATION UNITS. SO OPEN THE DOOR, STANDING BACK AND WATCH THEM 10, 15 SECOND AND HE HOPPED TO THE FRONT AND ACTED NORMAL. SO I THOUGHT WELL, HE'S GOT A LITTLE DELAY RESPONSE THERE TO NOVEL ENVIRONMENTS SO I'LL COME BACK WHEN I FINISH CHECKING. I'M JUST GOING TO DOUBLE CHECK AGAIN. SO 30 MINUTES LATER I WENT BACK AND 30 MINUTES LATER HE WAS LAYING DOWN ON HIS SIDE AND COMATOSE. THAT IS HOW FAST THE RABBIT WENT DOWN FROM LOOKING SUSPICIOUS STILL HOPPING AROUND, STILL LOOKING GOOD TO COMATOSE. BY THE TIME I WENT AND GOT -- IT IT WASN'T QUITE HOME COAS. VERY DESPONDENT, BY THE TIME I GOT THE ANESTHESIA TO EUTHANASIA IT, IT WAS DEAD. THAT WAS ABOUT ANOTHER 15 MINUTES. SO WHEN WE TALK ABOUT ALL THESE NICE THINGS TO DO, WE ALSO HAVE TO TAKE THE REALITY OF THESE MODELS WITH IT AS TRUE. WE CAN MAKE ADVANCE, AS WE DEVELOP MORE AND BETTER CLINICAL MARKERS OF DISEASE AND THINGS LIKE WE MAYBE ALLOWED TO REFINE THIS. BUT WE HAVE TO MONITOR THE SITUATION AS WELL. I DON'T THINK ANY OF YOU HAVE READ THROUGH THE PAMPHLET OR THE HAND-OUT FOR THE MEETING READING SOME OF THESE ABSTRACTS IN THERE BUT IT'S AMAZING SOME OF THE DATA WE'RE GATHERING ON CLINICAL MARKERS, VERY COMPLEX DATA. I THINK WE CAN USE THOSE CLINICAL MARKERS AS REAL OBJECTIVE CRITERIA IN MAYBE HELPING DETERMINE SOME OF THESE EARLIER END POINTS RATHER THAN RELYING ON CLINICAL SIGNS SO WE'RE MAKING PROGRESS THERE, BUT IT TAKES TIME AN RESEARCH TO DO THAT. THE PRIMATE MODEL, JUST IGNORE THAT PLEATLY WITH THE DISEASE PROGRESSION, THE OPPORTUNITIES FOR SUPPORTIVE CARE INCREASED, THERE'S MULTIPLE CLINICAL SIGNS EFFECTIVENESS OF END POINT CHECKLIST BECOMES MORE APPLICABLE AND EFFECTIVE. DIFFERENT MODELS CAN HAVE VERY DIFFERENT OUTCOMES AND THE IMPLEMENTATION OF SOME OF THESE THINGS CAN BE VERY DIFFERENT. NEXT SLIDE, PLEASE. WHAT SHOULD SUPPORTIVE CARE BE. THIS IS WHAT JIM THINKS IT IS. JIM AND JUDY, WE HAD A FEW DISCUSSIONS AND THOUGHT WHAT SHOULD SUPPORTIVE CAIFER BE AND STUDY DESIGN CONSIDERATIONS WHICH WE'LL TALK ABOUT NEXT SLIDE. IN MY OPINION, DESIGN CONSIDERATION WHICH REFLECTS IN THE NEXT SLIDE CONVERSATIONS WE HAD, SUPPORTIVE CARE SHOULD DEFINITELY HAVE TO BE DEFINED THE WIN IS A BIG ONE. ROSE MARY MADE THE COMMENT ABOUT HOPEFULLY 24/7 OBSERVATION. HOW DO WE DO THAT. I KNOW AT LEAST ONE TELEMETRY COMPANY WORKING ON A REMOTE NOTIFICATION SYSTEM THAT WHEN CERTAIN FIZZ QUO LOGICAL PARAMETERS ARE MET AND THE DATA IS RECORDED AND IT EXCEEDS YOUR ESTABLISHED PARAMETERS IT CAN REMOTELY NOTIFY THE VETERINARIAN, THE PI, WHOEVER, WHATEVER, AND MAYBE ALLOW SOME OF THAT 24/7 OBSERVATION. AGAIN, THIS IS IN THE -- I THINK IT'S ACTUALLY IN THE DESIGN STAGES FROM WHAT I UNDERSTAND THERE'S THINGS COMING ALONG WITH THIS CONCERN. 246/7 WHETHER REMOTE NOTIFICATION OR MORE TIME, TAKES A LOT OF RESOURCES. SOMEBODY WHO STUDY BL-4 AND WORKS FOR MONTHS ON END, AT SOME POINT YOU CAN'T DO IT ANY MORE. YOU CAN'T PHYSICALLY AND MENTALLY DO IT, IT'S UNSAFE AND THAT'S THE LAST THING WE WANT TO DO IS PUT PEOPLE IN THAT SITUATION WE HAVE TO HAVE RESOURCE THERE IS TO KEEP UP THAT LEVEL OF OBSERVATION AND ASSESSMENT. NEXT SLIDE PLEASE. BACK ONE MORE TIME I DON'T MEAN TO BE A PAIN. THE OTHER THING FROM THE VETERINARY STANDPOINT IS THE LAST BULLET. PRE-STUDY EVENT, YOU GET YOUR ANIMALS IN, IN QUARANTINE, YOU'RE FOLLOWING THROUGH, PRESTUDY EVENTS OR EXPERIMENTALLY RELATED. THESE HAVE TO BE DOCUMENTED THOROUGHLY AND LOT OF TIMES WE THINK THEY'RE NOT ON STUDY, WE CAN TAKE LIBERTY WITH THE DOCUMENTATION. ANYBODY IN THE FDA WILL TELL YOU THAT DATA ON ANIMALS BEFORE THE STUDY IT'S IMPORTANT TO HAVE BACKGROUND INFORMATION, AND IF IT IS GOING TO BE PART OF THE PACKET IT NEEDS TO BE DOCUMENTED. DON'T FORGET THAT ASPECT AS WELL. NEXT SLIDE, PLEASE. SO LET'S LOOK AT SOME OF THE THINGS THAT MIGHT WANT TO CONSIDER. THIS IS NOT A DEFINITIVE LIST, THIS IS THROUGH CHATTING AND DISCUSSIONS AND EMAIL TRAFFIC WE THOUGHT THESE ARE THINGS INTO CONSIDERATION THAT WE MIGHT WANT TO LOOK AT WHEN YOU'RE DESIGNING A STUDY. THE FIRST THING, THIS IS MENTIONED BEFORE, ABOUT BASIC VETERINARY CARE VERSUS SUPPORTIVE CARE. IN MY OWN MIND I CONSIDER SUPPORTIVE CARE TYPICALLY A PLANNED PART OF THE STUDY. SOMETHING THAT WHETHER A TREATMENT CRITERIA IN PLACE, WRAPPED UP AND DEFINED AS PART OF THE ANIMAL PROTOCOLTOR THE STUDY PLAN. BASIC VETERINARY CARE IS AN UNEXPECTED RESULT THAT REQUIRED MEDICAL INTERVENTION. YOU HEARD EARLIER ABOUT STANDARD VETERINARY CARE. YOU CAN BE DOING SUPPORTIVE CARE AS PART OF THE STUDY WHICH IS ALSO GOOD BASIC VETERINARY CARE. SO THEY CAN BE THE SAME BUT IN WAYS VIEWED DIFFERENTLY AS WELL MORE FROM A REGULATORY STANDPOINT. IMPACT ON THAT, NATURAL DISEASE COURSE THAT'S A QUESTION WE ALL ASK,s SCIALLY PAIN RELIEF QUESTION, WHAT'S THE N SAIDZ OR OPIOIDS, THE EFFECT ON IMMUNE SYSTEM AND PARAMETERS YOU MAYBE MEASURENING THAT ANIMAL. AND DOES IT HAVE IMPACT OR NOT ON THE DISEASE COURSE. HOW DOES IT REFLECT STANDARDS OF CARE IN HUMAN? THAT IS A BIG QUESTION THAT'S COME UP HERE. WE HAD A LOT OF DISCUSSION ABOUT THAT TODAY. WHAT'S THE STANDARD OF CARE DURING EMERGENCY EVENT. WE TOUCHED ON THAT FROM A FIELD EVENT VERSUS HOSPITAL CRITICAL CARE EVENT. BUT WHAT ABOUT AN EMERGENCY EVENT, WHAT ABOUT MASS EXPOSURE. WHAT IS YOUR STANDARD OF CARE THERE? THAT'S THE SCENARIO HERE. HOW DOES IT IMPACT MEDICAL COUNTER MEASURES IS A BIG ONE, WHAT'S SAFELY REPRODUCIBLY ADMINISTERED IN A HIGH CONTAINMENT ENVIRONMENT. DON'T FORGET SAFETY OF PEOPLE DOING THIS AS WELL. NEXT SLIDE, PLEASE. SO LET'S LOOK AT SUPPORT CARE IN HUMANS. I WANT TO PREFACE THIS OVER 30 YEARS AGO AS VETERINARY STUDENT I HAD A VERY WISE PROFESSOR TELL ME, HE SAYS ALL YOU YOUNG VETERINARIANS I WANT TO TELL YOU SOMETHING. PHYSICIANS SHOULDN'T TRY TO BE VETERINARIANS. AND VETERINARIANS SHOULD NEVER TRY TO BE A PHYSICIAN. I HAVE HELD THAT MY ENTIRE CAREER. I ALWAYS THOUGHT IT WAS A WOOFER SAYING AND I WON'T TELL MY WIFE TAKE A MOTRIN. LET THE PHYSICIANS DO IT. THAT'S LITTLE EXTREME. BUT I TRY TO TAKE THAT TO HEAR IN MY PROFESSIONAL LIFE. I WANT TO MAKE SURE YOU UNDERSTAND THESE THINGS I GOT CAME OUT OF A DOCUMENT, A VERY RECOGNIZE DOCUMENT, THAT'S THE MEDICAL MANAGEMENT BIOLOGICAL CASUALTY, THERE'S THE 7TH EDITION OUT NOW. ISN'T IT DOWNLOADABLE ON THE WEBSITE, YOU CAN GET ON THERE AND DOWNLOAD IT, IT'S A TREMENDOUS RESOURCE, IT'S VERY CONCISE. AND I THINK THEY DID A REVISION A FEW YEARS AGO SO IT IS PRETTY UP TO DATE. IF WE LOOK AT SMALLPOX YOU CAN SEE THE THINGS BASED ON THIS BOOK. THESE ARE SUPPORTIVE CARE, NOT TREATMENT, BUT SUPPORTIVE CARE BASICALLY. MAYBE THEY ENTERMIX BUT BASICALLY PICK OUT SUPPORTIVE CARE ISSUES. WITH SMALLPOX YOU'RE LOOKING AT MAINTENANCE HYDRATION, NUTRITIONAL SUPPLEMENTATION AND MANAGEMENT OF SECONDARY INFECTION. FOR VIRAL MEM RAJIC FEVER IT GETS MORE INTENSE, VIGOROUS FLUID RESUSCITATION ESPECIALLY IF THEY'RE HYPOTENSIVE. SEDATIVES OR ANALGESICS, RBC PLATELET, GUIDING FACTOR REPLACEMENT, AND YOU CAN SEE A DIFFERENCE OF WHAT WE TALKED ABOUT A FIELD ENVIRONMENT VERSUS WHAT THE BOOK SAYS YOU SHOULD BE DOING IN A MORE HOSPITAL INTENSIVE CARE ENVIRONMENT. THERE'S ALSO THE DIFFERENCES AS WE GO INTO THE ANIMAL MODELS AS WELL. NEXT SLIDE, PLEASE. SO HERE ARE A COUPLE MORE EXAMPLES THAT WILL GO THROUGH AND WORK THROUGH IN A TABLE FORMAT. REPLACEMENT OF FLU VOLUME DER SITS, CORTICAL STEROIDS IF THERE'S EDEMA OR MENINGITIS. AND FOR PNEUMONIC PLAGUE THE ONLY SUPPORTIVE CARE ISSUE I CAN SEE, OR I COULD FIND WAS IV CRYSTALOIDS AND HEMODYNAMIC MONITORING. SO THIS GIVES YOU AN IDEA, OF WHAT THE MEDICAL BOOKS ARE SAYING ARE THE SUPPORTIVE CARE USED FOR THESE DISEASES. SO LET'S MOVE ON YOU WON'T FIND MEDICAL TEXTBOOKS THAT DEAL WITH INHALATIONAL ANTHRAX. THIS IS ONE OF THOSE THAT COVERS A LOT OF THOSE THINGS THAT YOU'RE TRYING TO LOOK FOR BUT NEVER CAN FIND. IT'S A GREAT RESOURCECH NEXT SLIDE PLEASE. SO THIS IS JIM'S WORLD HERE. BEAR WITH ME. SEE IF WE GET A LITTLE BLOOD FLOW HERE, GET SOME OF THAT BLOOD MOVING FROM THE THE STOMACH AND BACK TO THE ARMS AN BRAIN HERE. I WANT TO ASK A QUESTION. AS WE LOOK AT THIS AND WE GOT OUR CATEGORIES UP THERE, THE CURRENT STANDARD OF CARE IN HUMANS WHICH COME FROM THE SLIDES I SHOWED YOU, WE GOT THE IMPACT ON NATURAL DISEASE COURSE WHICH IS ONE OF THOSE QUESTIONS WE ASKED. DOES IT REFLECT MASS CASUALTY STANDARD OF CARE, ITS IMPACT ON EVALUATION OF THE COUNTER MEASURE AND CAN IT BE SAFELY AND REPRODUCIBLY ADMINISTERED IN A HIGH CONTAINMENT ENVIRONMENT. YOU PROBABLY GOT DISAGREEMENT ON WHOA MY ANSWERS ARE -- WHAT MY ANSWERS ARE BUT FOR SUPPLEMENTAL HYDRATION SMALLPOX, WE TALKED ABOUT THAT, COULD THAT BE OFFERED AT THE BEGINNING OF THE STUDY OR WOULD THIS BE SUBCUTANEOUS LATER ON OR INTRAVENOUS LATER ON. PROBABLY NATURAL DISEASE COURSE, NEGLIGIBLE AS FAR AS SUPPLEMENTAL NUTRITION, PAIN CONTROL, ANALGESICS GOING TO HAVE IMPACT ON IT, PROBABLY NEGLIGIBLE. WHAT ABOUT PREVENTION OF SECONDARY INFECTION? IF YOU'RE TALKING ABOUT SOME OF THESE SAY ANAL JESUSSIC, DOES THAT HAVE IMPACT ON THAT OR NOT IF YOU LOOK UNDER MASS CASUALTY OF CARE ARE WE ABLE TO GIVE INTENSIVE SUPPLEMENTAL HYDRATION? PROBABLY NOT. NUTRITION. THERE'S ALL SORTS OF WAYS TO DO THAT, PROVIDE THAT IN A MASS ENVIRONMENT. PAIN CONTROL, PEOPLE WILL CLAMOR FOR IT, THAT'S THE ONE THING YOU HAVE TO ADDRESS. SO YOU CAN WALK DOWN THROUGH HERE, I MADE A COUPLE OF COMMENTS ABOUT SAFELY AND REPRODUCIBLY DEPENDING ON THE ROUTE. I'M LOOKING FORWARD TO MARK'S TALK ON INTENSIVE SUPPLEMENTATION. THERE ARE HIGHER RISK THE MORE YOU HAVE TO HANDLE THE ANIMAL THE MORE YOU HAVE TO INSTRUMENT THEM THINGS LIKE THAT, SO THERE'S A LOT OF THINGS TO CONSIDER. THAT'S JUST ONE, WE'LL START ON, LET'S GO TO THE NEXT ONE, PLEASE. THIS ONE ON HEMORRHAGIC FEVER, THE LIST GETS LONG ERGOING DOWN THERE. LET ME JUST ASK THIS. IF YOU WERE DOING A STUDY IN NON-HUMAN PRIMATES IN HEMORRHAGIC FEVERS AND YOU WANT TO USE PAIN CONTROL HOW MANY THINK THAT -- DON'T WORRY ABOUT WHAT I SAY, HOW MANY THINK THAT WOULD HAVE NEGLIGIBLE IMPACT ON THE NATURAL DISEASE COURSE GIVING SOME SORT OF ANALGESIC? A FEW. HOW MANY THINK IT WOULD HAVE A MODERATE IMPACT ON NATURAL DISEASE COURSE? ABOUT THE SAME NUMBER. HOW MANY THINK IT WOULD HAVE SEVERE IMPACT ON NATURAL DISEASE COURSE? FEW THERE. WE'RE ON THE SAME TRACK. MY POINT HERE THERE'S NO RIGHT ANSWER RIGHT NOW. THIS IS -- THESE ARE ALL THINGS, THIS IS JIM'S WORLD. REMEMBER THIS THAT. THIS ISN'T ANYTHING OFFICIAL. MY POINT WAS WE HAVE A LOT OF OPINIONS, AND ALL OF THEM PROBABLY HAVE VERY GOOD THOUGHT PROCESSES AND AND THEIR DI DE SITIONS THE PURPOSE OF THE EXERIZE IS THAT, JUST TO SHOW YOU EVEN WITH JUST THAT ONE THING, THAT ONE PAIN CONTROL ON ONE ASPECT NATURAL DISEASE COURSE WE HAD THREE ANSWERS. WE HAVE PEOPLE AGREE WITH THREE ANSWERSCH TAKE IT FOR EACH BLOCK AND SQUARES, AND EACH OF THOSE AREAS, IT WILL BE JUST AS DIVERSE FOR THE MOST PART. NEXT SLIDE. INHALATIONAL ANTHRAX. THIS IS THE LAST ONE TO GO THROUGH. OBVIOUSLY WHEN YOU START TALKING ABOUT THE IMPACT ON NATURAL DISEASE COURSE, IN HUMAN SUPPORTIVE CARE GENERATIONAL ANTHRAX ONE THING THAT WAS TALKED ABOUT WAS USE OF CORTICAL STEROIDS. HOW MANY THINK THAT IMPACT NATURAL DISEASE COURSE? FEW MORE HANDS THERE. I DON'T KNOW IF WE HAVE DONE THAT STUDY, I DON'T KNOW IF WE HAVE THAT DATA TO SHOW THAT. AGAIN, THAT'S TYPICALLY WHAT WE DO IN HUMANS SO SHOULD WE DO THAT IN ANIMAL. I GUESS I'M SORRY IF I DON'T HAVE THE ANSWERS YOU'RE LOOKING FOR WITH THE SLIDES MAYBE WE CAN START A DIALOGUE, WHAT ARE THE THINGS WE NEED TO BE LOOKING AT AS FAR AS EFFECTS OF SUPPORTIVE CARE. WHICH ONE OF THESE PROBABLY NOT ALL BUT WHICH ONES SHOULD WE AND PROBABLY MOORE, THERE'S BETTER IDEAS AND THERE'S ALSO OF GOOD IDEAS OUT THERE. LET'S START THE DISCUSSION ON WHAT ARE THE CATEGORIES, WHAT ARE THINGS WE SHOULD BE THINKING ABOUT, WHAT CAN WE DO, WHAT CAN'T WE DO AND HAVING THOSE DISCUSSIONS NOW. SO THAT IS REASON I WANT TO PUT THESE IN SLIDE FORMAT TO GET THOSE DISCUSSIONS GOING. NEXT SLIDE, PLEASE. I WANT TO GIVE A COUPLE OF EXAMPLES, THE FIRST ISN'T SUPPORTED CARE OBVIOUSLY BUT IT'S AN ISSUE THAT IS GROWING, AND I HEARD PEOPLE BRING UP AND DISCUSS. ANY OF YOU WHO ARE INVOLVED IN THE ANIMAL CARE AND USE OVERSIGHT IN YOUR IACUC AND THINGS LIKE THAT, INSTITUTIONAL ANIMAL CARE AND USE COMMITTEES PROBABLY HEARD THIS. THE NEW GUIDE FOR THE CARE AND USE OF LABORATORY ANIMALS USE AS PRIMARY STANDARDS, LIKE INTERNATIONAL USE AT THEIR PRIMARY STANDARD. THE NEW EDITION CAME OUT AND BASICALLY SAID GROUP HOUSEING IS THE DEFAULT. IF YOU'RE GOING TO DO ANYTHING BUT GROUP HOUSING YOU HAVE TO JUSTIFY WHY YOU'RE DOING THAT AND AND ESA CAME AN ENDORSED THAT AS WELL. THEY EXPECT YOUR ANIMALS TO BE GROUP HOUSEDCH HOW OFTEN HAVE WE GROUP HOUSED ANIMALS IN INFECTIOUS DISEASE STUDIES OTHER THAN RODENTS. NOT VERY OFTEN ESPECIALLY PRIMATES AND OTHER SPECIES, NON-HUMAN PRIMATES. EXCUSE ME. SO THERE'S A LOT HERE TO BE THINKING ABOUT. FORT MATILY AND THIS IS POSTER. I THINK THE ABSTRACT MAYBE IN THE BOOK BUT IT'S NOT GOING TO BE HERE. WHERE THEY DID LOOK AT SOME AT LEAST IF YOU PAIR HOUSED ANIMALS BEFORE THE STUDY, THEY COME IN, YOU PAIR HOUSE DURING THE QUARANTINE AND PRE-STUDY PERIOD MAYBE DURING IMMUNIZATION AN SEPARATE THEM WHEN THEY GO INTO THE ACTUAL EXPOSURE FRAME DOES THAT HAVE IMPACT ON THEIR IMMUNE SYSTEM AND COULD IT AFFECT THE STUDY AND AT LEAST BASED ON THIS STUDY IMMUNOLOGICAL PARAMETERS AND STRESS PARAMETERS THEY EVALUATED DIDN'T HAVE ANY SIGNIFICANT EFFECTS BY SEPARATING THEM WAS GIVING THEM A FEW DAYS TO ACCLIMATE TO THE THE SITUATION. TELEMETRY IS A BIT OF AN ISSUE, YOU HAVE TO HAVE ONE CAGE, ONE SEVER ONE TELEMETRY, NOW WITH DIGITAL SIGNALS, WITH ADVANCES IN THE RECEIVER DESIGN, MOST TELEMETRY COMPANIES YOU CAN PUT MORE THAN ONE ANIMAL IN A CAGE OR ENCLOSURE AND READ SIGNALS AND HAVE THOSE NOT GET MIXED UP AMONG EACH OTHER. SO THERE ARE ADVANCES THERE THAT MAY ALLOW THIS, I THINK TISSUE BEING WE HAVE TO HAVE THE CAGING CATCH UP WITH THE TECHNOLOGY. CERTAINLY I DON'T KNOW OF ANY -- THERE'S A GROUP HOUSE CAGES BUT IT'S FROM A PRIMARY CONTAINMENT STANDPOINT, I DON'T KNOW ANY MANUFACTURE MAKES PRIMARY CONTAINMENT CAGING THAT ALLOWS GROUP HOUSING. THESE ARE THINGS THAT WE'LL BE DEVELOPING AND THERELING A COMING. NEXT SLIDE PLEASE. PROTECTIVE MANAGEMENT AUGMENTS HEMODYNAMICS AND LETHAL TOXIN SHOCK, THIS WAS IN A MOUSE MODEL WHERE THEY PROVIDED I THINK -- WAS THIS A MOUSE MODEL? GETTING THEM MIXED UP. THEY PROVIDED HEMODYNAMIC SUPPORT IN ADDITION TO MONOCLONAL ANTIBODY THE SEE WHAT DIFFERENCE THAT MADE FROM A SUPPORTIVE CARE PERSPECTIVE I THOUGHT THIS TIED IN NICELY WITH SOME THINGS WE TALKED ABOUT EARLIER IN THAT EARLIER SLIDE. BASICALLY WHAT THEY SHOWED IS COMBINATION THERAPY INCREASE SURVIVAL OVER HEMODYNAMIC SUPPORT OR PA MONOCLONAL ANTIBODY ALONE ADMINISTERED ALONE. WE'LL REALIZE SUPPORTIVE CARE WILL ENHANCE SURVIVAL. THAT'S WHAT IT'S INTENDED TO DO. SO WE HAVE TO UNDERSTAND THE PARAMETERS, IT MAY MEAN EXTRA STUDIES TO SHOW WHAT -- HOW MUCH EFFECT IS FROM THE THERAPEUTIC, HOW MUCH IS SUPPORTIVE CARE BUT THOSE CAN BE DONE. NEXT SLIDE, PLEASE. ANOTHER EXAMPLE, THIS IS A POSTER HERE TOO, IF YOU HAVE A CHANCE TO LOOK AT THIS ONE. THIS IS A MOUSE MODEL, SWISS WEBSTER MICE, BUT LOOKING AT RADIATION INDUCED GAS INTRO INTESTINAL TOX SITY FROM A RADIOTHERAPY STANDPOINT. -- GASTRO INTESTINAL TOXICITY FROM A RADIOTHERAPY STANDPOINT. FLUID THERAPY OR ELECTROLIGHT THERAPY MORE PRECISELY. WHAT THAT PROVIDED AS FAR AS ADDRESSING GASTRO INTESTINAL DAMAGE. BASICALLY THEY FOUND THAT IT IMPROVED ELECTROLIGHT ABSORPTION AND TOXICITY FOLLOWING RADIOTHERAPY SO IN ITSELF THEY WERE ABLE TO OVERCOME TOXICITY JUST BY INTRODUCING ELECTROLIGHT THERAPY. SO AGAIN, GOOD POSTERS OUT THERE, TO EM FA SIZE GOING OUTLOOKING AT POSTER SO I'LL TRY TO HURRY HERE BECAUSE HE HAD PLENTY OF TIME TO DO THAT. NEXT SLIDE PLEASE. TO WRAP UP, LAST COUPLE OF SLIDES HERE, I WANTED TO AN OVERVIEW OF THINGS WE NEED TO CONSIDER AS WE MOVE FORWARD. WE HAVE TO KEEP IN MIND LETHALITY DUE TO PRIMARY EFFECTS OF DISEASE OR SECONDARY CAUSES SUCH AS DEHYDRATION. IN MOST DISEASES IT'S CERTAINLY ENHANCED BY THINGS LIKE DEHYDRATION HYPOTHERMIA, MALNUTRITION. BUT WE HAVE TO TAKE THOSE INTO CONSIDERATION AND KNOW HOW THEY PLAY IN THE ROLE OF PATHOGENESIS. THE EFFECT OF SUPPORTIVE CARE ON STUDY DATA AN FDA ACCEPTANCE. THIS IS WHERE I'M EXCITED ABOUT THIS WHOLE QUALIFICATION, MODEL QUALIFICATION EFFORT PUTTING FORWARD TO WHERE A LOT OF THESE HOPEFULLY CAN BE WORKED OUT RIGHT UP FRONT AND THEN THAT MODEL, YOU'RE NOT RESPONDING TO SOMETHING NOT LOOKED AT BEFORE AND GOING UH-OH. SO THAT'S A GREAT THING. WE HAVE TO LOOK AT SAFETY. THE PEOPLE DOING THIS. THE EFFECTS OF ADMINISTERING CARE TO THE ABOUT MALL. IT'S EASY TO SAY OKAY WE'RE GOING TO KNOCK THEM DOWN THREE TIMES A DAY. WORKING WITH NON-HUMAN PRIMATES IT'S PRETTY HARD IN A BLUE SUIT AND BL-4, IT'S HARD TO HAND RESTRAIN THEM. SO PRETTY MUCH FOR SAFETY HAVE TO KNOCK THEM DOWN TO ADMINISTER FLUIDS. THIS MAYBE SOMETHING MARK WILL FIX FOR US HERE. BUT THERE ARE ISSUES WITH JUST THE ANESTHESIA ALONE. NOW WITH JACKETS AND TETHERING, THOSE MAYBE OPTIONS. CERTAINLY IF YOU DO IT THAT WAY, YOU HAVE TO BE AWARE OF THE SAFETY ISSUES ASSOCIATED WITH THAT. NOT ONLY PEOPLE BUT ANIMAL. ANIMALS GETTING SICK AND YOU'RE KNOCKING THEM DOWN TO GET FLUIDS, HOW MUCH ARE YOU VETTING FROM FLUIDS VERSUS TAKING AWAY FROM THE ANESTHESIA, THE HYPOTHERMIA, THE RECOVERY PERIOD, THE EFFECTS ON METABOLISM AND PHYSIOLOGY AND SO FORTH. THAT IN ITSELF CAN CAN HAVE A HUGE EFFECT. AND I ALREADY MENTIONED PERSONAL RESOURCES, FISCAL RESOURCES. THERE'S A LOT OF SPECIALIZED EQUIPMENT OUT THERE, THERE'S CAGES YOU CAN INCREASE THE TEMPERATURE IN THE CAGE, MAINTAIN IF THEY START BECOMING HYPOTHERMIC THEY HAVE A PRICE TAG AS WE ALL KNOW. NEXT SLIDE. LASTLY THE PATH FORWARD. WHAT ARE THE VALUE-ADDED SUPPORTIVE CARE IS GOING TO BENEFIT BOTH PATIENT AND EVALUATION OF THE COUNTER MEASURE. WE CAN'T DO IT ALL, ESPECIALLY A CONTAINMENT ENVIRONMENT. SO I THINK WE HAVE TO IDENTIFY THOSE THINGS THAT ARE VALUE-ADDED. WE START FOCUSING ON THE ANATOMICAL WORKING GROUPS. I KNOW THEY ARE. THAT'S GREAT TO SEE. ANIMAL MODEL WORKING GROUP WORKING ON A LOT OF ISSUES AS WELL BETTER DEFINED POTENTIAL APPLICATIONS FOR SUPPORTIVE CARE. WHEN ARE THESE NEEDED. ARE THEY IN THE NEEDED. WHEN DO THEY INTERFERE, WHEN DO THEY NOT INTERFERE. THAT'S IN PLACE AN EXCITING AND COLLECT AS MUCH DATA AS WE CAN IN THE EARLY STAGES BECAUSE THAT DATA CAN BE USED LATER ON TO HELP IDENTIFY SOME OF THESE HOPEFULLY EARLY CLINICAL END POINTS AND INTERVENTIONS TRIGGERS AND THINGS LIKE THAT THAT WE MIGHT BE ABLE TO USE EFFECTIVELY RATHER THAN RELYING ON MORE OBJECTIVE OUTWARD CLINICAL SIGNS SO MY THOUGHTS ON THE PATH FORWARD AND I APPRECIATE YOU TAKING THE TIME TO LISTEN TO ME AND I DON'T KNOW IF WE HAVE TIME FOR QUESTIONS OR WHETHER WE NEED TO GET OUT AND TAKE POSTERS, I'LL LEAVE THAT UP TO OUR MODERATOR. [APPLAUSE] >> ANY QUESTIONS AT ALL? IF NOT I'LL TURN IT BACK OVER TO CALVIN. THANK YOU FOR COMING. >> IN THE INTEREST OF TIME AND EVERYTHING ELSE I THINK WE WERE ORIGINALLY SCHEDULED FOR A BREAK BUT BECAUSE WE GOT A LATE START WE WOULD LIKE TO KEEP MOVING FORWARD IF THAT'S POSSIBLE. IF THERE'S NO OBJECTIONS WE'LL INVITE OUR NEXT SPEAKER UP. >> FIRST MY FAME IS DR. CALVIN CARPENTER, DEPUTY DIRECTOR FOR THE NATIONAL CENTER FOR BIODEFENSE AND INFECTIOUS DISEASE. ONE OF THE 13 NIAID SUPPORTED REGIONAL BIOCONTAINMENT LABS, LIKE TO THANK THE GROUP HERE FOR INVITING ME TO HELP MODERATE THIS SESSION. FIRST PERSON UP IS COLONEL MARK KORTEPETER, INFECTIOUS DISEASE RESEARCH CLINICAL PRM AND PREVENTIVE MEDICINE AT THE USIS SCHOOL BETHESDA, RIGHT ACROSS THE STREET BUT AFTER THAT HE WAS AT USAMRID AND HAS EXPERIENCE WITH WORKING WITH BOTH PEOPLE AS WELL AS ANIMALS AND CONTAINMENT ENVIRONMENT. WITH THAT I'LL TURN IT OVER TO YOU, SIR. >> PEESHIATE COMING TO TALK TO YOU. IF I START >> I WILL START WITH TALKING ABOUT WHATEVER IS OUT THERE, THAT I COULD FIND IN TERMS OF HUMAN STUDIES ABOUT TRY TO FOCUS ON ANIMAL STUDIES WHY WE HAVE TO GO THAT WAY. ALSO TO GIVE YOU A SENSE ON WHAT ARE SOME OF THE CHALLENGES AND CONSIDERATIONS ESPECIALLY DOING IT IN A CONTAINMENT ENVIRONMENT. I -- THOUGH THIS IS EBOLA CASE STUDIES, I'LL TALK ABOUT VIRUSES IN GENERAL HERE. SO LET'S GO TO THE NEXT SLIDE. STANDARD DISCLAIMER I WORK FOR THE GOVERNMENT, THESE ARE MY OPINIONS AND THE WORK THAT I WILL DESCRIBE LATER DONE WITH ANIMALS DONE UNDER ALL THE APPROPRIATE REGULATORY REQUIREMENTS FOR CARE OF ANIMALS. NEXT SLIDE. SO BY THE WAY AM I GOING TO GET SOMETHING I CAN SEE HERE OR NOT? NOTHING THAT I SEE HERE. IF NOT, EBOLA AND MARBERG TO FILA VIRUSES, SINGLE STRANDED RNA VIRUSES, THAT ARE SEEN IN EXPLOSIVE OUTBREAKS AND UNPREDICTABLE AND CENTRAL -- SUB SAHARAN AFRICA, IMMUNE SUPPRESSIONS, SYSTEMIC -- MULTIPLE DIFFERENT ORGAN SYSTEMS MILTLY ORGAN FAILURE AN SHOCK. CASE FATALITY RATES DEPENDING ON STRAIN OR SPECIES OF THE 25 TO 90% FACILITATED BY CONTROL OR LACK OF INFECTION CONTROL EQUIPMENT. NEXT SLIDE. SO FOR THESE OUR BSL-4 PATHOGENS WHICH WE HAVE NO LICENSE VACCINES OR THERAPEUTICS, THERE HAVE BEEN SOME GOOD SUCCESS PRE-EXPOSURE AND IMMEDIATE POST EXPOSURE PROPHYLAXIS THUS FAR BUT NOTHING WE HAVE PROVEN AFTER THE ONSET OF ILLNESS. NEXT SLIDE. SUPPORTIVE CARE IS MAIN STAIN OF THERAPY AS WE HAVE BEEN DISCUSSING. WHY -- IF YOU LOOK HISTORICALLY AT THAT LITERATURE, THIS IS THE SAME PAPER THAT LISA CITED BY PAUL (INDISCERNIBLE) DISCUSSING WHAT'S USED TYPICALLY IN THESE OUTBREAKS. MEDICATIONS TO CONTROL NAUSEA VOMITING, AGITATION, PAIN AND FEVER, IN ADDITION BECAUSE IN A DIFFERENTIAL DIAGNOSIS FOR FELA VIRUS INFECTIONS AN AREAS WHERE THESE OCCUR ARE THINGS LIKE MALARIA, FIE TYPHOID SO APPROPRIATE ANTI-MA LAYERIALS ARE USED IN KNEW TRIEWTIONAL VITAMIN SUPPLEMENTS. AND FREQUENTLY ORAL HYDRATION BUT AS THERE'S LESS OR BETTER UNDERSTANDING OF HOW THESE SPREAD AND TO THE CAREGIVERS MORE FREQUENTLY IV FLUIDSES. NEXT SLIDE. IF YOU LOOK AT THE OTHER REPORTS WHEN THESE HAVE BEEN TAKEN CARE OF THESE ARE THE OTHER THERAPIES THAT HAVE BEEN UTILIZED BLOOD PRODUCTS STEROIDS, DIALYSIS, ATTEMPTED ANTIVIRAL WITH RIBO VIRIN AND OTHER THERAPIES. NEXT SLIDE, WHY DO WE THINK SUPPORTIVE THERAPY AS MAIN MAIN STAY. 'S COMMON SENSE. SOME TYPE OF CARE IS BETTER THAN NONE. IF YOU THINK ABOUT THE INITIAL SURVIVAL ASPECTS THEY DEAL WITH WHEN THEY TAKE CARE OF PATIENTS, IF SOMEONE IS (INAUDIBLE) TEMPERATURE, IF BLOOD PRESSURE IS LOW RAISE IT. IF ELECTROLIGHTS IN BALANCE, BALANCE THEM. IF IT'S OUT OF WACK BALANCE THAT. IF SOMEONE IS BLEEDING STOP THE BLEEDING. THAT'S ALL WE HAVE. THE REAL PROBLEM IS WHERE IS THE DATA. NEXT SLIDE. SO IF YOU LOOK AT GENERAL INDICATORS, WE HAVE APPROPRIATE USE OF ALGORITHMIC BASED THERAPY WITH D NEXT,GI FEVER, SHOCK SYNDROME, YOU CAN SEE IMPROVEMENT IN SURVIVAL. SOME OF THE DATA ON SEPSIS CARE, IN TERMS OF EARLY GOAL DIRECTED THERAPY BENEFICIAL REDUCING MORTALITY WHEN YOU CAN DO THINGS LIKE GETTING EARLY PROVISION OF FLUIDS, EARLY ANTIBIOTICS. MAINTAINING PRESSURE. THESE ARE GENERAL INDICATORS. IF YOU LOOK AT SPECIFIC ARTICLES ON THE OUTBREAKS THAT OCCURRED, REALLY UNNOORTLY WE DON'T HAVE GREAT DESCRIPTIONS. IN TERMS OF THE CLINICAL ASPECTS OF WHAT'S HAPPENING, THE FIRST OUTBREAK OCCURRED IN GERMANY AND YUGOSLAVIA. IN BEST DATA IN TERMS OF TIME COURSE OF INFECTION AND WHAT'S HAPPENING WITH HEART RATE AND FEVER CURVES, NOT SO MUCH BLOOD PRESSURE BUT YOU COMPARE THAT TO CASE FATALITY RATES OF LARGER SUB SAHARAN AFRICA OUTBREAKS WITH UP PER OF 80% OUTBREAKS, THE QUESTION IS WHAT'S THE DIFFERENCE. IS THERE DIFFERENT STRAINS INVOLVED, DIFFERENT ROUTES OF INFECTION, DIFFERENT DOSES, OTHER CO-MORBID ILLNESS OR GENETIC SUSCEPTIBILITIESCH ONE THING THAT WAS DIFFERENT IS PROVISION OF SUPPORTIVE CARE AND THE ASPECT OF MARBERG IN GERMANY AND YUGOSLAVIA, MORE AGGRESSIVE IN THE FIELD. NEXT SLIDE. ALSO IF YOU LOOK AT THE REPORTS AS LISA MENTIONED, FROM THE OUTBREAK OF MARBERG, THE CARE GIVERS IN THEIR WRITE UPS MENTIONED THE FACT THEY SAW IMPROVEMENTS IN THE PATIENTS WITH IV FLUIDS AND OTHER MEASURES. NOT MUCH OTHERWISE DOCUMENTED. IF YOU LOOK AT THE 1995 OUTBREAK, IN THIS THERE ARE ONE REPORT 7 OF 8 INDIVIDUALS WHO WERE GIVEN CONVALESCE SENT WHOLE BLOOD WHO SURVIVE. THIS IS COMPARED THEN WITH CASE FATALITY RATES DURING THAT OUTBREAK, 80% AND THE REASON BEHIND THIS, COULD IT BE RELATED BLOOD OR CLOTTING FACTORS. LATE IN THE OUTBREAK THERE'S DECREASED VIRULENCE, ONE THING FOR SURE IT'S APPEARED THERE'S BETTER SUPPORTIVE CARE. INTERESTINGLY WHEN YOU LOOK AT THESE CASES MORE CLOSELY REPORTED FOUR OF THE SEVEN THAT HAD ANTIBODIES TESTED AT THE TIME OF THE TREATMENT THEY HAD ANTIBODIES ON IGG AGAINST EBOLA. THESE ARE INDIVIDUALS WHO ARE PRE-SELECTED, SO THEY'RE TREATED AFTER FIRST WEEK OF ILLNESS AND IF THEY SURVIVE THE FIRST WEEK THEY TEND TO DO BEAR. INTERESTINGLY THEY MENTION 11 OTHER CASES DURING THAT OUTBREAK WHO DID RECEIVE WHOLE BLOOD, ONLY ONE SURVIVORRED. SO I HAVE NEVER BEEN SURE THE REASON WHY THESE 7 OR 8 WERE SELECTED OUT TO BE REPORTED. THERE'S ALSO 2,000 EBOLA SUDAN OUTBREAK WHERE THEY MENTION LATER IN THE OUTBREAK ONE OF FIVE INDIVIDUALS WHEREAS EARLIER OUTBREAK WHEN THERE'S LESS OPTIMUM SUPPORT OF CARE THEY RANGE 76% SO I WOULD SAY ALL THESE WOULD BE POTENTIAL INDICATORS THAT SUPPORT CARE IS BENEFICIAL BUT I WOULDN'T SAY THEY ARE PROVED SO UNFORTUNATELY WHY DON'T WE HAVE THE DATA? THERE HAVE BEEN RARE IMPORTED CASES OR LABORATORY EXPOSURES WHERE INDIVIDUALS ARE CARED FOR IN WESTERN OR DEVELOP SETTINGS BUT THOSE ARE FAIRLY RARE AND NOT ADEQUATE FOR US TO STUDY THE IMPACT OF SUPPORTIVE CARE. SO WHAT ARE SOME OF THE CHALLENGES IN THE FIELD? SOMEONE TOUCHED SOLOMON TOUCHED ON A LOT OF THESE BUT FIRST THESE ARE UNPREDICTABLE WHERE THESE OUTBREAKS OCCUR. WE CAN'T PREDICT DATE OR LOCATION, WE HAVE A SHORE TIME FRAME FROM ONSET TO THE THE TIME WE'RE RESPONDING. THEN WE DONE HAVE ANY STANDARDIZED ALGORITHMS IN PLACE IN ADVANCE. THOUGH ATTEMPTS TO DO THIS (INDISCERNIBLE) NEXT SLIETD. SO WE LACK INFRASTRUCTURE BASIC CLINICAL SUPPLIES, TRAINED LOCAL CARE PROVIDERS, UNFORTUNATELY SINCE THESE OCCUR AT DIFFERENT LOCATIONS SOME INDIVIDUAL WHOSE PROVIDE CARE LOCALLY MIGHT ACTUALLY GET PRETTY WELL AVERSED HOW TO CARE FOR THESE INDIVIDUALS BUT THE NEXT OUTBREAK OCCURS SOMEWHERE ELSE SO SOME OF THE LESSONS HAVE TO BE RELEARNED. SAFETY RISK FOR THE CAREGIVERS WHICH IS REALLY AN IMPORTANT FACTOR. LACK OF PPE, LACK OF -- REALLY RISK OF NEEDLE STICK EXPOSURE TO BLOOD SPLASHES, THINGS LIKE THAT. SOMETIMES PERCEIVEDDED INABILITY THAT WHAT THE CAREGIVERS DO WILL HAVE AN IMPACT SO THE -- MAYBE WE DONE NEED TO PROVIDE SUPPORTIVE CARE BECAUSE WE NEERT GOING TO AFFECT THE CLINICAL OUTCOME. THE OTHER THING THAT WAS MENTIONED BY LISA, YOU HAVE PAPER RECORD BUT THEY HAVE TO BE DESTROYED LATER FOR FEAR OF HAVING SOMEONE EXPOSED TO BODY FLUIDS AND POTENTIALLY CAUSE OTHERS TO BECOME ILL, YOU CAN'T DECONTAMINATE BLOOD PRESSURE. IN FREQUENT CASE THERE'S COMMUNITY RESISTANCE LOCAL POPULATIONS, RESISTANCE OF FAMILY MEMBERS IN ISOLATION WARDS, FEELING THAT IS THE DEATH SENTENCE. SOMETIMES RESISTANCE CAN BE VIOLENT. AND ULTIMATELY REGULATORY HURDLES, WE DON'T HAVE IRB PROTOCOLS ON THE SHELF. SO AND THEN WHEN WE DO, WHAT ARE THE ETHICS, HOW DO YOU STUDY THIS, DO YOU HAVE ACTUALLY WITHHOLDING CARE VERSUS THOSE WITH SUPPORTIVE CARE. THAT PROBABLY WOULDN'T FLY TOO WELL WITH IRB. POPULATION THAT MAY NOT QUITE UNDERSTAND THE CONCEPT, OF INFORMED CONSENT AND THEN HOW DO YOU ESTABLISH IRB IN SOME OF THESE LOCATIONS WHERE THEY MAY NOT BE I RBs. ULTIMATELY HAVING TRANSLATED TO LOCAL LANGUAGE TO HAVE THEM PRETTY MUCH READY TO GO AT THE TIME AN OUTBREAK OCCURS. AS SIMON SHOWED YOU YOU SAW ALL THOSE FEVER CURVES THERE IN PATIENTS. ONE OF THE CHALLENGES IS WHEN YOU HAVE DIAGNOSTIC DELAYS OR YOU DON'T HAVE APPROPRIATE DIAGNOSTICS UP FRONT, YOU MAY NOT KNOW ACTUALLY WHERE AN INDIVIDUAL IS SPECIFICALLY IN THEIR DISEASE COURSE WHEN THEY PRESENT. SO HOW YOU COMPARE ONE INDIVIDUAL TO ANOTHER INDIVIDUAL WHEN LOOKING AT OUTCOMES. NEXT SLIDE. SO ONE OF THE THINGS WE -- BASICALLY MY CONCLUSION IS IN HUMANS WE HAVE SOME ANECDOTAL DATA, WE HAVE CLINICAL OBSERVATIONS BUT I WOULDN'T SAY WE HAVE STUDIED THIS PHENOMENON OR THIS THERAPY AND THEN SO WE DONE HAVE ANY EVIDENCE BASIS UPON TO DRAW -- MAKE FIRM CONCLUSIONS. AND AS SIMON MENTION THERE HAD'S REAL CONCERN THE PROVISION OF SUPPORTIVE CARE WITH IV FLUIDS COULD POTENTIALLY BE HARMFUL FOR PATIENTS SO FOR THE TIME BEING WE ARE SOMEWHAT FORCED TO TURN TO ANIMAL MODELS TO WORK SOME OF THIS OUT. IF YOU LOOK AT ANIMAL STUDIES OUT THERE, THEY'RE FOCUSED ON PATHOGENESIS HOST IMMUNE RESPONSE POST EXPOSURE VACCINES AND THERAPEUTICS, ANTIVIRALS ANTIBODIES. SUPPORTIVE CARE MAY IMPACT ALL THESE ESPECIALLY THE THERAPEUTIC MEASURES THIS IS NOT SPECIFICALLY STUDIED. WHAT IS THAT IMPACT? NEXT SLIDE. SO THUS FAR THE PATHOPHYSIOLOGY OF DISEASE AND ANIMALS IS NOT WELL CHARACTERIZED AND UNFORTUNATELY MEASURING BASIC PARAMETERS SUCH AS VITAL SIGNS REQUIRES SEDATION BECAUSE THE ANIMALS ESPECIALLY NON-HUMAN PRIMATES CAN BE DANGEROUS TO BE AROUND WORKING WITH BSL-4 CONTAINMENT TRYING TO ROACH OUT AND GRAB YOU, THEY CAN SCRATCH YOU AND DO ALL SORTS OF OTHER NASTY THINGS IF YOU GET TOO CLOSE. IN ORDER TO MEASURE THESE YOU HAVE TO RISK PARAMETERS AN MORTALITY RATE. I POSTULATE UNDERSTANDING SUPPORTIVE CARE REQUIRES UNDERSTANDING OF PATHOPHYSIOLOGY TO DETERMINE THINGS LIKE WHAT IS THE BASELINE WHICH WE CAN COMPARE DIFFERENT INTERVENTIONS THAT WE WOULD CONSIDER ROUTINE IN PATIENT CARE AND TIME COURSE AND OPTIMAL TIME POINTS FOR INTERVENTION. NEXT SLIDE. SO I'M GOING TO DESCRIBE A STUDY WE DID THAT YOU SAW AND REALLY THE IDEA BEHIND THIS WAS TO GET A SENSE OF WHAT'S SOME OF THE DISEASE PATHOPHYSIOLOGY DISEASE TIME COURSE AND DIFFERENT PARAMETER OAFERS THE COURSE OF DISEASE. AND PRELIMINARY ASSESSMENT OF WHAT HAPPENS WHEN YOU DO GIVE FLUID RESUSCITATION TO ANIMALS WITH EBOLA. SO WE IMPLANTED TELEMETRY CENTERS. CATHETER 8 TO 12 DAYS BEFORE CHALLENGE. THERE ARE NO EXTERNAL WIRES SO IF YOU HAVE AN INCISION THAT HEALS AND FOR THE INTRAVENOUS CATHETER, IS IMPLANTED TO THE JUGULAR AND TUNNELED UNDER THE SKIN AND OUT THE BACK, THEN THE ANIMALS WEAR A TETHERED JACKET SUCH THAT THE IV FLUID CATHER CAN GO THROUGH THE TETHER WHICH GOES THEN OUTSIDE THE CAGE SO THE ANIMAL CAN FREELY MOVE WITHIN THE CAGE BUT CAN'T GET TO THE CATHETER AN TEAR IT OUT, THAT'S TWHAI DO IF THEY CAN GET TO IT. WE RECORD PARAMETERS PRE DURING AND DURING ILLNESS 24/7 THEN VISUALIZE -- VISUALLY ASSESS ANIMALS TWICE DAILY AN MORE FREQUENTLY THEREAFTER. NEXT SLIDE. THIS IS WHAT ONE OF THESE TELEMETRY SENSORS, THESE ARE T-27 F 1B SENSORS FROM ITS INCORPORATED. WITHIN THEM THEY HAVE EKG LEAD, THEY HAVE A LEAD THAT GOES IN THE AORTA FOR PRESSURE, LEFT VENTRICULAR PRESSURE AND ONE IS INTRATHORACIC FOR INTRATHORACIC PRESSURE. SO YOU CAN MEASURE HEART RATE, BLOOD PRESSURE, RESPIRATORY RATE. THEN WE HAVE -- SO WHAT HAPPENS IS THERE'S AN ANTENNA IN THE SIDE OF THE CAGE WHERE THE SIGNAL IS PICKED UP AND IT'S HARD WIRED TO BAY STATION OUTSIDE THE LAB. NEXT SLIDE. THEN YOU CAN MONITOR THESE DIFFERENT PARAMETERS IN REAL TIME. SO THIS STUDY WE DID CHALLENGED US APPROXIMATELY 50 PFUs OF EBOLA, 1995 AND THEN THIS DOSE QUZ A LOWER DOSE TYPICALLY HAS BEEN USED FOR CHALLENGE STUDIES. THE REASON FOR THAT IS WE WANT TO SEE IF BY HAVING A LOWER DOSE PERHAPS WE WOULD SEE A LITTLE BETTER GET A LITTLE BETTER UNDERSTANDING OF THE TIME COURSE TO CHARACTERIZE THE DISEASE OVER TIME AND THEN THE IDEA IS IF WE WERE GOING TO SEE IMPACT OF FLUIDS PERHAPS HAVING A LOWER DOSE MIGHT GIVE US AN OPPORTUNITY TO SEW THE IMPACT. NEXT SLIDE. NINE ANIMALS TOTAL. FIVE ARE CONTROLS, FOUR TREATED. THE TREATED ANIMALS, WHAT HAPPENED IS WHEN THE BLOOD PRESSURE THE MEAN ARTERIAL PRESSURE DROPS BY 20-MILLIMETER OF MERCURY AN ALLOWED US TO START FLUID BOLUSES 20 MLs PER KILOGRAM AND AT THE -- IF THE BLOOD PRESSURE STAYED BELOW A CERTAIN LEVEL WE CAN CONTINUE THOSE FLUID BOLUS AS LONG AS ANIMALS SEEM TO BE DOING OTHERWISE OKAY. NORMAL SALINE GIVEN CATHERS OPEN, THE WHOLE IDEA IS TO GIVE FLUID AND ALSO DRAW BLOOD WITHOUT SEDATING THE ANIMALS. THEN WE DID DAILY LABORATORIES, LIVER FUNCTION, HEMATOLOGY, ET CETERA. AND ANIMALS ARE EUTHANIZED BASED ON CLINICAL SCORE. NEXT SLIDE. WHAT DO WE SEE? IF YOU LOOK OVERALL, IF -- UP HERE ARE THE UNTREATED FIVE ANIMAL AN BELOW HERE ARE THE FOUR TREATED ANIMALS THESE ARE LOOKING AT DAYS TIME COURSE SO THE RHESUS EBOLA IS HERE WITHIN 7 TO 10 DAYS AND I HAVE SHADED THAT YELLOW. THE JORTY OF ANIMALS DID/-- THE MAJORITY DID SUCCUMB DURING THE TIME FRAME. WE DID HAVE THREE SURVIVORS BEBEYOND NORMAL TIME COURSE. ONE OF THE FOUR TREATED SURVIVED. SO WE DID NOT SEE A MORTALITY BENEFIT HERE BUT SO THIS ONE ANIMAL SUCCUMBED AT DAY 18, EUTHANIZED AS A RESULT OF AN EYE INFECTION BUT OTHERWISE DOING WELL T OTHER TWO SURVIVORS WENT OUT TO FIVE MONTHS AND COMPLETELY RECOVERED AND THEY WERE EUTHANIZED AT FIVE MONTHS. ALL ANIMALS BECAME ILL SO THEY HAD ALL FEVER, RASH, DROP IN PLATELETS, LIVER FUNCTIONS AS WELL AS VIREMIA. NEXT SLIDE. IT'S INTERESTING TO SEE IN TERMS OF SERENDIPITY WHAT WE SEE IN TERMS OF DIFFERENCES BETWEEN SURVIVORS AN NON-SURVIVORS. SURVIVORRING ARE SHOWN DOWN HERE WITH THE DOTTED LINES SO THERE IS A DIFFERENCE IN TERMS OF VIRAL RNA LEVELS IN THE BLOOD 23579 TIMES TEN TO THE 4TH AND 10 THE TO THE 5TH WERE NON-SURVIVORSCH WHAT'S INTERESTING IS THIS IS SEEN BEFORE IN STUDIES THAT LISA HENSLEY AND TOM HAS DONE BUT THIS IS WITHOUT ANY SPECIFIC THERAPY. NEXT SLIDE. IF DO YOU WANT LOOK AT COMPARING PARAMETERS IN THE NOT SURVIVORS VERSUS SURVIVORS, THIS IS A NON-SURVIVOR. WENT OUT THE TO DAY 8. DURING BASELINE PERIOD AFTER INFECTION HERE AT DAY ZERO YOU CAN SEE PATTERNS IN THE HEART RATE WHICH IS IN GREERNTION THE SYSTOLIC PRESSURE IN BLUE AND DIASTOLIC WILL RED. SO I SEE THESE PATTERNS UNTIL OFFSET OF FEVER AT DAY 5 AT THE TIME OF ONSET OF FEVER YOU START SEEING THE HEART RATE LAUNCH ESSENTIALLY ON UPWARD TRAJECTORY UNTIL THE END AN AT THE SAME TIME YOU START SEEING SYSTOLIC AND DIASTOLIC PRESSURES WHERE THEY CROSS EACH OTHER. A BENEFIT OF THIS IS YOU CAN LOOK AT OTHER FACTORS IN TERMS OF LABORATORIES SO HERE SOMETIME BETWEEN DAY 7 AND 8 LIKELY WHEN THE BLOOD PRESSURE IS DROPPING BELOW SYSTOLIC OF 100 YOU SEE RISE IN LACTATE LEVELS AND CREATININE SO THE ANALES ARE GOING -- IN THE ANIMALS, THEY'RE ATTEMPTING COMPENSATION. IN ADDITION YOU SEE NEAR THE END LACTIC ACIDOSIS WITH ACUTE RENAL FAILURE. NEXT SLIDE, THIS IS ONE OF THE SURVIVORS AND YOU CAN SEE SOME DISTINCT DIFFERENCES HERE. SO YOU SEE SIMILARLY, THESE PATTERNS OF PARAMETERS BUT DAY 5 WHEN THE ANIMAL IS FIBRIL YOU SEE ELEVATION OF HEART RATE NOT TO THE DEGREE YOU SAW IN THE NON-SURVIVOR, YOU YOU SEE A DIP INSIS TOLLIC AND DIASTOLIC PRESSURE BUT YOU SEE RECOVERY WITH HEART RATE COMING DOWN AND BLOOD PRESSURE GOING BACK UP. THIS ONE ANIMAL HAD A SLIGHT BUMP IN THE LACTATE LEVELS HERE BETWEEN DAY 8 AND 9 THEN CAME BACK. INTEREST WHY THIS ANIMAL RECOVERED VERSUS OTHERS, HARD TO KNOW WHY. NEXT SLIDE. THE OTHER THING I SHOULD MENTION IS WHEN WE STAW DECLINE IN BLOOD PRESSURE YOU SAW A DECLINE IN CONTRACT UNTILTY OF THE HEART SO MAKES YOU WONDER WHAT PART OF THIS DECLINE IN BLOOD PRESSURE COULD BE PARTLY SYSTEMIC FASHION RESISTANCE, CARD CARDIO GENIC EFFECT. THEN LOOK -- KIND OF ALONG THE LINES OF WHAT SIMON WAS SAYING EARLIER, RESPIRATORY RATE IS A VERY IMPORTANT PARAMETER TO FOLLOW. YOU SEE THIS DIE EARNAL PATTERN IN THE FIRST I SHOWED YOU YOU SEE ELEVATION IN RESPIRATORY RATE AS TEMPERATURE GOES UP AND THEN IT CONTINUES TO CLIMB UNTIL THE ANIMAL IS EUTHANIZED. AND THEN AT SOME POINT THE TEMPERATURE STARTS TO FALL, THE ANIMAL BECOMES HYPOTHALAMIC THIS IS DIFFERENT THAN WHAT WE SAW WITH THE SURVIVOR WHERE DIVERGENCE OF TEMPERATURE AND RESPIRATORY RATE YOU SEE THE TWO MOVING IN TANDEM. SO RESPIRATORY RATES RISEN AND THE TEMPERATURE FALLS, RES PTORY RATE COMES DOWN NICELY. AND QUESTION IS WHY IS THAT RESPIRATORY RATE CONTINUE TO DECLINE THE ANIMALS TRYING TO CONCENTRATE WHAT'S GOING ON. TO SHOW YOU THE PARAMETERS, THIS IS LACTATE AND YOU CAN SEE IN THE NON-SURVIVORS, AQUEUE RISE IN LACTATE LEVELS, ON THE DAY JUST BEFORE YOUTH EUTHANASIA. THIS ONE IN BLUE IS ONE I SHOWED YOU SUR VIEFER PRETTY MUCH THE VIRUS TO KEEP THE LACTATE LEVELS LOW. WHAT WE SEE FLUID ON THIS, WE SAW NO IMPACT ON SURVIVOR AS I SAID, TRANSIENT FOR MEAN ARTERIAL PRESSURE, I WILL NOT SAY THOSE WERE SUSTAINED EFFECTS. WE DID KNOW SEE APPRECIABLE IMPACTS, THIS GETS TO BE A BIG CONCERN ABOUT HOW MUCH FLUID CAN YOU GIVE AND WHAT'S SAFE. WE DIP SEE AN APPRECIABLE IMPACT ON RESPIRATORY EXCEPT ONE ANIMAL, THE ONE ANIMAL RECEIVED THE MOST FLUID SO 1100 MLs OF FLUID OVER A PERIOD OF 40 HOURS ( AND THIS ANIMAL ALSO RECEIVED FLUIDS A LITTLE EARLIER THAN THE OTHER THREE AND OVER THIS PERIOD OF FLUIDS HAD A TRANSIENT DECLINE IN TEMPERATURE WHICH CAME BACK UP LATER. INTERESTINGLY THIS IS THE ONLY ANIMAL OF THE TREATED ONES THAT SURVIVED. SO BEGS THE QUESTION MAYBE THE FLUIDS WERE POTENTIALLY DETRIMENTAL FOR A WHILE BUT WHEN WE STOPPED THEM THE ANIMAL WAS ABLE TO RECOVER. NEXT SLIDE. WHAT WAS INTERESTING WHEN FIRST LOOKING AT THE DATA, WE DIDN'T REALIZE UNTIL WE WERE PRIET WRITING UP FOR PUBLICATIONCH THESE ARE SMALL NUMBERS BUT STILL INTRIGUING. NONE BUMPED CREATININE. ANIMALS THAT DIDN'T SURVIVE, THE ONES WITH FLUIDS WITH LOWER CREATININE LEVELS IS ONE-THIRD AS HIGH AS THE ONES THAT GOT NO TREATMENT. SO IT'S VEEGING TO SEE THAT. VERSUS 1.8. NEXT SLIDE. YOU SAW TWO AND A HALF TIMES DIFFERENCE IN TERMS OF THE LEVELS OF UNTREATED ONES HERE AT THE TOP. VERSUS THE TREATED ONES. IT IS INTRIGUING, I WOULD SAY IT'S SOMETHING THAT WOULD BE INTERESTING FOR FURTHER STUDY AND CERTAINLY WE CAN PRESERVE ONE ORGAN SYSTEM THERE'S POTENTIAL THAT WE COULD PRESERVE OTHER ORGAN SYSTEMS, AND YOU LOOK AT REPORTS THAT OPERATE INDIVIDUALS THAT GO INTO RENAL FAILURE DON'T DO WELL. THIS IS IN CONCERT WITH WHAT WE SEE IN HUMANSCH NEXT SLIDE. A LOT OF CHAL ENGS THOUGH WITH STUDY OF THIS NATURE SO JUST THE LOGISTICS OF TRYING TO SET THIS UP IN TERMS OF NOT ONLY TIME IN THE BSL IV LAB BUT GETTING THE SENSORS IN, GETTING CATHETER PIPES IN THE RIGHT FASHION LINED UP IN TIME IS VERY DIFFICULT. THEN REALLY WHEN YOU'RE TRYING TO DO THIS SOPHISTICATED ASSESSMENT OF FLUID BOLUS, TRYING TO COMMUNICATE WITH PLEEGS IN THE LAB, SOME WERE OUTSIDE, SOME WERE INSIDE AND WE DID A COMBINATION OF EMAIL WRITING ON THE -- IN THE CHALK BOARD TRYING TO TIME THAT HAS BEEN DIFFICULT. MAINTAINING THE CATHETER PACE IS A CHALLENGE SO WHAT HAPPENS OFTEN THESE CATHETERS BUMP AGAINST ONE OF THE INTERNAL WALLS OF THE VESSEL AND IT'S HARD TO DRAW BLOOD. SOMETIMES EASIER OVER THE LONG TERM TO CONTINUE GIVING FLUIDS. OTHER THING IS WAKE SLEEP CYCLES SO A CERTAIN HOUR OF THE DAY THE LIGHTS GO OUT. FIGURE PERSONNEL WORKING IN THE LABORATORY TRYING TO DO OBSERVATIONS NOT ONLY IS IT HARDER BECAUSE YOU HAVE TO BE IN THERE WITH A FLASHLIGHT BUT IT'S ALSO DANGEROUS TO BE IN A BSL-4 LAB WHEN THE LIGHTS ARE OUT. TRANSIENT CHANGES IN ANIMAL ACTIVITY. IF YOU'RE THERE OBSERVING THE ANIMALS OR YOU HAVE TO HAVE A WAY TO OBSERVE THEM WHEN YOU'RE IN THE ROOM THEY'RE PHYSIOLOGIC PARAMETERS CHANGE AND THEIR ACTIVITY CHANGES SO THAT CAN INFLUENCE PARAMETERS AT LEAST SHORT TERM. THEN TRYING TO PROCESS MULTIPLE LABORATORIES USING BEDSIDE DIAGNOSTIC KITS IS CHALLENGING TO GET THEM DONE IN THE RIGHT TIME FRAME INFLUENCING THE PARAMETERS. NEXT SLIDE. IF WE TALK ABOUT QICU CARE, I SEE MORE CHALLENGES, AS MENTIONED EARLIER MAN POWER. THIS GETS MORE TRICKY WHEN YOU START TALKING REQUIREMENTS FOR INDIVIDUALS TO BE IN THE LABORATORY AND IN SOME CASE VERSUSSING A SECOND PERSON BECAUSE YOU'RE WORRIED ABOUT SOMEONE TRYING TO DO SOMETHING NEFARIOUS. SO IN ADDITION TO HAVING MORE PEOPLE IN THE LABORATORY WE HAVE INCREASED RISK TO THE CARE GIVERS BY HAVING MORE PEOPLE IN THERE AND CROWDED IN MORE TUBES AND LINES IF YOU'RE TRYING TO DO TRUE ICU YOU MAY HAVE TO CARRIE HART LINE AS WELL AS SOME KIND OF INTRAVENOUS CATHETER, MORE POTENTIAL FOR NEEDLE STICKS. I MENTIONED DARK LIGHT CYCLES BUT ALSO NIGHTTIME AND ENSURING IN THIS SITUATION AND ENSURING YOU HAVE ADEQUATE SEDATION SO ISSUES TO DEAL WITH AND THE EUTHANASIA CRITERIA IF YOU CAN'T USE ACTIVITY LEVEL AND ALERTNESS. IF YOU DO THIS WHERE YOU'RE SEDATING ANIMALS ON YOUR DATA AND MULTIPLE THINGS AS YOU WOULD IN ICU HOW DO YOU PARSE OUT INDIVIDUAL IMPACTS OF EVERYTHING YOU'RE DOING. NEXT SLIDE. I'M GETTING NEAR THE END HERE. SO A COUPLE OF CRITICAL QUESTIONS. I THINK THIS STUDYSOR OF RING BRINGS UP. ULTIMATELY WE NEED TO THANS QUESTION IN ANIMAL, ARE FLUIDS GOOD OR BAD? COLOID OR CRYSTALOID? EARLY OR LATE? IT'S -- IN TERMS OF FLUID RATES, WEIGHT AS OPPOSED TO CLINICAL OBSERVATION AN BOLUSES, AND TRY TO -- WHAT CAN WE USE AS OBJECTIVE MEASURES IN ADDITION TO RESPIRATORY RATE, PULSE OX, CHEST X-RAYS, ECHOCARDIOGRAM, CARDIAC CONTRACT UNTILTY. THE OTHER QUESTION THAT IS KEY IN MY MINE IS VASOPRESSORS, IF IT LOOKS LIKE DECLINE IN CONTRACT UNTILTY, WOULD BASAL PRESSURES WORK SO THAT'S SOMETHING TO LOOK AT AND MORE MINOR THINGS THAT CAN BE LOOKED AT, WHAT DO WE DO ABOUT ACID BASE, OXYGEN MANAGEMENT, DIALYSIS, YOU DON'T WANT TO GET DIALYSIS UNLESS YOU CAN RAISE BLOOD PRESSURE LIKE PRESSERS. ULTIMATELY THERE'S NOT A LOT OF INTEREST IN TERMS OF FUNDING AGENCIES. SO HOW DO YOU FUND SUCH A STUDY. BUT THIS COULD HAVE MORE IMPACT IN THE FIELD ENVIRONMENT THAT SIMON DESCRIBED AND SOME OF THE OTHER THINGS THAT MIGHT TAKE LONGER TO GET THROUGH REGULATORY CHANNELS. NEXT SLIDE. WE HAVE TO CONSIDER IMPACT OF FLUIDS OR WHATEVER OTHER INTERVENTIONS WE'RE DOING BPO BOTH IN CONTROL GROUP AND TREATED GROUP SO WE'RE NOT GIVING UNQUANTIFIABLE ADVANTAGE TO THE TREATED GROUP. FINAL SLIDE. LOOKING AT -- IF WE IMPROVE OUR HUMAN DATA CAPTURE THAT WILL HELP US FEED BETTER QUESTIONS TO OUR ANIMAL STUDIES. IMPROVING INFRASTRUCTURE. SIMON MENTIONED PULSE OX, I MENTION THINGS HERE, NOW THAT WE HAVE BEAR ELECTRONIC DATA CAPTURE SYSTEMS COULD WE SOME DAY USE TABLETS OR SOME WAY TO TRANSMIT DATA OUTSIDE THE CONTAINMENT WARDS, THINGS LIKE THAT. THEN ULTIMATELY GET IRB APPROVALS IN PLACE IN ADVANCE, IN CONJUNCTION WITH LOCAL MINISTRIES OF HEALTH, TRANSLATE INTO LOCAL LANGUAGE WHERE OUTBREAKS OCCUR HISTORICALLY SUCH THAT WE'RE READY TO GO EVEN BASIC FLUID MANAGEMENT IF POSSIBLE. AND FINALLY IF THERE ARE PROMISING INTERVENTIONS, THERE'S MORE INTERESTING DATA COMING OUT ABOUT ANTIBODY THERAPY. INTERVENTIONS WE CAN GET OUT TO THE THE FIELD FOR COMPASSIONATE USE QUICKLY. THAT'S ALL I HAVE AIND EEL TAKE ANY QUESTIONS IF THERE'S TIME. [APPLAUSE] >> WHAT WEAL DO IS BRING THE LAST PRESENTER UP AND THEN AFTER THAT PRESENTATION WE'LL BRING ALL THE PRESENTERS UP AND HAVE ARE THE PANEL READY TO GET READY FOR ANY QUESTIONS. OUR NEXT PRESENTER IS DR. MACVITTIE, PROFESSOR OF ONCOLOGY AT THE UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE. HE'S A RECOGNIZED INTERNATIONAL EXPERT ON THE EFFECTS OF RADIATION ON THE HEMATOPOIETIC AND GASTROINTESTINAL SYSTEMS. >> THANK YOU SO MUCH, JUDY. WE ARE SITTING, THANK YOU VERY MUCH FOR THE OPPORTUNITY TO PRESENT SOME OF OUR WORK AND THINKING TO THIS GROUP. I DON'T HAVE A SLIDE BUT JUST UP FRONT GUY FOR TREMENDOUS GROUP OF PEOPLE AT THE UNIVERSITY OF MARYLAND, KEY TECH STAFF TO WORK WITH NON-HUMAN PRIMATES 7 DAYS A WEEK. MY LONG TIME COLLEAGUE AN DI IS OVER THERE. OVER SEVEN YEARS WORKING CLOSELY WITH A NUMBER OF NIAID COLLEAGUES WHICH DAVID (INDISCERNIBLE) AN DI DECARLO AND A GOOD GROUP OF PEOPLE. YOU DON'T DO THIS KIND OF WORK WITHOUT WORKING WITH A GOOD TEAM. SO JUDY ASKED ME TO TALK ABOUT MEDICAL MANAGEMENT, SUPPORTIVE CARE AND WE REFER TO MEDICAL MANAGEMENT, IT GIVES YOU MORE OF A PERSONALIZATION OF IT RATHER THIS THAN JUST SUPPORTIVE CARE SO WE'RE TRYING TO MAKE THAT SWITCH SUPPORTIVE CARE FROM SUPPORTIVE MANAGEMENT, IT WAS GREAT TO FOLLOW JIM SWEARING AGAIN, WE WERE ON A PANEL DOWNTOWN AND I SHOULD HAVE NOTICED WHEN I SAW HIM NAME HERE, IT'S NICE TO EMPHASIZE THE GOOD POINTS JIM WAS MAKING. ONE THING I'M GOING TO OW NAIL DOWN HOPEFULLY IS A READ OUT. AND I WILL TELL YOU I BELIEVE HOPEFULLY YOU'LL GO ALONG WITH ME, EXACTLY WHY MEDICAL MANAGEMENT A CSHA SUPPORTIVE -- AKA SUPPORTIVE CARE IS GOOD, INCREASES SURVIVAL AND MEANdŽ– SURVIVAL TIME, WITH DATA WITH DOGS AN MONKEYS THAT AFFECT ON THE OTHER HAND REASON WE'RE HERE, I'M HERE IS WE WANTED TO DEVELOP MEDICAL COUNTER MEASURES TO TREAT RADIATION AND DO SEQUELLA. SO I'LL PLANT MY RED NUKE FLAG HERE TO MY BIOFRIENDS. NEXT SLIDE, I'M SORRY. SO THIS IS WHAT I'M GOING TO GO THROUGH, WE ABSOLUTELY HAVE TO TALK ABOUT ANIMAL MODELS SO ISLE GO THROUGH THE ANIMAL MODELS, I CAN TELL YOU A LOT ABOUT THEM BUT IT IS CRITICAL FOR US TO DEVELOP ANIMAL MODELS, WE SPENT A LOT OF MONEY OVER THE PAST SEVEN YEARS DEVELOPING THEM. I'LL GO THROUGH SOME MODELS AND WHAT'S ESSENTIAL ABOUT DEVELOPING AN ANIMAL MODEL. THEY ASKED ME (INDISCERNIBLE) DOCUMENT, ALL THE CLINICAL WORK MUST BE DONE IN RADIATION NUCLEAR SCENARIO OR BIOSCENARIO. WE TALK MEDICAL MANAGEMENT, SUPPORTIVE CARE AND THE MAJORITY OF MY TALK IS ON NON-HUMAN PRIMATES. THAT'S WHAT WE DO. IT'S ESSENTIAL TO LOOK AT TRIGGER TO TREAT AND TRIGGERS TO STOP. I'LL GO THROUGH THAT AS SUPPORTIVE CARE MEDICAL MANAGEMENT. IN OUR RADIATION NUKE SCENARIO WE ALSO HAVE MAJOR SEQUELLA WE'LL FOCUS ON, THE HEMATOPOIETIC SYNDROME, GASTRO INTESTINAL SYNDROME AND ALL THREE SEQUELLA. THEN EFFICACY OF MEDICAL MANAGEMENT SO A READ OUT FOR WHAT HAPPENS WHEN YOU USE WHAT WE CALL GOOD MODERATE MEDICAL MANAGEMENT. AND THEN JUDY ALSO ASKED ME TO TALK ABOUT SOME LESSONS LEARNED AND CHALLENGES, NEXT SLIDE PLEASE. SO THERE'S NO DOUBT ABOUT THIS, JIM MENTIONED EARLIER EVERYTHING WE DO IN OUR LABORATORY ADHERES TO THE FDA, SAY (INDISCERNIBLE) DOCUMENT. EVERYBODY IN THE LAB READS THAT, EVERYBODY THAT COMES INTO THE LAB IS TOLD TO READ THAT. IF I GET A CALL FROM A COMPANY I TELL THEM THE FIRST THING YOU NEED TO DO IS READ THE GUIDANCE DOCUMENT OF THE FDA. IT'S ABSOLUTELY CRITICAL. THERE'S A TREMENDOUS NUMBER OF GEMS IN THERE. YOU HAVE TO UNDERSTAND IT, USE IT. WE HAVE TO DEVELOP DOSE RESPONSE RELATIONSHIPS. THE HEMATOPOIETIC GAS STROA -- GASTRO INTESTINAL AND LUNG. WE HAVE TO UNDERSTAND ALL THREE FOR IS SEQUEL LAIRK THERE'S NO SENSE STARTING A PROGRAM UNLESS YOU UNDERSTAND THE DOSE RESPONSE RELATIONSHIP, THAT INVOLVES TIME COURSE OF MORBIDITY AND MORTALITY AS WELL AS MECHANISMS OF ACTION AND EVERYTHING ELSE IN THE GUIDANCE DOCK. THERE IS ALSO A GROUP DISCUSSION IN LABORATORY VERSUS ANIMAL MODELS. I DIDN'T HEAR THIS OUT IN THE BIO PART BUT IN THE RED NEW PART THIS IS A SIGNIFICANT DILEMMA WE'RE FACING NOW. DO YOU CONTINUE TO DEVELOP ASSAY EFFICACY IN A LABORATORY MODEL THAT HAS NO RELEVANCE TO WHAT HAPPENS IN THE RED (INAUDIBLE) TRYING TO GET A MODEL FOR WHICH PIECES CAN MOVE AROUND SO YOU CAN GET MULTIPLE MODELS FROM THE BASE MODEL, TOO EXPENSIVE TO CONTINUE TO DEVELOP MODEL AFTER MODEL AFTER MODEL. OF COURSE THIS HAS TO BE DONE IN CONTEXT. NEXT SLIDE, PLEASE. I WANT STO EMPHASIZE -- TO EMPHASIZE, JIM EMPHASIZED, IT IS CRITICAL WITH EVERYTHING WE DO. WE NEED TWO SPECIES SO PART OF THE CONSORTIUM CALLED MEDICAL COUNTER MEASURES AGAINST RADIO LOGICAL THREATS FUNDED BY NIAID. WE HAVE MULTIPLE LABS IN THE CONSORTIUM THAT SPECIFICALLY DEAL WITH MOUSE MODELS. WE HAVE A LAB FOR HEME, A LAB FOR GUT AND A LAB FOR LUNG THAT FOCUSES TO OUR LAB WHICH IS NON-HUMAN PRIMATE MODELS FOR ALL THREE SEQUELLA. WE HAVE TO DEVELOP OUR END POINTS, THE END POINT MUST BE CLEARLY RELEVANT IN A PRIMARY CLINICALLY RELEVANT PARAMETER THAT THE FDA IS LOOKING FOR. IT MAKES NO SENSE TO SPEND MONEY TO DO SOMETHING THE FDA ISN'T LOOKING FOR, WE CAN QUICKLY AGREE ON THAT. IT MUST DRIVE WHAT YOU DO. YOU HAVE TO UNDERSTAND THE RATIONALE FOR THAT. THIS INCLUDES MORBIDITY AND MORTALITY DEPENDING WHAT YOUR PRIMARY CLINICALLY RELEVANT OR SECONDARY PARAMETER IS. THIS IS PART OF WHAT THE DOCUMENT WILL HELP YOU UNDERSTAND IF YOU HAVEN'T READ IT, WE NEED TO UNDERSTAND THE HOST RESPONSE, WE NEED TO UNDERSTAND SPECIES DIFFERENCES. WE NEED TO KNOW TWO SPECIES, WHAT'S THE DIFFERENCE BETWEEN A MOUSE AND NON-HUMAN PRIMATE OR CANINE. STRAIN DIFFERENCES IN MICE, ABSOLUTELY THAT ARE. WHAT STRAIN DO YOU USE? WHAT IF A SPECIFIC STRAIN IS GOOD FOR RADIATION NIEWM NIGH AT THIS, ANOTHER RADIATION NEWS FIBROSIS, USE THE SAMEo7O STRAINS FOR HEMATOPOIETIC, ESPECIALLY WANTING A CONSORTIUM WE NEED IT TO LINK EVERYTHING DWOA FROM MOUSE AN NON-HUMAN PRIMATE OR CANINE TO HUMAN PROTOCOL. I ALREADY TALKEDDED ANT ESTABLISHING DOSE RESPONSE RELATIONSHIP. WE MUST KNOW TIME COURSE OF MORBIDITY AND MORTALITY AND THIS LINKS INTO NATURAL HISTORY. YOU ABSOLUTELY HAVE TO UNDERSTAND WHAT THAT ANIMAL IS GOING THROUGH. THAT DETERMINES MECHANISM OF ACTION OF WHAT THE STRESSOR DOES, IN THIS CASE RADIATION. IT ALSO SETS THE BASE HOW WE UNDERSTAND WHAT THE MEDICAL COUNTER MEASURE DOES. TO US THIS IS WHAT THE FDA IS ASKING FOR, I WOULD NEVER GO SIT IN FRONT OF FDA AND NOT BE ABLE TO ANSWER THESE QUESTIONS. I KNOW THEY'LL ASK THEM OF THE GROUP WE'RE WITH. TRIGGERS TO TREAT AND STOP. I'LL GO INTO SOME OF THAT. ORGAN SPECIFIC AS WELL. IF WE GO FROM CASUALTY SCENARIO OF 100 PEOPLE, IF WE GO TO A THOUSAND OR 10,000 ARE THE MEDICAL MANAGEMENT PROTOCOLS USING AMENABLE TO THESE SCENARIOS. NEXT SLIDE, PLEASE. SO THIS IS ONE OF OUR CURRENT TONES, NON-HUMAN PRIMATE IN CASE YOU HAVEN'T RECOGNIZED IT, ONE OF THE FIRST PEOPLE WE PRESENTED THIS TO SAID IT LOOKED LIKE ONE OF HIS SOCK MONKEYS. WONDERFUL CHILDHOOD, THAT'S TERRIFIC. SO WHAT WE HAVE DONE HERE IS THIS IS THE BONE MARROW THROUGHOUT THE WHOLE ANIMAL FROM THE FEET TO THE HEAD TO THE SKULL. YOU HAVE TO BE COGNIZANT OF THAT. WE ALSO LOOK AT THE GUT AND WE LOOK AT THE LUNG SO OUR RATIONALE IS FOR THREE MAJOR SURVIVORRABLE SEQUELLA FROM ACUTE RADIATION RESPONSE THAT EITHER IS LIMITED BY ACUTE LIMITED RADIATION RESPONSE OR SURVIVABLE ENOUGH TO UNDERSTAND THE DELAYED EFFECTS OF ACUTE RADIATION EXPOSURE. THAT'S THE OTHER ACRONYM YOU SEE IN OUR SLIDES. DELAYED EFFECTS OF ACUTE RADIATION EXPOSURE WHICH THE LUNG IS THE PRIMARY ORGAN SEQUELLA WE'RE LOOKING AT. SO WE HAVE THREE MODELS THAT MIMIC THOSE SEQUELLA. WE HAVE ESTABLISHED DOSE RESPONSE RELATIONSHIP US, TIME COURSE MORBIDITY AND MORTALITY FOR EVERY ONE OF THEM. I WOULD BE HAPPY TO SHARE THOSE OR IF YOU WANT TO COME OUT TO MARYLAND IF YOU'RE INTERESTED IN A RAD NUKE WE CAN GO OVER THEM. NEXT SLIDE PLEASE. LET ME EMPHASIZE, BACK TO MY OTHER LITTLE LINE EARLIER, THESE ARE LABORATORY MODELS. SO THE TWO TOTAL GUY RADIATION MODELS ARE FOR HEMATOPOIETIC AND GUT. THE LUNG MODEL IS CALLED WHOLE LUNG THORACIC RADIATION. ESSENTIALLY WE EXPOSE THE ANIMAL THROUGH THE TO RA SICK AREA. IT ALLOWS US IN TWO OF THOSE AREAS TO FOCUS ON THE ORGAN OF INTEREST. WE CAN DO THAT FOR TBI BECAUSE WE HAVE A DOSE RANGE FOR THE GUT AND WE KNOW THE DOSE RANGE FOR THE HEMATOPOIETIC SYNDROME AND YOU CAN SEPARATE THEM TO A CERTAIN DEGREE. WE CAN ARGUE ABOUT THE CROSS-OVER BETWEEN HIGH HEME AND LOW GUT BUT WE DON'T NEED TO DO THAT TODAY. BUT WTLI MODEL ALLOWS US TO FOCUS PRIMARILY ON THE LUNG SO WE CAN ASK QUESTIONS ABOUT RADIATION EFFECTS ON THAT ORGAN SYSTEM, DOSE RESPONSE RELATIONSHIP IS THE BASE THAT ALLOWS US TO JUMP INTO WHAT WE CALL A REALITY MODEL THAT I'LL TALK TO YOU IN THOSE FOUR LIEDZ. THESE ARE LABORATORY MODELS, NO FREAKING WAY SOMEBODY IS GOING TO GET EXPOSED TO AP DOSE OF RADIATION, UNIFORM MIDLINE TISSUE DOSE IF A NUKE GOES OFF, RIGHT? THESE ARE GOING TO BE UNILATERAL. WITH DOSE DISTRIBUTION YOU HAVE A SIGNIFICANT AMOUNT OF -- YOU CAN BE BEHIND A FIRE HYDRANT AND GET YOUR TIBIA SHIELD. SO WE HAVE TO GET AWAY FROM THINKING A LITTLE BIT BECAUSE I THINK THE FDA IS GOING TO ASK US WHAT IS THE CLINICAL SCENARIO. WHAT'S REALLY GOING TO HAPPEN. IS THE PATIENT GOING TO HAVE ONE SCENARIO OR ARE THERE THREE COINCIDENT SCENARIOS THAT OCCUR FROM MINUTE ONE TO YEAR ONE. THAT IS THE TRUTH. THOUGH THE LUNG DAMAGE DOESN'T APPEAR FOR TWO MONTHS YOU KNOW DOMINOES ARE FALLING FROM DAY ONE. TIME AFTER TIME AFTER TIME THE MECHANISM IS TICK AGO WAY, ALMOST LIKE BANG AT THE TWO MONTH PERIOD FOR WHATEVER REASON MECHANISM OF ACTION WE CAN SEE ON A CT SCAN PNEUMONIGHTIS CONSOLIDATION AND SBL-2 DEGREASE. HERE IS A PROTOCOL FOR ORGAN SPECIFIC PRIMARILY DESIGNED FOR THE HEMATOPOIETIC SYNDROME, ALL THE COMPONENTS ARE THE SAME, IT'S A MATTER OF HOW MUCH YOU USE THEM. IT'S A TRIGGER TO TREAT AND STOP. ONE KEY ISSUE WE HAD TO DEAL WITH HEMATOPOIETIC SYNDROME WAS ADMINISTER ANTIBIOTICS PROPHYLACTICALLY. IN THE WORLD YOU DON'T DO THAT. NOBODY RECOMMENDS GIVING ANTIBIOTICS PROPHYLACTICALLY SO WE ARGUED THIS IN FRONT OF FDA, ARGUED IN A GOOD SENSE ABOUT SIX YEARS AGO AND THEY QUESTIONED US. HOW CAN YOU SAY YOU NEED TO GIVE ANTIBIOTICS PROPHYLACTICALLY? WE THEN WENT BACK INTO THE LITERATURE, DID A COMPLETE SEARCH OF ALL THE ANIMAL MODELS, ALL THE ARTICLES BY INFECTIOUS DISEASE DOCS WHAT LETHAL DOSE OF RADIATION IF YOU LOOK AT THE GUIDANCE DISEASE SITE OF AMERICA NATIONAL CANCER CARE NETWORK ALL THE CLINICAL TRIALS WE LOOKED AT AND THE CHERNOBYL DATA I'LL SHOW YOU ONE SLIDE OF, YOU CAN ADMINISTER ANTIBIOTICS IF YOU KNOW THAT AFTER ASC OF 500, THE MINUTE THE ANC IS 100 PER MICROLITER AND GO TO NEUTROPENIA. IF YOU LOOK AT ALL THE LETHALITY DATA, AND NON-HUMAN PRIMATES AND ANECDOTAL DATA YOU CAN, FOR HUMANS, THIS IS EXACTLY WHAT HAPPENS WHEN YOU'RE EXPOSED TO DOSES AT LEAST 30% TO 80% LETHAL NO DOUBT ABOUT THAT. I'LL SHOW YOU THIS DATA. YOU HAVE TO GIVE ANTIBIOTICS PROPHYLACTICALLY YOU'RE FIGHTING A WAR THAT'S A BATTLE YOU HAVE TO WIN. YOU CANNOT WAIT UNTIL THE ANIMAL IS FEBRILE NEUTROPENIC. WHAT'S NICE ABOUT THE NON-HUMAN PRIMATE THESE NUMBERS CORRELATE NICELY WITH PEOPLE SO UNLESS ASC LESS THAN 100 IS GRADE 4 NEUTROPENIA. NEXT SLIDE PLEASE. HERE'S SOME OF THE DATA WE HAVE ACCUMULATED A LOT OF ANIMALS, A LOT OF NON-HUMAN PRIMATES IN OUR LABORATORY AND OTHER LABORATORIES AND I WANT YOU TO KEEP THIS TIMING IN MIND. I'M GOING TO DRIVE HOME A POINT WE GET IN GOOD ARGUMENTS WITH BARTA ABOUT ALL THE TIME SO I'M GOING TO TAKE THIS OPPORTUNITY TO GIVE YOU MY SIDE. THE FIRST IS FIVE DAYS PROPHYLACTIC. FEVER HERE. SO WE HAVE A FIVE DAY DURATION AFTER LETHAL DOSE OF RADIATION BEFORE WE GIVE ANTIBIOTICS ACCORDING TO THIS TRIGGER TO START. IF WE THEN LOOK AT FIRST DAY THE AANC IS OVER 100 IN LESS THAN -- SO THE CRITERIA USED IN THE LITERATURE TO HAVE RATIONALE FOR USING PROPHYLACTIC ANTIBIOTICS. 12 THE DAYS SO WITHIN A WEEK THESE ARE NEUTROPENIC, THERE'S IN THE A NEUTROPHIL THERE. THEY'RE IN TROUBLE. WHAT'S THE FIRST DATA UNDER NEUTROPENIA? TEN DAYS. WE ID THE BACTERIA, SENSATIVETY OF THE BACTERIA, WE CAN PUT OTHER ANTIBIOTIC AT THAT TIME. IF BUGS ARE RESISTANT WE SWITCH TO OTHER ANTIBIOTIC. SAME YOU DO IN THE CLINIC. WHEN WE SIT DOWN AS INCLUSIVE AS POSSIBLE, WE ASK ID AT MARYLAND, TO DEVELOP MEDICAL MANAGEMENT PROTOCOL AT THE UNIVERSITY OF MARYLAND. NEXT SLIDE, PLEASE. SO THIS I HAVE A LITTLE TRANSFUSION. I PUT THIS ON ONE SLIDE THE OTHER DAY. SAME WOULD APPLY TO BLEEDING. SO THE TWO KEY PARAMETERS ARE NEUTROPENIA, INFECTION, SO WHAT IS TRANSFUSION. ANIMAL CRASHES AN GETS BLEEDING DOWN TO MICROLITER AND NON-HUMAN PRIMATES ARE 300,000 PER MICROLITER. SO WE ADHERED THIS TO GET TRANSFUSION. THE FIRST DAY THE PLATELETS DROPPED AT 20,000 OR 10,000, THERE'S IN DIFFERENCE. THE SLOPE SO STEEP WHEN PLATELETS ARE DROPPING, NO DISTANCE BETWEEN THE DAY OF 20,000 OR 10,000. THE FIRST DAY WE AVERAGE TRANSFUSION IS 13 TO 14 DAYS. NEXT SLIDE, FIRST DAY, DAY 5, FIRST DAY WE NEED THE GIVE A TRANSFUSION DAY 13 OR 14. WHAT ABOUT READ OUT? DOES THIS MAKE A DIFFERENCE? ABSOLUTELY IT DOES. WE HAVE A LOT OF ANIMALS IN DOGS AND MONKEYS TO SHOW THIS. ONE PARAMETER IS MEAN9 TIME BECAUSE LOWER DOSE THESE ARE SURVIVORS, AND THEN THE OTHER PARAMETER MEAN SURVIVAL TIME OF DECEDENTS. WHY IS THAT IMPORTANT? WHICH ONE OF US WOULDN'T WANT THREE OR FOUR EXTRA DAYS OF SURVIVAL GETTING SUPPORT OF MEDICAL MANAGEMENT TO BE ACTING. SO WE'RE NOT GOING TO DO THIS IN A -- WE BELIEVE WE'RE GOING TO BE RECEIVING THEM MEDICAL COUNT MEASURE SO MECHANISM OF ACTION ALLOW AS MEDICAL COUNTER MEASURE ADDITIONAL TIME TO ACT. TO INCREASE NEUTRAFILLS, INCREASE PLATELETS TO DO WHATEVER IT HAS TO DO. THE MAJORITY OF THE DATA IS IN THE HEMATOPOIETIC SYNDROME. THAT'S THE BEST I CAN TELL YOU YOU MAY ALREADY KNOW, THERE ARE KNOW NON-HUMAN PROI MATE OR CANINE MODELS OF RADIATION NIEWM NIGHTIS OR -- KNEW MOW NIGHTIS OR FIBROSIS. WE DEVELOPED THESE WITH OUR NIAID FUNDING OVER THE PAST FIVE YEARS. THE ONE THAT WAS SOMEBODY'S MODELS IS THOUGH WE DON'T HAVE THE NON-SUPPORT DOSE RESPONSE RELATIONSHIP. THE REASON WE DON'T IS ONE THING I DIDN'T THINK WAS EMPHASIZED ENOUGH BY JIM OR THE OTHER SPEAKER, THAT IS, IACUC INVOLVEMENT IN YOUR MODELS. AND WHAT YOU DO, WHATEVER YOU ARE. I KNOW THEY'RE DIFFERENCE BECAUSE WE HAVE AN ASSOCIATE IN CANADA WHO HAS A DIFFERENCE APPROACH OF WHAT THEY DO THAN WHAT WE CAN DO SO THE IACUC HAS A TREMENDOUS IMPACT ON WHAT YOU CAN DO RELATIVE TO SUPPORT OF CARE. IN MARYLAND WE NEVER CONDUCT A STUDY WITHOUT SUPPORTIVE CARE. WHY ERADIATE 50 OR 60 NON-HUMAN PRIMATE, BEAUTIFUL ANIMALS AND WATCH THEM DIE WITHOUT SUPPORTIVE CARE OR GIVE THEM SUPPORTIVE CARE. DOESN'T MAKE SENSE TO ME. IT WAS DONE 50 YEARS AGO, WE KNOW THE DATA. ISLE SHOW YOU THAT DATA. -- I'LL SHOW YOU THAT DATA. NEXT SLIDE PLEASE. STAN NEEDS SURVIVAL TIME WE DID ONE AT ATHLETE, COMP THEM RARE AT THAT POINT, WE DID NEED SUPPORTIVE CARE, CANINES BELIEVE THAT. WHERE CANINES AN NON-HUMAN PRIMATES ARE USED AS BASIC ANIMAL MODELS BACK IN THE 50s AND 60s. BOTTOM LINE IS THAT MEAN SURVIVAL INCREASED 14 DAYS WITH NO MEDICAL MANAGEMENT TO 19 DAYS WITH MEDICAL MANAGEMENT. A FIVE DAY INCREASE IN MEAN SURVIVAL TIME OF DECEDENTS. EVERYBODY AT THE LOW END SURVIVED. SO SHIFTED, I'M GIVING ADVANCE NOTICE HERE, THE SURVIVAL CURVE. NEXT SLIDE. HERE IS THE SLIDE FOR THE CANINE A LOT OF HISTORKAL DEA T NON-SUPPORT CURVE. SO THIS IS A PROBE IT PLOT, MORTALITY ON THE AXIS, AND PROBE IT DOSE ON X AXIS. NO SUPPORTIVE CARE LD-50 ABOUT 260 CENTIGRADE. WITH SUPPORTIVE CARE 338 CENTIGRADE. EVERYTHING HERE IS SHIFTED TO THE RIGHT. EXACTLY WHAT YOU WANT TO HAVE HAPPEN, A BEAUTIFUL DEMONSTRATION OF THE FACT THAT SUPPORTIVE CARE MEDICAL MANAGEMENT IN CANINE MODEL OF REDUCE LETHALITY INCREASE SURVIVAL TIME OF DECEDENTS AS WELL AS SURVIVAL AND SHIFT IT IS LD-30. NON-HUMAN PRIMATES, A COUPLE OF YEARS AGO. HERE IS THE PROBLEM WITH THE PRIMATES. WE'RE NOW IN MARYLAND, WE DOWN WITH THIS IN MARYLAND. WE GO BACK, EVERYTHING DWOA YOU HAVE TO KEEP YOUR EYE ON YOUR REAR-VIEW MIRROR. SO TO OFFSET MEANS GO BACK INTO THE LITERATURE. WHAT WAS DONE IN THE 50s AN 60S, WE FOUND ONE STUDY THAT USED TWO RADIATION, WE FOUND ANOTHER STUDY, USING COBALT 60 WHICH IS 1.1 MEB. HE GAVE US THAT DATA. THEY SIT ON TOP OF EACH OTHER WHICH SAYS ANIMAL CAN'T SEE A DIFFERENCE BETWEEN TWO, X-RAY AND 1.1 COBALT 60 WHICH IS REASONABLE, NOT GOING TO BE A RELATIVE BIOLOGICAL EFFECT THERE. SO THAT'S HISTORICAL NON-SUPPORTED CONTROL. WE DID A STUDY WITH 50 ANIMALS OVER HERE WITH SUPPORTIVE CARE WHERE THEY JUST GIVE YOU A FEW MINUTES AGO, THIS IS THE DATA POINT WHERE I WAS AT -- WE HAD DONE A SINGLE DOSEHB– SUPPORTIVE CARE. FIT BEAUTIFULLY ON THAT SLOPE. PROBE AND PLOT WE USE ALL THE TIME. DOSING GRAY ON X AXIS, SO IT SHIFTED AN AVERAGE LD 5030 FROM 6.5 TO 7.2. NEXT SLIDE. SO AGAIN, ANOTHER DATA SET, SHOWING EVERYTHING SHIFTED TO THE RIGHT. SURVIVAL TIME INCREASES OF DECEDENTS AND SURVIVING FACTORS AS WELL. CANINE FACTORS IS 1.3. IF I DIDN'T SHOW YOU THIS DATA HERE 250 KVP X-RAY, 1.4 FOR DATA I I SHOWED YOU USING HISTORICAL CONTROLS USING PHOTON SOURCE AT MARYLAND. IT'S 1.16. I CAN GO INTO THE REASON WHY THESE ARE DIFFERENT IF YOU WANT TO KNOW THAT, ASK ME LATER. NEXT SLIDE. FORGET THE LAB MODELS. WHAT ABOUT A REALITY MODEL, HOW DO YOU EVEN THINK ABOUT DEVELOPING A REALITY MODEL? LOOK IN THE REAR-VIEW MIRROR, ALL THE ANECDOTAL LITERATURE THAT YOU CAN, TALK TO PEOPLE, READ SOME OTHER STUFF YOU DID DECADES AGO, UPDATING MYSELF. AND OTHER COLLEAGUES, AND WHAT DOES IT SAY ABOUT THE AMOUNT OF BONE MARROW THAT MUST BE SHIELDED BEFORE YOU OVERWHELM THE SYSTEM SO IT DOESN'T MAKE SENSE TO DEVELOP A MODEL WHY SHIELD 50% OF THE BONE MARROW. EVERYBODY IS A SURVIVOR, IT'S A HUGE BONE MARROW TRANSPLANT. SO YOU HAVE TO CONTINUE TO DECREASE THE AMOUNT OF MARROW YOU THINK MAYBE RELEVANT IN A RED NUKE SCENARIO. SO WE GOT TO RATIONALIZE MODELS TO LOOK AT. HEMATOPOIETIC, GUT, -- IF YOU GO BACK TO ANECDOTAL LITERATURE THAT'S WHAT PEOPLE RL SUFFERING FROM. SO A VOLUME OF LIT THATTURE THAT SAYS YOU NEED TO MINIMIZE BONE MARROW AT LEAST 5% OR BOW LOW OR YOU WILL INFLUENCE SOME OF THE OTHER SEQUELLA. WE DON'T WANT TO DO THAT. WE STILL WANT TO USE A TBI OR WTLI BASE. SO LONG STORY SHORT WE COME UP WITH 5%. WE SHIELD ESSENTIALLY 5% OF THE BONE MARROW, HOW DO WE KNOW WHAT 5% IS. LOOK IN THE REAR-VIEW MIRROR, YOU FINE OUT WHAT ESSENTIALLY 5% IS. SO THAT'S 5% OF ANKLES AND FEET. EVERY MONKEY OUR PARTIAL BODIER RADIATION RIGHT SLASH BONE MARROW 5 SPARING MODEL HAS TIBIA ANKLES AND FEET SPARED. EVERYTHING ELSE GETS IRRADIATEDDED. WE THEN DO A DOSE RESPONSE RELATIONSHIP. WE NEVER VARY FROM WHAT I TOLD YOU WE DID IN THE BEGINNING. CAN'T DO IT. DON'T COME TALK TO US IF UP TO MOVE AWAY FROM THAT. THAT'S THE BASE FOR EVERYTHING WE DO FROM THAT POINT ON. WE HAVE A DOSE RESPONSE RELATIONSHIP FOR WHAT HAPPENS WITH THE GUT, WHAT HAPPENS WITH THE LUNG AND WHAT HAPPENS WITH THE HEMATOPOIETIC SYNDROME. YOU CAN IMAGINE NOW, THE LD-50, 60 FOR THE HEMATOPOIETIC SYNDROME IN THE MONKEY WAS 7.5 GRADE. THAT'S WHAT I SHOWED YOU IN ONE SLIDE. TALK PROBABLY WENT THROUGH IT PRETTY QUICK. 50% OF ANIMALS IF YOU DO TBI WILL DIE, 50% SURVIVE ON AVERAGE. BECAUSE WE SPARE 5% BONE MARROW ALL WE CAN SPARE THAT AMOUNT, THAT'S COOL. THAT'S A REALISTIC THING. THE LD 50, 60 NOW FOR THE HE HE MAT POIETIC SYNDROME IS 11 GRADE. SO THAT MEANS IN THEIR REALITY SCENARIO AND WE CAN TOGGLE GOOD COLD SAM ADAMS AS TO WHETHER UNILATERAL EXPOSURE IS THE WAY TO DO IT OR TRY TO CONTROL AS MUCH AS WE CAN AND DO A TOTAL BODY BUT SPARE SOMETHING. SO THERE'S REASONS WE DO THAT. WE SHIFT THE LD SIGNIFICANTLY, MARROW IS GIVING A SMALL BONE MARROW TRANSPLANT. WHAT IT ALSO ALLOWS US TO DO IS TO CONTINUE TO LOOK T THE GUT AND CONTINUE TO LOOK AT THE EVOLVING LUNG DAMAGE. THAT'S THE TRAIN COMING DOWN THE TRACK. SO NOW WE CAN TEST MECHANISM OF ACTION, BIOMARKERS, ANYTHING YOU WANT IN A MODEL THAT IS THREE COINCIDENT SEQUELLA OCCURRING AT THE SAME TIME THROUGHOUT THE EVOLUTION OF THE TIME COURSE OF MORBIDITY AND MORTALITY. NEXT SLIDE. NEXT SLIDE. SO LITTLE BIT OF CHER NO BILL DATA. THERS THES ARE FIREMEN YANKING ALL THAT RADIOACTIVE STUFF OUT OF THE REACTOR. ALL I WANT TO SHOW YOU HERE IS THAT THE RUSSIANS BELIEVE THIS IS A NEAR UNIFORM EXPOSURE. HERE THE TIME TO ANC UNDER 500, 6 AND 8 DAYS. BACK TO WHAT WE WERE TALKING ABOUT WITH THE MONKEY, FIVE DAYS PLUS. A GUY USED THIS AS A BIODOE SIMILAR TEAR. ANYWHERE FROM 5 TO 9 GRAY NEAR UNIFORM TOTAL BODY RADIATION. IF YOU DO NOT KNOW THE NUMBER, THE LD 5060 FOR PEOPLE GETTING SUPPORTIVE CARE IS 6 GRAI. WITHOUT SUPPORT ACTIVE CARE IT'S 4.5 GRAY. THIS IS MY SECOND TO LAST SLIDE. SO I'M EMPHASIZING THE VALUE OF SUPPORTIVE CARE. ALL THOSE PEOPLE GOT SUPPORTIVE CARE. HERE ARE THE NUMBERS. AFC LESS THAN 500, 6 AND 14 DAYS, PLATELETS UNDER 20,000 AT 16 DAYS SO BACK -- NEXT SLIDE, IT GOES BACK TO THE POINT OF TIMING FOR MEDICAL MANAGEMENT, YOU DON'T IT IMMEDIATELY, NEXT SLIDE, PLEASE. YOU DONE NEED IT IMMEDIATELY. IN FACT IT MAYBE THE ONLY MEDICAL COUNTER MEASURE GIVEN TO ANY ONE OF US AT ITS OPTIMUM TIME. ESPECIALLY IF YOU BELIEVE YOU HAVE TO GET A MEDICAL COUNTER MEASURE ANY OF THEM THAT I AM AWARE OF WITHIN 24 HOURS AFTER EXPOSURE. WHAT YOU NEED TO CONSIDER IS USE MEDICAL MANAGEMENT PLUS THE MEDICAL COUNTER MEASURE AND HOPEFULLY 1 PLUS 1 AT LEAST EQUALS TWO. SO JUDY ASKED ME TO GO OVER LESSONS LEARNED. THIS DRIVES OUR LABORATORY, NOTHING IS EASY. YOU AND I SIT DOWN AND SAY WHY DON'T WE DO THIS AND IN TEN MINUTES WE FIND TEN THINGS THAT WILL AFFECT IT. NOTHING IS EASY TO DO. WE LIRNG MOUSE AND NON-HUMAN PRY MAI. ANOTHER DIFFICULT PROPOSITION IN THE RED NUKE COMMUNITY. WE NEED AN ANIMAL MODELS OF PEDIATRIC AND ELDERLY. ANOTHER DIFFICULT THING, I CANNOT IMAGINE DOING THIS IN NON-HUMAN PRIMATES. WE NEED TO DEFINE THE POSITIVES AN NEGTIS OF LAB VERSUS REALITY AND FDA CLINICAL CONTEXT. WE'RE ALWAYS TRYING TO BE INCLUSIVE, WE THINK KEEN, DEFINE GAPS, MEET WITH FDA OFTEN AND EARLY, IT'S A TREMENDOUS EXPERIENCE FOR US, EVERY TIME WE MEET WITH THEM WE LEARN SOMETHING. AND REMEMBER RULE NUMBER 1. THANK YOU VERY MUCH FOR YOUR ATTENTION. APPRECIATE IT. [APPLAUSE] >> THANK YOU ALL FOR STAYING. WE WOULD LIKE TO PRESENT OUR PRESENT -- INVITE OUR PRESENTERS UP FOR -- UP ON STAGE, THEN TAKE ANY QUESTIONS THAT THE GROUP MIGHT HAVE. >> A WE'RE TAKING MODERATORS PRIVILEGES HERE AND FEELING AS THOUGH THIS IS A REALLY IMPORTANT PART OF ANIMAL MODEL DEVELOPMENT AND APPLICATION ARE THESE CONCEPTS OF SUPPORTIVE CARE AND HUMANE END POINTS TO HAVE AN OPEN DISCUSSION RIGHT HERE IS REALLY IMPORTANT. SO THANKS FOR BEARING WITH US. >> IS THIS ON? OKAY. (INDISCERNIBLE) NIAID. DR. PETER TOWARDS THE END OF HIS TALK HAD A SLIDE OF QUESTIONS WHICH WERE REALLY GOOD QUESTIONS, BUT I THINK THEY WERE ORIENTED TOWARDS INFORMING CLINICAL CARE. IS THAT CORRECT? >> I THINK THOSE QUESTIONS I PUT UP THERE ARE THINGS LIKE FLUIDS VERSUS CRYSTALOID. THOSE ARE BOTH HUMAN AN ANIMAL QUESTIONS. I THINK THINGS LIKE IF WE COULD WORK OUT A WAY TO LOOK AT SRI SEW PRESSERS IN THE LAB WHICH WOULD BE CHALLENGING, IT CERTAINLY COULD HAVE CLINICAL APPLIATION, PERHAPS NOT IN A PLACE LIKE CENTRAL AFRICA BUT MAYBE IN A LABORATORY EXPOSURE. >> I THINK IT'S IMPORTANT TO DISTINGUISH -- THERE ARE TWO AREAS, TWO ISSUE, ONE STUDIES TO INFORM CLINICAL MANAGEMENT VERSUS QUESTIONS THAT DEVELP BETTER ANIMAL MODELS TO DEVELOP COUNTER MEASURES. AND I THINK YOUR QUESTIONS DEALT WITH CLINICAL CARE. I THINK THAT'S GOOD BUT FROM AN ANIMAL MODEL DEVELOPMENT PERSPECTIVE AT LEAST IN THE ID ARENA, I REMAIN UNCONVINCED THAT SUPPORTIVE CARE IS -- I DON'T SEE A REASON TO DO IT, THERE'S A HUGE LEVEL OF COMPLEXITY IF YOU GIVE SUPPORTIVE CARE TO CONTROLS AN SURVIVING ABOUT NUMBERS GO UP YOU NEED ALTERNATE END POINTS BSL-4 SPACE IS LIMITED. WE CAN TIE UP JUST FOR QUESTIONS TODAY BSL-4 SPACE COULD BE TIED UP JUST TO ADDRESS THOSE QUESTIONS. SO I THINK WE HAVE TO BE -- I'M NOT SAYING NOT DO IT BUT WE HAVE TO GO IN WITH EYES WIDE OPEN ON THIS SUPPORTIVE CARE AND REALLY IS IT WORTH IT, THE BEST WAY TO USE RESOURCES? >> I'M NOT CLEAR IF THAT WAS A QUESTION OR COMMENT. BUTLY MAKE A COMMENT THAT PART OF WHAT I WANTED TO SAY AT THE END THERE IN TERMS OF IF DO YOU WANT ASSESS WITH TRUE ICU CARE 24/7 CHALLENGES ARE ENORMUS. I PUT IT OUT AS A CAUTIONARY NOTE. TO DO THIS IN ANIMAL MODEL AND ASSESS THAT IS CHALLENGING. IN TERMS OF THE ANIMAL MODEL WHERE THEY CAN HELP US IS SPECIFIC TARGETED ASPECTS OF SUPPORTIVE CARE WHERE YOU ONLY PERHAPS SELECT SINGL ASPECTS TO ASSESS OR YOU COULD POTENTIALLY GO -- YOU HAVE A PLACEBO CONTROL TRIAL OR NO CARE FROM ONE GROUP AND SOME SPECIFIC SUPPORTIV CARE FOR ANOTHER GROUP. HARDER TO DO SOMETHING LIKE THIS IN THE FIELD ENVIRONMENT OF HUMANS. >> MY QUESTION WAS RELATIVELY SIMILAR, I SUPPOSE THE THIRD PERSON WAS AS WELL, NAMELY THAT THERE'S THOUSANDS OF DIFFERENT KINDS OF INTERVENTIONS YOU CAN DO AND TOM DISCUSSED PREEMPTIVE INTERVENTION LIKE MITIGATION. RADIATION DIFFERENT THAN INFECTIOUS DISEASE MIGHT BE AMENABLE TO THAT QUALIFICATION FDA CONCEPT. I WONDER HOW CLOSE YOU ARE IF YOU THINK OF DOING THAT IDENTIFYING A BEST SUPPORTIVE CARE THAT YOU USE AS PART OF THAT REGIMEN. >> HOW CLOSE WE ARE, I DON'T KNOW. BECAUSE WE HAVEN'T BEEN THERE YET. I DON'T THINK ANYBODY ELSE HAS BUT WE THE MARYLAND GROUP AND NIAID HAVE BEEN VERY INTERACTIVE WITH THE FDA AND OUR GROUP, THE IMAGING GROUP AND JERRY DAVIS I THINK I SAW JERRY TALKED THIS MORNING, ROSE MARY AND LISA, IT IS OUR EFFORT TO GET EVERY ANIMAL MODEL WE HAVE WHICH WE HAVE FOUR RIGHT NOW TO QUALIFY AS DDT. WE'RE WELL ALONG THAT ROUTE BECAUSE OF FUNDING WE HAVE HAD SO WE'RE FORTUNATE. IT'S INCUMBENT UPON US TO DO THAT. BUT I DON'T THINK WE'RE THERE YET. BUT WE WILL HAVE ACTIVE MEETINGS TO AT LEAST GET THE RADIATION MODELS QUALIFIED AS A DDT. >> I WOULD LIKE TO ADD THIS THAT'S A MOVING TARGET BECAUSE THAT IS GOING TO CHANGE BASED ON HOW ANIMALS RESPOND TO CERTAIN ANTIBIOTICS AND WHAT MEDICAL MANAGEMENT IS, THOSE RECOMMENDATIONS BY VETERINARIANS AND IAKUKs BECAUSE THAT CHANGES OVER TIME AS WELL. >> I AGREE. WE WILL NEED GUIDANCE FROM JERRY AND ROSE MARY ON THIS, WE'RE GOING TO WALK DOWN THE PATH AND TAKE IT AS IT COMES BUT WE'RE FARTHEST ALONG AND WEAL MAKE THE EFFORT TO DO THAT. >> RYAN YATES UT (INAUDIBLE) TOM, ONE THING MAYBE THAT ECHOS SOME OF THE FRUSTRATION THE GENTLEMAN BEFORE, PART WAS COMING FROM US TRYING TO DO MEDICAL COULD BEER MEASURES. WE START TALKING ABOUT BEST SUPPORTIVE CARE AND USE TERMS LIKE IT'S A MOVING TARGET. SO IN THE MIDST OF THE BATTLE AND TARGET IS MOVING, PART OF THAT WAS WE NEED TO GET TO SOME TYPE OF CONCLUSION SO WE CAN TRULY DO EFFICACY TESTING. >> I DON'T KNOW -- I WOULDN'T HAVE USED THE WORD MOVING. AS I SAID IN MY PRESENTATION WE ARE AS INCLUSIVE AS POSSIBLE. THIS IS THE REASON WHY WE'VE MOVED OFF SUPPORTIVE CARE WHICH MAYBE WERE DEFINITIVE TO MEDICAL MANAGEMENT THAT ALLOWS YOU LEE WAY. BUT PRIOR TO -- I WOULD THINK ANY COMPANY PRIOR TO APPROACHING THE FDA YOU NEED TO HAVE YOUR DUCKS LINED UP, YOU NEED YOUR MODEL REFINED AND HOPEFULLY YOU HAVE HAD A DATABASE ALREADY USING THAT SUPPORTIVE CARE. IT HAS BEEN THE RESULT OF A VERY INCLUSIVE INTERACTION WITH THOSE OF US THAT USE ANIMAL MODELS BOTH MOUSE AND NON-HUMAN PRIMATE, OR K-9. TO US MEDICAL MANAGEMENT WILL BE THE STANDARD OF CARE TO US BEING FOCUSED HERE, CAN YOU NOT IMAGINE USING MEDICAL MANAGEMENT IN A RADIO SCENARIO. SO I DON'T KNOW WHY TEST ANIMALS WITHOUT USING IT PARDON MY BUY BIOIAS. WE NEED TO DRIVE HARD ON THOSE QUESTIONS. >> SUE GARGAS NIAID. I WONDER IF DR. PETER WANTED TO COMMENT SORT OF A FOLLOW ON FROM YOUR WORK. I BELIEVE YOU'RE COLLABORATING WITH A GROUP IN CALIFORNIA USING STATISTICAL ALGORITHMS TO ANALYZE YOUR DATA, BRING THINGS TOGETHER AND MY POINT IS IT'S GREAT WHEN THERE'S EFFORTS TO MINE THE DATA TO GET ALL THE INFORMATION OUT. SO DR. PETER, CAN YOU COMMENT ON THAT? >> YOU MAYBE REFERRING TO WORK THAT JAMES LAWLER CO-AUTHOR MAYBE DOING. I DO OHIO I WILL SAY -- I WILL SAY THERE'S OTHER DATA THAT WE DID NOT PUBLISH. UNFORTUNATELY THE RED LIGHT WAS FLASHING, I WAS TALKING SO I NEVER GOT TO LAST LLOYD TO SAY THAT THE DATA I TALKED ABOUT WAS PUBLISHED. ONLY AS MUCH AS WE COULD FIT IN THE ARTICLE SO THERE ARE OTHER DATA LIKE CYTOKINE DATA. THINGS LIKE THAT WOULD BE NICE TO SOMEHOW GET OUT EVENTUALLY IF I CAN DO -- LOOK AT MY CO-CONSPIRATORS THERE, MAYBE WE COULD GET THAT DONE BUT CERTAINLY YOU WANT TO TRY TO GET AS MUCH AS YOU CAN. I THINK THERE MAYBE SOME DISCUSSION ABOUT THIS TOMORROW IN TERMS OF TELEMETRY. THERE'S A HUGE AMOUNT OF DATA YOU CAN CAPTURE. AND OTHER DATA TO FIND, SO A CHALLENGE IS TRYING TO GET IT ALL IN A SUCCINCT FORMAT, AND GET IT PUBLISHED. >> I HAVE A QUESTION FOR MARK. I FEEL SORRY FOR THE DIFFICULTIES YOU HAVE GOT COMPARED TO HUMAN PATIENTS WHO JUST LIE PASSIVELY WITH HEMORRHAGIC FEVER, MARBERG AND EBOLA, AND ALL OVER THE PLACE PHYSIOLOGICALLY YOU CAN SEE THE EXTREMELY VARIABLE AND THEY WON'T LIE DOWN, WAY WANT TO SIT UP AND SO ON. DIFFICULTY IS TRYING TO DO AN ORAL FLUID F YOU DON'T REACH THE POINT MAYBE WHERE JUST PARALYZING AND VENTILATING THE DAMMED CREE CHRS WHICH IS WHAT I DO IN MY EMERGENCY DEPARTMENT IF TROUBLESOME AGGRESSIVE VIOLENT TOTALLY UNMANAGEABLE PATIENT. MY INTENSIVE CARE COLLEAGUES WILL DO IT FOR SOMEONE WHO FITS RECURRENTLY SO ON JUST TO KEEP THINGS STABLE BECAUSE YOU HAVE ENOUGH SURROGATE MARKERS THERE TO KNOW IF YOU'RE SUCCEEDING OR NOT, YOU ONLY HAVE TO DO IT TEN DAYS, VIRAL RNA IS RISING OR OR IF YOU SUCCEEDED. YOUR QUESTION IS WHETHER WE SHOULD DO SOMETHING LIKE SEDATE THE ANIMALS FOR THE PERIOD WE CAN ASSESS, AS LONG AS WE RECOGNIZE BY SEDATING ANIMALS WE'RE CHANGING THE BASELINE SO YOU ESSENTIALLY ESTABLISH A NEW BASELINE WITH CONTROLS, WHERE IF THAT'S ALL YOU'RE DOING YOU HAVE A BASIS TO COMPARE. YOUR DISCUSSION EARLIER ABOUT USING ORAL FLUIDS, CLEARLY THE BODY HAS ITS OWN WAY OF DETERMINING HOW MUCH FLUID IS GOING TO ABSORB. SORT OF ADOPTING TO WHATEVER YOU GIVE IT, IN IF GI SYSTEM SO IF YOU COULD DO A MODEL WHERE YOU'RE GIVING ORAL FLUIDS THAT WOULD BE WONDERFUL, ONLY WAY IT CAN HAPPEN I COULD SEE WOULD BE TO SEDATE ANIMALS BECAUSE THESE WOULD -- THEY TEAR OUT -- IF YOU HAD TO PUT A GASTRIC TUBE, THEY TEAR IT OUT. WHEN THEY TEAR OFF THEIR JACKETS THEY START GOING IMMEDIATELY AFTER THE CATHETER AND THE OTHER THING THEY LIKE TO DO IS REACH OUT THE CAGE AND GRAB WIRES FOR THE TELEMETRY SYSTEM AND CHEW THROUGH THEM SO LOTS OF CHALLENGES. I THINK IF YOU CAN HAVE A PROTOCOL THAT IS -- DOES -- THE IACUC IS OKAY WITH, OR YOU COULD HAVE ESSENTIALLY FULL CARE WHERE YOU SEDATE ANIMALS AND IF NECESSARY EVEN DO ORAL FLUIDS EVEN POTENTIALLY KEEP THEM GOING WITH A INVENTORY LAYTOR, IF FLUIDS PUT THEM PULMONARY EDEMA, THAT'S INTERESTING TO SEE. >> I WOULD LIKE THE MAKE A COMMENT, THAT IS, ISN'T SUPPORTIVE CARE AND HUMANE ENDS POINTS, IT'S ABOUT APPROPRIATE AND HUMANE USE OF ANIMALS THE LABORATORY SPACE PROTOCOL VERSUS TO PASS THROUGH AN IACUC AND THEY HAVE A PROTOCOL THAT SAYS YOU'RE MAKING ANIMALS SICK AND THESE ANIMALS COULD SUFFER AND DIE. SHOW US WHAT YOU'RE GOING TO DO TO SUPPORT THE ANIMALS OR SHOW US WHAT YOU'RE GOING TO DO TO DEFINE HUMANE END POINTS SO THAT ANIMALS DON'T SUFFER AND DIE INHUMANELY. EVEN IF CATEGORY E STUDIES, PAIN AND SUFFERS WILL BE ENDURED BY ANIMALS. THE PROCESS HOW THAT'S MANAGED IN THE PROTOCOL HAS TO BE DEFINED AND APPROVED BY THE IACUC. THE IMPORTANCE OF THE TEAM PUTTING TOGETHER A PROTOCOL THAT INVOLVES NOT ONLY PI BUT INTENDING VETERINARIAN AND IACUC TO DEFINE HOW THESE SITUATIONS ARE HANDLED. AND ALSO INVOLVING FDA PARTNERS AND MEETING STUDY OBJECTIVES SO THE PARTNERSHIP AND THIS DIALOGUE AND COMMUNICATION SO CRITICAL TO DEVELOPING THE KINDS OF STUDIES THAT THE HUMANE CARE AND USE OF ANIMALS IS ACHIEVED, AND THE LONG RUN WE USE ANIMALS AND AS HUMANELY AS POSSIBLE. >> GOOD POINT. IF YOU HAVE AN ANIMAL THAT DIES FROM HYPOBOLEMIC SHOCK THEY'RE DEHYDRATED. YOU CHANGED YOUR MOTTO, WE HAVEN'T PROVED ANYTHING BECAUSE THERE'S CERTAIN AFFLICTIONS THAT YOU KNOW YOU WILL ENCOUNT IR. SO YOU HAVE AN ANIMAL DIE OF STARVATION BECAUSE HE'S NOT EATING THAT CHANGES YOUR MIND. >> I WOULD LIKE TO ADD ONE THING TOO. OBVIOUSLY THE PRESENTERS HAVE BEEN EXCELLENT TODAY AND ONE THING THAT STRUCK ME IS THE FACT EVERYBODY WANTS TO DO ONE THING TO PROVIDE SUPPORTIVE CARE BUT IT'S EXTREMELY IMPORTANT THAT EVERYBODY IS DOING IT IN THE SAME WAY. SO THAT FROM ONE PUBLICATION TO ANOTHER OR ONE GROUP TO THE ANOTHER GROUP, EVERYTHING IS DOING THINGS CONSISTENTLY SO WE CAN INTERPRET DATA PROPERLY. SO >> SO WE HAVE A QUESTION FROM TV LAND. MOVING -- THAT THE ACCURATELY REFLECT THE CARE AVAILABLE IN A MASS CASUALTY SITUATION? >> WE DESIGNED OUR MEDICAL MANAGEMENTVR MEDICAL MANAGEMENT, ANTI-BUYIOTICS, PLATELET WHOLE BLOOD TRANSFUSIONS ON A TRIGGER TO TREAT, TRIGGER TO STOP. AND WE PULL ANECDOTAL DATA FROM HUMAN ACCIDENTS. THAT SUGGEST IF YOU USE THIS MODERATE MEDICAL MANAGEMENT REGIMEN, THE TIMING OF IT IS SUCH THAT IT MAY MAKE IT MORE AMENABLE. SO IN A RED NUKE SCENARIO, THE FIRST THING I WOULD THINK I'M NOT A MODEL OR EMT TYPE PERSON BUT YOU GET PEOPLE OUT OF THE AREA. SO I WORK IN BALT MARCH, NEW EXPWRER SI, GOING TO GO TO PENNSYLVANIA, IF YOU'RE GOING TO MAYBE ENHERE, MARYLAND, PLENTY OF SITES WITHIN 50-MILES, HOW LONG IT TAKES TO TRANSPORT PEOPLE 50-MILES? IF YOU DON'T NEED TO GIVE ANTIBIOTIC FOR A WEEK, PLATED TRAN FUSION FOR THREE WEEKS BUT SHOULD GIVE FLUIDS PROBABLY AS SOON AS POSSIBLE FLUIDS CRITICAL COMPONENT. WE CAN'T SEPARATE THOSE AND DO THE STUDY IN A RED NUKE SCENARIO, I WOULD LIKE TO HEAR MORE DISCUSSION FROM THE PLAN ALL THIS STUFF ON HOW THAT FILTERS IN TO THE THINKING ABOUT THE ABILITY TO PROVIDE MEDAL MANAGEMENT ESPECIALLY LOOKING AT MEDICAL COUNTER MEASURE DEVELOPMENT TODAY IN THE RULE FOR NIAID AND BARTA IS MEDICAL COUNTER MEASURE MUST BE EFFECTIVE WHEN GIVEN 24 HOURS AFTER THE EVENT. GO FIGURE. MEDICAL COUNTER MEASURE 24 HOURS AFTER EVENT YOU CAN'T GIVE FLUIDS OR ANTIBIOTICS, IT'S TOM SIT SO UB LIKE TO THINK THERE'S RATIONALE APPROACH THE THAT AN GOOD SUPPORTIVE CARE BECAUSE OF TIMING LENDS ITSELF TO BE ABLE TO DO THAT >> BARTA TALK ABOUT MODELING WORK IN TERMS OF DEPLOYING COUNTER MEASURES. I'M NOT FAMILIAR WITH THE RAD NUKE ARENA BUT IN THE BIO WORLD THERE'S TALK ABOUT THE TIME IT TAKES TO DEPLOY SOME OF THE COUNTER MEASURES SO FOR EXAMPLE ANTIBIOTIC AND KNOWING THAT IT WOULD TAKE TIME TO DO THAT PRE-POSITIONING THINGS SO YOU CAN GET THEM -- MAKE THEM AVAILABLE TO MASS CASUALTY SITUATIONIN A FASTER TIME FRAME. I DON'T KNOW ANYTHING ABOUT THE RAD NUKE AREA. >> THE NUKE AREA TALKS ABOUT QUITE A BIT, I'M SURE IF WE CAN GET A GROUP OF PEOPLE THAT TALK ABOUT THESE PODS AND DEVELOPING THESE THINGS IN PHARMACIES AN SUPERMARKETS AND THINGS LIKE THAT WHERE THEY'RE READILY AVAILABLE. I SHOULD SAY ONE THING ABOUT THE RAD NUKE COMMUNITY VERSUS THE BIO. RAD NUKE IS BOOM. SO THE CLOCK STARTS THEN. FOR BIO, TO ME THAT'S THE INSIDIOUS PART ABOUT BIOLOGICAL WEAPONS. YOU MAY NOT KNOW WHEN THE BOOM HOW MANY TIME, WHERE HAS THE BUG GONE, THE PROBLEMS THIS COMMUNITY HAS RELATIVE TO OUR COMMUNITY ARE HIGHLY SIGNIFICANT SO I WANT TO MAKE CLEAR, IT'S SO EASY FOR ME BECAUSE IT ISN'T A WAY BECAUSE I KNOW THE STARTING TIME, THESE GENTLEMEN, THE LADIES, THEY DON'T. >> JUST MAKE A COMMENTS. IN GENERAL IN TERMS OF DESIGNING COUNTER MEASURES FOR LARGE MASS CASUALTYsdA„ EVENTS, WE KIND OF LOOK AT THE IDEAS OF STEP CARE SO THE LARGER THE MORE RUE MEN TEAR THE CARE. SO THE LARGEST YOU'RE LOOKING AT BASIC CIRCUMSTANCE LAIG, SMALLER EVENT THAN PERHAPS PROVISIONING OF IV FLUIDS AND MORE SOPHISTICATED, THE FEWER THERE ARE. SO IF YOU THINK OF BOTULISM REERMS. THE LARGEST EVENT MAYBE ALL YOU CAN DO IS OBSERVE PEOPLE WATCHING THEM FOR THE RESPIRATORY RATES STEE ANY EAR NOT HANDLING SECRETIONS IF THEY'RE NOT DOING WELL AT THAT POINT MAYBE GIVE ANTI-TOXIN. IF YOU HAVE A LESSER EVENT MAYBE THOSE YOU'RE CONCERNED ABOUT HAVING BEEN EXPOSED YOU MIGHT GET ABT ANTI-TOXIN TO AND IF YOU HAVE A HANDFUL OF PEOPLE MAYBE (INAUDIBLE). THAT'S WHAT I WAS THINKING BUT YOU HAVE DIFFERENT STEPS YOU GO DEPENDING ON HOW MANY PEOPLE AND WHAT IS PROVISION OF SUPPLIES. >> ANOTHER QUESTION FROM TV LAND. THIS IS FOR DR. KORTEPETER. IN THE EXAMPLE OF THE DOSE USED WHAT'S THE EXAMPLE OF HIGHER DOSES, HUNDREDS OF TIMES HIGHER? >> GOOD QUESTION. KEY THING IS FOR CONSISTENCY, SO THAT DOSE I THINK CONSISTENTLY AT LEAST WITH E EBOLA, YOU'RE GETTING CONSISTENT FATALITY RATES NEAR 100%. FRSES >> OKAY. I WANT TO THANK EVERYONE FOR SOME GREAT PRESENTATIONS AND GREAT DISCUSSION TODAY. AND REMIND YOU ALL THAT AMAZINGLY I THINK THINK WE'RE ALMOST -- NOT QUITE EXACTLY ON TIME BUT THERE ARE SOME WONDERFUL POSTERS OUT IN THE POSTER ROOM LIKE 65 OF THEM SO PLEASE GO AND LOOK AT THOSE, I THINK THAT'S REALLY WHERE MUCH OF THE ANIMAL MODEL WORK THAT'S GOING ON IS BEING CAPTURED AND COMPARED TO THE DISCUSSION OF ISSUES GOING ON IN THIS ROOM SO PLEASE GO VISIT THE POSTERS AN THANKS FOR EVERYONE PAYING ATTENTION ONLINE AND I'LL SEE -- WE'LL SEE YOU AGAIN AT 8 O'CLOCK TOMORROW MORNING.