>> GOOD MORNING EVERYONE AND WELCOME. I'M LALITHA SHANKAR ARE AT THE NATIONAL CANCER INSTITUTE, AND WE ARE CO-SPONSORING THIS WORKSHOP WITH THE INTERNATIONAL SOCIETY FOR IMAGE GUIDED SURGERY SWMS THE WORLD MOLECULAR IMAGING SOCIETY. WE'RE VERY HAPPY TO HAVE A VERY ACTIVE AND ENTHUSIASTIC PARTICIPATION BY THE FDA, BOTH COMPONENTS OF THE AGENCY. WE WILL HAVE PRIMARILY DISCUSSIONS ABOUT THE REGULATORY PATHWAYS FOR BOTH AGENTS AND DEVICES REGARDLESS OF WHICH IS INVESTIGATIONAL ORE -- OR NOT BECAUSE THERE'S A LOT OF CONFUSION ABOUT THAT. FOR THE PARTICIPANTS IN THE ROOM, I WANT TO REMIND YOU THAT THIS EVENT IS BEING VIDEOCAST IN ITS ENTIRETY AND WILL BE AVAILABLE AT THE NIH VIDEOCAST WEBSITE FOR ETERNITY OR SOME VERSION OF IT. [LAUGHTER] SO A FEW THINGS TO SORT OF KEEP IN MIND. WE ARE GOING TO HAVE A FAIRLY FULL AGENDA, SO IF YOU WOULD STICK TO YOUR TIMES AND LEAVE A LITTLE ROOM IN YOUR ALLOTTED TIME SPOT FOR QUESTIONS, I'M SURE FOLKS WOULD APPRECIATE THAT SO THAT THE DISCUSSION WILL BE MORNING MEANINGFUL. IN ADDITION, WHEN YOU HAVE QUESTIONS, PLEASE MAKE SURE THAT YOU HAVE YOUR MIC ON AND YOU IDENTIFY YOURSELF SO THAT PEOPLE WHO ARE WATCHING BOTH HERE AND ACROSS ON THE WEB WILL KNOW WHO IS ASKING THE QUESTIONS. OTHER THAN THAT, I DON'T HAVE VERY MUCH TO SAY OTHER THAN THAT WE'RE VERY HAPPY AND EXCITED TO HAVE THIS WORKSHOP GET STARTED. AND WITHOUT MUCH FURTHER ADO, WE'LL HAVE DR. EEB EN -- WITHOUT MUCH FURTHER ATORQUES WE'LL HAVE DR. EBEN ROSENTHAL START WITH THE FIRST PRESENTATION. >> Eben Rosenthal, MD: GOOD MORNING. IT'S A REAL PLEASURE TO BE HERE AND TO BE ABLE TO INTRODUCE THIS TOPIC, AND IT CAME ABOUT REALLY FROM PAULA AND LALITHA WORKING WITH MYSELF, MIKE, TWEEDLE AND JIM BASILION WITH MANY PHONE CALLS IN ORDER FOR THIS TO COME TOGETHER IN A WAY WE HOPE WILL BE VERY PRODUCTIVE FOR EVERYBODY. IN ADDITION, THE FDA, MULTIPLE BRANCHES HAVE BEEN WILLING TO COME AND PARTICIPATE, SO THAT REALLY HOPEFULLY WILL MAKE THIS A VALUABLE OPPORTUNITY FOR FOLKS. I DO HAVE SOME CONFLICTS. ONE IS THAT I DO LOVE DOGS. THE OTHER IS THAT I HAVE SOME GRANTS AND EQUIPMENT LOANS AS WELL AS ON THE ADVISORY BOARD OF SOME COMPANIES THAT ARE LISTED. HERE ARE THE DOGS MAKING SURE THAT THERE ARE NO SQUIRRELS IN MY BACKYARD, VERY, VERY VIGILANTLY. ALSO THERE ARE MANY DIFFERENT TYPES OF THINGS THAT WE ALL ENJOY HEARING ABOUT, DOOR BELLS AND MAILMAN AND BLARG AND WE SLEEP THROUGH ALL THAT AND THEN SOMETHING CATCHES OUR ATTENTION, HOPEFULLY FOR EVERYBODY IN THE ROOM THAT WILL BE CANCER IMAGING. I WANT TO PRESENT THE PROBLEM IN ABOUT TEN MINUTES AND THE QUESTION IS WHY DO WE NEED CONTRAST ENHANCED ONCOLOGIC SURGERY, WHERE IS THE NEED? I THINK THERE HAS BEEN AN EXPLOSION OF MATERIAL OVER THE PAST TEN YEARS WHERE THE TECHNOLOGY CAME TOGETHER WITH A SIGNIFICANT INCREASE IN THE NUMBER OF PUBLICATIONS AND THERE'S BEEN SOME VERY HIGH PROFILE ITEMS THAT HAVE PRESENTED ITSELF TO THE MEDIA IN ORDER TO HELP DRAW ATTENTION TO IT. I WOULD LIKE TO TAKE YOU THROUGH A CASE STUDY OF A PATIENT. THIS IS ONE OF OUR PATIENTS THAT WAS INCLUDED IN THIS TRIAL, AND THIS IS A 56-YEAR-OLD WITH A RECURRENT CUTANEOUS SQUAMOUS CELL CARCINOMA PREVIOUSLY OPERATED ON WITH A SKIN GRAFT AND FAILED. SO THE AREA THAT YOU CAN SEE HERE IS ACTUALLY SKIN GRAFTED. THERE WAS DIFFUSE CHANGE AFTER RADIATION AND PREVIOUS SURGERY IN THIS WHOLE AREA, SO THE PATIENT UNDERWENT SURGERY. YOU CAN SEE HERE THE VERY BROAD MARGIN THAT WAS OBTAINED GIVEN THE DIFFICULTY IN ASSESSING ON ANATOMICAL IMAGING AND ON THE NATURE OF THE WOUNDED CELLS. SO THIS LESION WAS WIDELY EXCISED AND FAR TOO WIDELY EXCISED. 1 CENTIMETER MARGIN IS APPROPRIATE. SO THE PERIPHERAL MARGIN WAS FAR TOO LARGE. UNFORTUNATELY, THE PATIENT RECURRED AND DIED AS A RESULT OF THE DEEP MARGIN, THE DEEP MARGIN WAS POSITIVE. SO THAT WAS CLEAR ON OUR IMAGING WHERE WE COULD SEE BASED ON FLUORESCENCE THAT THE TUMOR BROACHED THIS PORTION, THE DEEP PORTION OF THE WOUND. SO THIS IS AN EXAMPLE OF WHERE WE MADE THE MISTAKE AT THE PERIPHERY AND AT THE DEEP MARGIN, AND THIS IS AN AREA WHERE POTENTIALLY THIS KIND OF TECHNOLOGY COULD HELP. SO MEASURING MARGINS IN HEAD AND NECK IS CHALLENGING AND IN MANY OTHER TUMOR TYPES. I'M USING HEAD AND NECK AS AN EXAFERL. BUT SIMPLY -- AS EXAMPLE. BUT SIMPLY BASED ON THE SAMPLING ERROR, THIS IS VERY, VERY DIFFICULT. THERE'S JUST A LOT OF TISSUE TO SAMPLE. MARGINS MATTER. MARGINS DON'T MATTER IF THEY'RE POSITIVE OR NEGATIVE, THEY MATTER IF THEY'RE CLOSE. CLOSE MARGINS ARE ASSOCIATED WITH THE WORST SURVIVAL IN MANY CANCER TYPES AND REQUIRE REOPERATION. HERE IS A POSITIVE MARGIN, HERE IS A CLOSE MARGIN, HERE IS A NEGATIVE MARGIN, SO THAT DISTANCE IS IMPORTANT. SO AS A SURGEON AND AS AN INTERACTING PATHOLOGIST THAT I WORK W THIS IS A REALLY BIG FRUSTRATION FOR US IS UNDERSTANDING HOW WE CAN DO THIS. PATHOLOGY IS DPERNT ON SAMPLE LG ERROR -- PATHOLOGY IS DEPENDENT ON SAMPLING ERROR. IF YOU DON'T GET THE TISSUE ON THE SLIDE, TM NOT BE EE -- IT WILL NOT BE EFFECTIVE IN IDENTIFYING THE CANCER. THE CANCER HAS TO GET ON THE SLIDE. IN ORDER TO GET ON THE SLIDE, YOU HAVE TO KNOW WHERE TO MAKE THE FIRST CUT. IF YOU MAKE IT TOO BIG, LIKE WE DID ON THE PREVIOUS CASE, THEN THE PATIENT HAS TOO MUCH NORMAL TISSUE OBTAINED. IF YOU MAKE IT TOO CLOSE, YOU HAVE A POSITIVE MARGIN. THAT'S THE FIRST SAMPLING ERROR. THE SECOND SAMPLING ERROR IS WHERE TO BIOPSY WITHIN THIS AREA. YOU CAN'T SAMPLE THE WHOLE THING, SO YOU HAVE TO SAMPLE A PERCENTAGE AND USUALLY THAT'S ABOUT 5, 10%. THEN WHEN YOU HAVE A MARGIN, YOU CAN ONLY GET TWO SLICES, THE PATHOLOGIST WILL TYPICALLY TAKE TWO SLICES, SO THIS IS A SORT OF COMPOUNDED PROBLEM OF A SAMPLING ERROR THAT WE SEE AND I'M USING HEAD AND NECK AS AN EXAMPLE, BUT IT'S MANY DIFFERENT TUMOR TYPES. THIS IS SIMPLY THE SAME THING CONSUMED HERE WHERE THERE'S THE PROCESS OF SAMPLING ERROR IN ADDITION TO THE FACT THAT THERE ARE MANY TUMOR TYPES WHERE YOU SIMPLE CAN'T GET THE TISSUE SECTIONED, FOR EXAMPLE, BONE, FAT R OTHER SAMPLES DON'T RESECTION WELL. THE OTHER THING IS YOU HAVE TO ACTUALLY RESECT IT TO GET IT ON THE SLIDE. IF IT'S A CRITICAL STRUCTURE LIKE AN EYELID OR OTHER CRITICAL STRUCTURES, IT'S REALLY HARD TO GET THEM ON THE SLIDE. IT'S HARD TO TAKE THAT NORMAL TISSUE TO GET IT ON THE SLIDE. THE OTHER THING THAT IS REALLY WORTH POINTING OUT IS THAT NOT ALL SURGICAL PROCEDURES ARE THE SAME AND THAT THE FLUORESCENT TECHNOLOGY IS GOING TO WORK BETTER IN SOME THAN OTHERS. I DON'T THINK WE KNOW YET WHICH IT'S GOING TO WORK THE BEST IN AND THE OPPORTUNITY TO DO THAT IS IMPORTANT. INFILTRATIVE FIXED TO KEY STRUCTURES SUCH AS BRAIN AND PANCREAS IS OFTEN REQUIRED, PEOPLE KIND OF NIBBLE AWAY AT IT AND THEN THEY ALWAYS LEAVE SOME. A WIDE LOCAL EXCISION, AS SOME OF THE CASES I PRESENTED, WHERE THE WHOLE RESECTION IS PERFORMED AND MARGINS ARE ASSESSED, THERE ARE MULTIPLE EXAMPLES OF THIS AS WELL. THIS IS WHERE THE POSITIVE MARGINS OCCUR FOR THOSE PATIENT AND THE OPPORTUNITY TO IDENTIFY POSITIVE MARGINS AND GO BACK AND RESECT THEM CAN IMPROVE SURVIVAL . WHOLE AR BEGAN RESECTIONS INCLUDE THINGS LIKE BLARENJECTOMY, DOCTORS WITH A WHOLE ORGAN IS EXCISED. THE OTHER AREA IS WHERE THERE IS DIFFUSE PERITONEAL METASTASIS, OTHER METASTATIC DISEASES AND THE BULGING OCCURS AND IMPROVES SURVIVAL. PROBABLY ONE OF THE KEY FINDING, KEY STUDIES WAS DONE IN BRAIN WITH 5LA, IDENTIFIED PROGRESSION FREE SURVIVAL WAS IMPROVED IN PATIENTS WITH DECREASED MORBIDITY. THIS IS PROBABLY ONE OF THE ONLY STUDIES THAT HAS SHOWN AN OUTCOME BENEFIT, THIS IS PROBABLY WHERE WE WANT TO GET TO BUT IT'S DIFFICULT TO DO. BRAIN IS UNIQUE IN THIS WAY BECAUSE EVERYBODY DIEPS AT 12 TO -- BECAUSE EVERYBODY DIEPS -- BECAUSE EVERYBODY DIES AT 12 TO 15 MONTHS. MOST CANCERS AREN'T LIKE THAT. MOST OF THE CANCERS WE'RE ASSESSING, WE DON'T HAVE THAT OUTCOME WE CAN MEASURE. WE'LL TALK ABOUT THAT IN THE AFTERNOON TODAY ABOUT WHAT KIND OF OUTCOMES WE SHOULD HAVE. LYMPH NODE IS ALSO A LARGE OPPORTUNITY FOR THIS, MANY FOLKS ARE WORKING ON THAT. HERE IS AN EXAMPLE FROM ONE OF OUR PATIENTS WHERE THE LYMPH NODE WAS IDENTIFIED WITHIN THE NECK AND THE OVERLAY DEMONSTRATES THAT. SO IN ORDER TO KIND OF START THE DISCUSSION, I'LL LEAD INTO THE ISSUES THAT I THINK PAULA IS GOING TO ADDRESS, HOW ARE TUMOR ENHANCING AGENTS USED TO IMPROVE OUTCOMES TODAY? IN OTHER WORDS, WHAT ARE THE ELEMENTS OF TODAY'S CLINICAL CARE THAT ARE USED THAT ARE SIMILAR TO THE WORK THAT WE'RE DOING, TRYING TO DO IN FLUORESCENT ENHANCEMENT SURGERY? HERE IS EXAMPLE OF A VASCULAR AGENT, WHICH IS A CONTRAST MEDIA, INJECTED INTO A PATIENT IN ORDER TO IDENTIFY AN AREA FOR A NEEDLE BIOPSY. SO THIS IS A PROCEDURE, AN INVASIVE PROCEDURE WHERE A CONTRAST AGENT IS USED BEFORE THE PROCEDURE IN ORDER TO HIGHLIGHT THE LESION, BIOPSY IS THEN PERFORMED BASED ON THAT AREA OF ENHANCEMENT AND ONE COULD PERHAPS DRAW A PARALLEL THAT THIS IS AN ENHANCEMENT OF A LESION, THIS IS A PATIENT WHO HAD A PREVIOUS NECK DESECTION AND A SCAR AND THE FLUORESCENCE IMAGING DEMONSTRATED A LESION HERE AS A STANDARD PROTOCOL THE SCAR IS EXCISED AFTER A PREVIOUS NECK DESECTION AND OCCURRENCE WHICH IS WHAT HE HAD, THIS IS SIMILAR THAT IT REQUIRES FURTHER INVESTIGATION. IT'S NOT DIAGNOSTIC, JUST AS THIS IS NOT DIAGNOSTIC. IT SIMPLY REQUIRES FURTHER ASSESSMENT. MOLECULAR IMAGING ALSO PROVIDES ADDITIONAL INFORMATION, MUCH IN THE WAY THAT FLUORESCENT CONTRAST COULD PROVIDE INFORMATION. IT PROVIDES INFORMATION BUT IS NOT DIAGNOSTIC. SO ON A PET SCAN YOU CAN SEE THE NODE IS SUSPICIOUS ON THE ANATOMIC IMAGING AND THEN WHEN CORRELATED WITH PET IMAGING, IT LOOKS POSITIVE AND THEREFORE DECISIONS ARE MADE TO DO THAT, PERFORMED THAT NECK DESECTION. HERE IS ANOTHER EXAMPLE OF ENHANCEMENT WITH LOTS OF DIFFUSE ENHANCEMENT, BUT THE DIFFUSE ENHANCEMENT SURROUNDING THAT IS NOT ACTED UPON BECAUSE IT'S RECOGNIZED AS A PATTERN ASSOCIATED WITH NORMAL ENHANCEMENT. SO WHAT ABOUT REALTIME SURGERY? WHAT'S THE PRECEDENT FOR REALTIME SURGERY? MRI USE GADOLINIUM AS A VASCULAR CONTRAST ENHANCEMENT. APPROXIMATELY 90 HOSPITALS IN THIS COUNTRY HAVE MRI GUIDED SURGERY. THE MRI ENHANCED -- WITHIN THE OPERATING ROOM IS A MAJOR INVESTMENT. THE MACHINE ALONE IS 4 TO $7 MILLION. IT SILOS THE MACHINE TO ONLY DO INTRAOPERATIVE IMAGING, IT CAN'T DO OTHER IMAGING WITHIN THE SYSTEM, SO IT'S NOT A DEVICE THAT CAN BE USED FOR OTHER PURPOSES, AND USUALLY IT REQUIRES TWO OPERATING ROOMS. SO YOU BASICALLY, WITH OPERATING ROOMS BEING THE VOAS VALUABLE REAL ESTATE WITHIN -- BEING THE MOST VALUABLE REAL ESTATE WITHIN A HOSPITAL, YOU'RE TAKING ONE OF THOSE AND PUTTING AN MRI IN IT. SO IT'S A MAJOR INVESTMENT, BUT IT'S BECOME ALMOST THE STANDARD IN BRAIN SURGERY FOR GLIOMAS. HERE IS AN EXAMPLE OF HOW THAT'S USED. SO THE PATIENT HAS HAD A PORTION OF THIS REMOVED, HAD A PORTION OF THE GLIOMA REMOVED, THEY GO INTO THE SCANNER AFTER THE PARTIAL RESECTION, THIS ENHANCEMENT IS OCCURRING. BASED ON THE MR INFORMATION, THE VASCULAR CONTRAST, THERE'S NOTHING SPECIFIC ABOUT IT, THEY GO BACK AND RESECT MORE. SO THIS IS AN EXAMPLE WHERE ENHANCEMENT IS USED TO DRIVE SURGERY AND PEOPLE ACT UPON THAT INFORMATION AND IT WORKS. IT WORKS REALLY WELL AND WORKS EVEN BETTER WHEN IT'S COMBINED WITH FLUORESCENCE EN HANMENT, EVEN -- ENHANCEMENT, EVEN GIVEN LIMITATIONS, LIKE MOLECULE 5LA. THERE'S OTHER AREAS WHERE THIS IS THE INDICATION AS WELL. I BROUGHT UP THE MRI BECAUSE IT'S SO EXPENSIVE AND HAS BEEN SO BROADLY ADOPTED, BUT THERE'S MANY EXAMPLES WHERE REALTIME ANATOMIC OR ENHANCEMENT IS PERFORMED IN THE OPERATING ROOM IN ORDER TO OBTAIN TISSUE OR PERFORM RESECTIONS. AND ONE OF THE KEY THINGS, ULTRASOUND-GUIDED OF LIVER SURGERY IS, DISCLOSES THE TRUEX TENT OF TUMORS, INCREASES IDENTIFICATIONS FOR HEPATECTOMY AND RENDERS SURGERY SAFER. I'LL GO BACK FOR A MINUTE WHERE THIS WAS THE AREA IDENTIFIED DURING PRECLINICAL WORK-UP AND IN ORDER TO RESECT THE ENTIRE SCAR IN THESE CASES AND THAT LESION DID TURN OUT TO BE CANCER BASED ON OUR HISTOLOGIC EVIDENCE. OKAY. SO THERE ARE MANY DEVICES THAT ARE CURRENTLY AVAILABLE AND SOME OF THOSE DEVICES ARE WORTH CONSIDERING DURING THIS TIME. IT IS INTERESTING THAT THERE ARE SO MANY ENHANCEMENT OPPORTUNITIES THAT ARE BEING USED TODAY IN ORDER TO DRIVE CLINICAL CARE, AND IT'S A MAJOR INTEREST TO US IN ORDER TO IDENTIFY HOW WE CAN MOVE FORWARD WITH FLUORESCENT ENHANCEMENT TO GUIDE THERAPY NOT AS A DIAGNOSTIC TOOL. SO JUST A COUPLE THINGS, IN ADDITION TO THANKING EVERYBODY, I WOULD ASK THAT EVERYBODY STAY ON TIME, AND I THINK THAT LALITHA AND PAULA AND I ARE ALL GOING TO TRY TO WAVE YOU DOWN IF THE TIME IS OVER BECAUSE WE REALLY WANT TO PROVIDE OPPORTUNITY FOR DISCUSSION AND I HOPE THAT EVERYBODY WILL PARTICIPATE AND SPEAK THEIR MINDS IN ORDER FOR US TO OBTAIN A CONSENSUS. I THINK EVERYBODY HAS THEIR AGENDA AND WE'LL BE ABLE TO KIND OF SEE WHAT THE TOPICS ARE. ARE THERE ANY QUESTIONS ABOUT THAT? WE'RE AHEAD OF SCHEDULE ALREADY. ARE THERE ANY QUESTIONS? OKAY. I THINK BETSY WILL TALK FIRST AND I'LL HAVE YOU PULL UP YOUR SLIDES BECAUSE I'M NOT SURE WHICH YOURS ARE. >> GOOD MORNING, EVERYBODY, AND WELCOME. I WANT TO THANK THE OPPORTUNITY FOR GOING OVER THIS, PARTICULARLY FOR PAULA FOR GIVING ME SOME OF HER TIME TO PRESENT AN OVERVIEW FROM THE FDA PERSPECTIVE. THIS WILL BE VERY HIGH LEVEL BECAUSE A LOT OF THE TOPICS I'LL BRIEFLY PRESENT HERE WILL BE DISCUSSED IN FURTHER DETAIL WITH LATER PRESENTATIONS SO DON'T BE CONCERNED IF YOU THINK YOU'VE MISSED SOMETHING. YOU HAVE A PRODUCT. WHERE DO YOU GO? SO WHO DO YOU CONTACT FOR DEVICE DEVELOPMENT WHEN YOU'RE DOING AN IMAGING DRUG? WELL, YOU WOULD GO TO THE CENTER FOR THE DRUG EVALUATION AND RESEARCH, AND PARTICULARLY FOR THESE IMAGING PRODUCTS, YOU'RE GOING TO END UP IN THE OFFICE OF DRUG EVALUATION IV AND THAT'S BROKEN DOWN TO THE DIVISION OF MEDICAL IMAGING PRODUCTS OR DMIP, AND THIS IS TYPICALLY WHERE YOU'LL START YOUR DRUG DEVELOPMENT PROCESS. CORRESPONDINGLY FOR THE DEVICE SIDE, YOU'LL END UP IN CDRH, THE CENTER FOR DEVICES AND RADIOLOGIC HEALTH AND WITHIN THAT YOU'LL BE IN THE OFFICE OF DEVICE EVALUATION, ODE. FIRST GO ROUND, THEN LATER AS YOU REFINE THE CHARACTERISTICS AND LEARN TO ADAPT IT TO OTHER AREAS, YOU MAY END UP GOING ON A MORE SPECIALIZED POSITION. FOR THE MOST PART THEY'LL COME INTO THE DIVISION OF SURGICAL DEVICES. AND IN THAT DIVISION OF SURGICAL DEVICES, THEY'RE GOING TO GO INTO THE GENERAL SURGERY BRANCHES. THEY'RE DIVIDING THE 1 AND 2, THE ONLY IMPORTANT THING HERE IS THAT GENERAL SURGERY BRANCH 1, GSDB1, IS TYPICALLY THE BRANCH THAT HANDLES THE LIGHT-BASED DEVICES AND EVALUATION, SO THIS IS TYPICALLY THE BRANCH THAT YOU'LL BE DEALING WITH. WHEN WE GET A SUBMISSION, IT'S A MULTIDISCIPLINARY REVIEW TEAM THAT'S INVOLVED, IN ARE CDER, EDEIV, IT WILL TYPICALLY BE AFIND TO A MEDICAL OFFICER AND THEY'LL DETERMINE WHICH DISCIPLINES NEED TO BE INVOLVED IN THE REVIEW. ALL OF THEM MAIBT BE INVOLVED -- MAY NOT BE INVOLVED AT THE START OF PRODUCT DEVELOPMENT BUT CERTAINLY DURING THE COURSE OF THE PRODUCT DEVELOPMENT AT SOME POINT IN TIME, PROBABLY ALL OF THESE DISCIPLINES WILL BE INVOLVED. ADDITIONALLY, BECAUSE WE'RE TALKING ABOUT DEVICES AND DRUGS HERE, USING THEM TOGETHER, YOU'RE GOING TO HAVE COLLABORATIVE INTERACTIONS WITH OTHER CENTERS AS WELL, SO YOU'RE GOING TO TYPICALLY HAVE TO GO TO CDRH AND SOMETIMES EVEN CDER DEPENDING ON THE PRODUCT. THREES THE CDER MILESTONE SUBMISSION MEETINGS AND REQUIREMENTS THAT WE HAVE. YOU TYPICALLY WILL START WITH AN INVESTIGATIONAL NEW DRUG APPLICATION OR IND AND THERE ARE SEVERAL PHASES FOR THAT, STARTING WITH THE PRE-EX PLOR TO HER, WHEN YOU -- PRE-EX PLORATORY WHEN YOU FIRST GET YOUR IDEA, LOOKING AT THE AREAS YOU WANT TO EVALUATE, THEN AN ORIGINAL IDE. EARLY PHASES 1 AND 2 YOU'LL COME BACK TO US AND LOOK AT THE DATA AND SEE IF IT'S ADEQUATE TO ALLOW YOU TO PROGRESS TO ANOTHER LEVEL OR AS THE DRUG DEVELOPED GOES FURTHER, THEN WHEN YOU'VE COMPLETED ALL THE PHASE 1 AND 235EUZ WORK TION WE USUALLY HAVE YOU COME IN AND TALK TO US PRIOR TO STARTING YOUR PHASE 3 BECAUSE WE WANT TO DISCUSS THE PIVOTAL TRIAL AND WHAT IT'S GOING TO LOOK LIKE AND COME TO AN AGREEMENT ON HOW THAT'S GOING TO WORK. ONCE YOU'VE COMPLETED THE 235EUZ, THEN YOU'LL GO INTO THE ACTUAL NDA OR NEW DRUG APPLICATION OR BLA AND WE ALWAYS REQUIRE PRESUBMISSION FOR THAT. WE'LL GO OVER THE DATA IN PHASE 2 TO MAKE SURE THAT THE DATA YOU HAVE FROM YOUR TRIALS ARE ADEQUATE TO SUPPORT THE NEW DRUG APPLICATION AND IT HAS TO BE SUBMITTED IN THIS 21ST CENTURY REVIEW PROCESS. FOR CDRH THE TYPES OF SMITIONZ WE SEE ARE A LITTLE -- SUBMISSIONS ARE A LITTLE DIFFERENT. THE K SUBMISSION IS USUALLY DESIGNED TO ANSWER SPECIFIC QUESTIONS. A SPECIFIC QUESTION, IS THIS PROTOCOL ACCEPTABLE, ARE THESE END POINTS OKAY, DO I HAVE ENOUGH INFORMATION ON THE DEVICE, SO THEY'RE TYPICALLY VERY SHORT, VERY FOCUSED REVIEWS, BUT THEY CAN PROVIDE A LOT OF OPPORTUNITY FOR INTERACTION WITH THE FDA AND WOULD HE ENCOURAGE USING THIS FORMAT WHEN YOU HAVE SOME UNCERTAINTY OR WANT SOME QUESTIONS THAT YOU HAVE ANSWERED. WHAT'S A LITTLE DIFFERENT IS FOR CDRH, THIS 510 [K] , THAT'S A DEVICE FOR WHICH YOU CAN FIND A DEVICE THAT'S ALREADY BEEN CLEARED THAT'S VERY SIMILAR, WHAT WE CALL A PREDICATE. IT HAS TO BE SUBSTANTIALLY EQUIVALENT. IT DOESN'T HAVE TO BE EXACTLY THE SAME, BUT IT HAS TO BE SUBSTANTIALLY EQUIVALENT. IF YOU HAVE THAT, THEN IT CAN GO THROUGH THE 510 [K] PROCESS. THE IDE WOULD BE THE INVESTIGATIONAL DEVICE EXEMPTIONS, THERE ARE SEVERAL TYPES. EARLY FEASIBILITY PROGRAM, WHICH IS BASICALLY THE FIRST IN HUMAN PROGRAM, THE TRADITIONAL FEASIBILITY AND THE PIVOTAL TRIALS AND ULTIMATELY RESULTING IN A PMA APPLICATION. HOW IS THE REVIEW DONE? SUBMISSION IS RECEIVED BY THE DIVISION, IT'S ASSIGNED TIE PROJECT MANAGER AND MEDICAL OFFICER, WE DETERMINE WHAT ADDITIONAL DISCIPLINES WILL BE NEEDED AND ALSO WHAT CONSULTS WILL BE NEEDED NOT ONLY WITHIN THE CENTER BUT ALSO COLLABORATIVELY ACROSS CENTERS. FOR THE OPTICAL IMAGING DEVICES, I'LL CHANGE THINGS A LITTLE BIT HERE, THESE ARE TYPICALLY COMBINATION PRODUCTS. SO IT'S USUALLY A LIGHT-BASED DEVICES, USUALLY FROM WHAT WE'VE SEEN, MOST OF THEM ARE IN THE INFRARED RANGE, AND IT'S TYPICALLY AN IMAGING AGENT TAGGED WITH A FAILURE -- TAGGED WITH A FLUOROFOR, THAT FLUORESCES AT A PARTICULAR WAVELENGTH. ONE IS YOU USE AN OFF THE SHELF, ALREADY CLEARED DEVICE, YOU'RE NOT DOING ANYTHING WITH IT TO ACHIEVE WHAT YOUR GOAL IS. SOMETIMES DEPENDING ON THE FLUOROPH ORE, YOU MAY NEED TO MAKE ADJUSTMENTS, ADDING FILTERS OR MINOR MODIFICATIONS TO THE DEVICE ITSELF OR YOU MAY HAVE A NEW DEVICE ALTOGETHER AND DEPENDING ON WHICH OF THESE DEVICE PRODUCTS YOU'LL BE DOING, YOU MAY HAVE DIFFERENT REQUIREMENTS YOU'LL HAVE TO MEET AND DIFFERENT DATA AND PERFORMANCE THAT'S GOING TO HAVE TO BE APPLIED. TYPICALLY THE FLOOR FORS WE'VE BEEN SEEING ARE APPROVED DRUGS THAT HAVE BEEN APPROVED OR ALREADY APPROVED BIOLOGICS, SMALL MOLECULES, THEY CAN BE BUY LOGICS IN ADVANCED STAGE OF DEVELOPMENT, SO SOME OF THE ANTIBODY TYPE OR HUMAN ANTIBODY TYPE STUFF, THEY CAN BE ENZYME ACTIVATED PRODUCTS THAT ARE TAGGED WITH A FLOOR WITH A FLUOROFORE, WE'VE ALSO SEEN SUPRA PARAMAGNETIC IRON OX I HAD BEING USED FOR IMAGE DETECTING AND THEN NANO PARTICLES AND WE CURRENTLY HAVE GOLD NANOPARTICLES UNDER REVIEW AS WELL. SO THE REASON WHY WE THINK THIS IS IMPORTANT IS TO GIVE YOU A SCOPE, THE NUMBER OF SUBMISSIONS HAVE DOUBLED EACH YEAR IN THE LAST 3-4 YEARS. THE NUMBER OF CONSULTS WE SEE FROM OTHER CENTERS HAS ALSO INCREASED AND CURRENTLY WE'RE ABLE TO IDENTIFY AT LEAST 26 SUBMISSIONS THAT ARE UNDER REVIEW EITHER IN THE IND OR IDE PROCESS, SO IT GIVES YOU A SENSE OF HOW THIS AREA IS GROWING AND THE INTEREST THAT THERE IS. FOR CONTACT INFORMATION CCDRH, I WOULD GEEF YOU NEIL OGDEN, THE BRANCH CHIEF FOR AND HE CAN BE A GOOD CONTACT PERSON. IF IT DOESN'T FIT IN HIS BRANCH, HE CAN HELP WHERE YOU IT GOES. FOR CDER, KAYE KANG IS THE PROJECT MANAGER SUPERVISOR AND SHE ALSO KNOWS THE ADMINISTRATIVE PROCESS AND CAN HELP DIRECT YOUR SUBMISSION TO THE APPROPRIATE AREA. THEN I'M JUST GOING TO CLOSE WITH SOME OF THE PERTINENT GUIDANCES THAT YOU'LL NOT SEE IN OTHER PRESENTATIONS THAT YOU MAY FIND HELPFUL AS WELL. >> ARE THERE ANY QUESTIONS? >> ARE YOU GOING TO MAKE THE PRESENTATIONS AVAILABLE? AT LEAST THE GUIDANCES, AND THE CONTACT INFORMATION. >> YES. 9 PRESENTATIONS WILL ALL BE MADE PUBLIC -- THE PRESENTATIONS WILL ALL BE MADE PUBLIC. >> MICHAEL TWEEDLE FROM OHIO STATE UNIVERSITY. AN EQUIVALENCE WAS THE PRIMARY CRITERIA AND IS THAT EQUIVALENCE BOTH EFFICACY AND -- >> USUALLY FOR 510 [K] IT CAN BE BOTH. YOU WANT TO SHOW THAT YOU'RE SUBSTANTIALLY EQUIVALENT WANT ONLY FROM A TECHNOLOGIC STANDPOINT, BUT THAT IF YOU DECIDE YOUR INDICATION IS K, THAT YOUR PRODUCT CAN ACTUALLY PERFORM X LIKE A PREDICATE PRODUCT. SO PRODUCT X IS GOING TO -- HAS BEEN APPROVED, IT'S ON THE DEVICE, YOU WANT TO MAKE SURE THAT YOUR DEVICE HAS SIMILAR CHARACTERISTICS AND THAT IT PERFORMS IN THE SAME FASHION. SO IT SOMETIMES REQUIRES, SOMETIMES IT DOES REQUIRE CLINICAL DATA, SOMETIMES IT CAN BE DONE ON A STRAIGHT TECHNOLOGIC BASIS, BUT IT JUST DEPENDS ON WHAT THE PRODUCT, WHAT YOUR DEVICE IS AND WHAT INDICATIONS YOU'RE LOOKING FOR. DOES THAT ANSWER YOUR QUESTION? >> THERE'S OPPORTUNITY FOR INTERACTIONS BOTH IN THE PANELS AND AT BREAKS. WE HAVE A LOT OF PEOPLE HERE FROM THE FDA. GO TALK TO THEM. MEET THEM. >> I'M GOING TO TRY TO GIVE A VERY BRIEF OVERVIEW OF SOME OF THE THINGS WHICH HAVE ALREADY BEEN APPROVED OR ARE ALREADY BEING USED, WHETHER OR NOT THEY HAVE, IN FACT, BEEN APPROVED FOR THOSE PURPOSES. WHICH YOU ALL KNOW. THE FIRST THING I WANT TO EMPHASIZE THE COMPLEXITY OF THIS AREA. MANY OF US ARE USED TO DRUGS, MANY OF US ARE USED TO DEVICES. THESE ARE DEFINITELY NOT THE SAME THING. THIS IS IMAGING USED IN SURGERY TO IDENTIFY SPECIFIC TISSUES, AND I THINK I WILL WARN YOU ALL THAT THE LAST CLINICAL AND SCIENCE THAT WE ARE SEEING IN THIS WORKSHOP WAS PROBABLY EBEN'S INTRODUCTION. MOST OF THIS IS GOING TO BE ABOUT THE REGULATORY ASPECTS AND TRIAL END POINTS AND THINGS LIKE THAT. IT INTRINSICALLY AFFECTS THE PATIENT TREATMENT, WHICH IS AGAIN DIFFERENT FROM MANY TIMES EARLY IMAGING DRUGS, YOU DON'T ALLOW THEM TO CHANGE THE PATIENT'S TREATMENT AND YOU CAN DO THAT FOR AN IMAGING DRUG. YOU CAN'T DO THAT FOR THIS KIND OF PROCESS. IT'S GOT TO CHANGE. GENERALLY IT INVOLVES ONE OR MORE DEVICES. MANY OF THESE ARE STARTING TO BE INTEGRATED INTO THE ROBOTIC SURGERY DEVICES. OFTEN IT INVOLVES A DRUG WHICH MAY BE NONSPECIFIC, IT MAY BE SPECIFIC, IT MAY BE ACTIVATABLE. REGULAR TOISH USE, WHICH BETSY HAS -- REGULATORY ISSUES, WHICH BETSY HAS GONE OVER, I LOOK AT A LITTLE DIFFERENTLY. CLASS 2 DEVICES ARE ROUGHLY EQUIVALENT TO A MARKETED DEVICE AND ARE CLEARED BY A 510K PROCESS, YOU BASIC HAVE TO DEMONSTRATE THAT IT IS SAFE AND EFFECTIVE AND SUBSTANTIALLY EQUIVALENT TO A LEGALLY MARKETED DEVICE. IF YOU'RE LUCKY, THIS IS ALL JERG -- THIS IS ALL ENGINEERING. IF YOU'RE NOT, YOU'LL NEED SOME ADDITIONAL CLASS. CLASS 3 DEVICES ARE CLEARED BY THE FREE MARKET DEVICES, THOSE THAT SUPPORT OR SUSTAIN HUMAN LIFE, SUBSTANTIAL IMPORTANCE FOR PRESENTING IMPAIRMENT OR WHICH PRESENT A POTENTIAL UNREASONABLE RISK OF ILLNESS OR INJURY. MANY NEW DEVICES FALL INTO THIS CATEGORY. DRUGS ARE A LOT SIMPLER. THEY ARE APPROVED BY THE NEW DRUG APPLICATION PROCESS. THERE'S NO VARIATIONS THERE. THERE MAY BE DIFFERENCE INSIDE WHAT YOU HAVE TO DO TO GET THEM APPROVED BECAUSE EACH ONE IS UNIQUE AND SCIENTIFICALLY DISTINGUISHABLE, BUT THERE'S NO SEPARATE PROCESS LIKE CLASS 2 OR CLASS 3 IN THE DEVICES. THERE ARE VARIATIONS ON THIS THEME AND THEY'RE EITHER FOR THE SCIENCE, MEDICINE OR FOR COMMERCIAL REASONS. YOU CAN HAVE A DRUG WITH NO DEVICE. I WILL GO THROUGH SEVERAL OF THESE. YOU CAN HAVE A DEVICE WITH NO DRUG. YOU CAN HAVE A DRUG WITH AN ALREADY APPROVED CLEARED DEVICE. YOU CAN HAVE A DEVICE WITH AN APPROVED DRUG. DEVICE WITH A SPECIFIC REQUIRED DRUG. AND A DRUG WITH A SPECIFIC REQUIRED DEVICE. ALL OF THESE ARE A LITTLE BIT DIFFERENT, AND SOME OF THESE YOU MAY BE ABLE TO CHOOSE, YOU MAY BE ABLE TO CHOOSE, FOR EXAMPLE, THAT WITH YOUR DEVICE, THAT YOU WILL ABSOLUTELY REQUIRE THAT IN THE INSTRUCTIONS FOR THAT DEVICE, THAT A SPECIFIC CONFIGURATION OF AN ALREADY EXISTING DRUG BE USED, AND TECHNICALLY THEN UNDER THE LABELING FOR THAT YOU CAN'T USE ANOTHER VERSION OF THE SAME DRUG. YOU MIGHT DECIDE TO DO THAT FOR COMMERCIAL REASONS. YOU MIGHT DECIDE TO DO IT BECAUSE YOU WANT A DIFFERENT FORM OF CONTROL. FOR A DRUG WITH NO DEVICE, THEY'RE APPROVED AS A DRUG. ISOSOFEN FOR SIMPLE NODE IS APPROVED. THAT'S BLUE DYE PEOPLE USE AROUND A TUMOR TO PLACE WHERE THE LYMPHATICS GO. METHYLENE BLUE IS ALSO USED FOR SNOAD, FOR SENTINEL NODE, IT IS NOT APPROVED FOR THIS USE. IT WAS RECENTLY APPROVED FOR THE FIRST TIME EVER I THINK LAST MONTH FOR A DIFFERENT PURPOSE, BUT THAT IS THE STANDARD OF CARE IN MANY SITUATIONS AT THIS POINT. THEY ARE GENERALLY INJECTED SUBCUTANEOUSLY, LABELED METHOD, THEY CAN BE INJECTDZ AROUND THE TUMOR OR INTRADERMALLY. THEY'RE EVALUATED VISUALLY. YOU SEE THE BLUE DYE, YOU WATCH WHERE IT GOES, THEN YOU GO AFTER THAT NODE. THESE ARE VERY OLD DRUGS, EVEN SPECIFIC NDA'S ARE RECENT, IN MANY CAIPSZ THE KIND OF DATA THAT YOU WOULD NEED NOW TO GET A DRUG APPROVED IS NOT AVAILABLE SO YOU CAN'T RELY ON WHAT'S KNOWN ABOUT THOSE AS AN EXAMPLE FOR WHAT YOU WILL DO WITH YOUR DRUG. YOU CAN HAVE A DEVICE FOR NO SPECIFIC DRUG, THEY'LL BE CLEARED AS A DEVICE. THAT COULD RELY ON INTRINSIC PROPERTIES OF BIOLOGICAL TISSUES. I THINK BOB NORDSTROM WILL TALK ABOUT THIS A LITTLE MORE, IT CAN AUTOFLUORESCENCE OF TISSUE, SPECTROSCOPY SK LOOKED AT INVESTIGATIONAL C MIRROR IR SPECTROSCOPY HAS BEEN LOOKED AT. IN OPHTHALMOLOGY THEY DON'T REQUIRE ANY AGENTS. THERE ARE ALSO GENERAL IMAGING DEVICES LIKE PET WHICH ABSOLUTELY REQUIRES A DRUG BUT DRUGS ARE NOT APPROVED WITH DEVICES IN THIS CASE. MR, CT, ULTRASOUND CAN BE USED WITH OR WITHOUT DRUGS. BUT THERE THE DEVICES ARE CLEARED AS DEVICES. YOU CAN HAVE A DRUG WITH A CLEARED GENERAL DEVICE, AND I DON'T KNOW IF THESE ARE REGULATORY TERMS, BUT IT'S HOW I THINK OF THEM. YOU CAN USE ANY CLEARED DEVICE THAT QUALIFIES FOR THESE THINGS. A TYPICAL EXAMPLE WOULD BE COLOID WHICH SAYS USE HANDHELD BEGAN MA COUNTER, PLANAR IMAGING TECHNIQUES. THIS IS FOR SENTINEL NODE. AGAIN, HANDHELD GAMMA COUNTER FOR LYMPHOSEEK, THAT'S FOR INTRADERMAL, SUBCUTANEOUS, PERITUMORAL. ANY HANDHELD DEVICE THAT HAS BEEN CLEARED YOU CAN USE. INDOCYANINE GREEN IS USED FOR HEPATIC FUNCTION, QUOTE, RECORDING DENSITOMETER, IMAGING EQUIPMENT. THIS IS ABOUT AS GENERAL AS YOU CAN GET FOR WHAT THE DEVICE SHOULD BE. YOU CAN DO A DEVICE AN APPROVED DRUG. THERE ARE CAMERA ASSISTANTS FOR USE WITH INDOCYANINE GREEN WHICH ARE NOT SOLD WITH OUR BRANDED VERSION OF INDOCYANINE GREEN SPECIFIED. TYPICAL EXAMPLE IS THIS PARTICULAR ONE. IT'S 510 SC APPROVED FOR -- 510K APPROVED FOR USE WITH I UNDERSTAND SEEN GREEN, IT WAS APPROVED BY THE FDA, THE LINK THERE IS TO THE CDRH DATABASE OF 510 [K] CLEARED DEVICES WHICH HAVE SOME INFORMATION ABOUT WHEN IT WAS CLEARED, HOW IT WAS CLEARED ACCIDENT HOW IT WAS CLASSIFIED AND SOME OF THE DATA OR THE TYPES OF DATA THAT ARE INCLUDED, FLUOPTICS IS APPROVED FOR USE WITH 510 [K] BUT NONE OF THOSE REQUIRE YOU USE THEY'RE BRAND OF INDOCYANINE GREEN OR EVEN A SPECIFIC ONE AT THIS POINT. THE PRED CAT DEVICE FOR THOSE TWO WAS THE NOVADAQ SPY, WHICH WAS NOT CLASSIFIED AS A COMBO AT THAT TIME IT WAS APPROVED BUT STILL REQUIRED INDOCYANINE GREEN IN ORDER TO WORK. NONE OF THESE CAMERA SYSTEMS ARE CLEARED FOR THE USE OF OTHER DRUGS EVEN IF THEY HAVE THE SAME SPECTRAL CHARACTERISTICS. THAT CERTAINLY DOES NOT STOP YOU FOR PUTTING IN IDE AND USING THESE DRUGS ON AN IDE BASIS, BUT YOU CAN'T JUST ASSUME THAT BECAUSE YOUR DRUG HAS THE SAME CHARACTERISTICS, THE SAME SPECTRAL CHARACTERISTICS AS I UNDERSTAND SEEN GREEN BUT OF COURSE -- AS INDOCYANINE GREEN BUT OF COURSE YOU CAN IMMEDIATELY USE IT. THAT HAS TO GO AS PART OF YOUR CLINICAL PROTOCOL FOR YOUR DRUG. YOU CAN HAVE A DRUG WITH A REQUIRED PRICE. COMBINATION PRODUCT FOR BLADDER CANCER WAS NOT THAT LONG AGO APPROVED, SOMETHING CALLED CYSVIEW, IT REQUIRES THE PDD SYSTEM WHICH WAS CLEARED FROM A PMA, THE KARL STORTZ D LIGHT SYSTEM. THESE WERE ISSUED ON THE SAME DAY SO THAT THE ENTIRE PROCESS COULD DO AND YOU CANNOT USE CYSVIEW WITH ANY OTHER LIGHT SYSTEM. I DON'T THINK THERE IS ANY OTHER ONE. YOU CAN HAVE A DEVICE WITH REQUIRED DRUG. THE NOVADAQ SPY FLUORESCENT IMAGING SYSTEM. IT'S CALLED OUT IN THE 510 [K] THAT CAN BE CHANGED BY SUPPLEMENTS THAT PEOPLE CAN ALSO USE THINGS OFF LABEL, BUT THIS IS HOW IT HAS BEEN CLEARED. THE DA VINCI FIREFLY IS FOR VISIBLE AND NEAR IR FLUORESCENCE, IT'S 510 [K] CLEARED, IT REQUIRES A SPECIFIC INDOCYANINE GREEN KIT THAT IS CALLED OUT IN THE 510 [K] DRUG GENERAL DEVICE. I'LL GO THROUGH A CUP OF COUPLE OF THESE -- A COUPLE OF THESE IN MORE DETAIL. A FAIRLY RECENT DRUG APPROVED IN 2013, LYMPHOSEEK, CR REPEAT DOSE STUDIES IN RATS, RABBITS AND DOGS. -- SINGLE DOSE IN RATS, RABBITS AND DOGS, REPEAT DOSE IN RATS AND DOGS. GENE OHTOXICOLOGY, THREE STUDIES, GENERAL AM CARDIAC STUDIES. PK STUDIES WERE DONE IN DOGS SHES RABBITS AND -- IN DOGS, RABBITS AND RATS, AND THAT WAS UNDOUBTEDLY, I DON'T HAVE THE DETAILS, ALMOST UNDOUBTEDLY INTEGRATED INTO THE TOXICOLOGY STUDY, AND BIODISTRIBUTION WAS ALSO PERFORMED. LYMPHOSEEK IS A 99 SPEC AGENT. CLINICAL STUDIES FOR THAT, THREE STUDIES THE APPROVAL WAS BASED ON. ALL THESE ARE CALLED OUT IN THE SUMMARY BASIS FOR APPROVAL OF A DRUG AND YOU CAN ACCESS THESE ONLINE AND YOU CAN SEE A GREAT DEAL OF DETAIL ABOUT WHAT IS NECESSARY IN ORDER TO GET A DRUG THROUGH. THIS CAN BE VERY HELPFUL WHEN YOU'RE LOOKING YOURSELF AT DRUGS. REALLY OLDER DRUGS DO NOT HAVE SUMMARY BASIS OF APPROVAL FOR THE MOST PART. THIS HAD 411 PATIENTS TOTAL IN THOSE THREE STUDIES, IN MELANOMA, BREAST AND SQUAMOUS CELL CARCINOMA, GENERALLY ORAL CAVITY, THERE WAS A COMPARISON OF PLAY MARCH SENTIGROP -- PLANAR SCINTIGRA PH Y WITH THE 457BD HELD DEVICE -- WITH THE HANDHELD DEVICE. THAT'S HOW THEY ESTABLISHED THE EFFICACY OF WHAT THEY WERE DOING, AND THERE WAS A COMPARISON WITH BLUE DYE WHICH I WAS NOT ABLE TO DETERMINE WHICH BLUE DYE IT WAS FROM THE SUMMARY BASIS AND APPROVAL. FOR SAFETY, THERE WERE A TOTAL OF 531 PATIENTS EXPOSED. SO THIS WILL GIVE YOU AN IDEA OF PROBABLY ABOUT THE ABSOLUTE MINIMUM YOU WOULD NEED. THIS IS A SUBCUTANEOUSLY INJECTED, NOT INTRAVENOUS, SO IT'S NOT SYSTEMIC IMMEDIATELY, ALTHOUGH I BELIEVE THE BIODISTRIBUTION INDICATED THAT THE BASIC MATERIAL WAS VERY QUICKLY ABSORBED AND RENALLY EXCRETED. THE SECOND ONE I'LL GO THROUGH, THIS IS CYSVIEW AS A MODERN EXAMPLE OF A COMBINATION PRODUCT. IT'S INDICATED, YOU CAN READ THAT. THE DRUG IS INSTILLED INTO THE BLADDER AND THEN THE BLADDER INSIDE THE BLADDER IS VIEWED THROUGH A FIBER OP I -- FIBEROPTIC FIRST IN WHITE LIGHT AND THEN IN BLUE LIGHT, THEN THE LESIONS CAN BE PICKED UP AND THEY CAN BE EXCISED OR BIOPSIED AT THAT POINT. IT WAS GIVEN A PRIORITY REVIEW IN 2009, IT HAD BEEN APPROVED IN EUROPE FOR I THINK ABOUT FOUR OR FIVE YEARS BEFORE THEY BROUGHT IT HERE AND IT WAS APPROVED. IT DIDN'T TAKE THAT LONG TO APPROVE IT. IT WAS APPROVED AS A COMBINATION PRODUCT AND THERE WAS ONE PRIMARY EFFICACY STUDY. BUT THERE WAS IN THAT ONE A GREAT DEAL OF SAFETY DATA FROM THE EUROPEAN EXPERIENCE. THE DEVICE THAT WAS APPROVED WITH IT WAS IN THE ORIGINAL PMA CLEARANCE IS NOT DESIGNATED AS A COMBO PRODUCT, IN THE DATABASE THAT I ACCESSED FROM THE FDA, BUT IN FACT IT WAS SO STATED THAT IT WAS IN THE CLEARANCE LETTER. THE CLEARANCE LETTER AND THE SUMMARY GAVE A SUMMARY OF BENCH TESTING AND STERILIZATION PROCESSES. THE DEVICE PIECES ARE RESTERILEIZED AND REUSED, SO CLEANING AND RESTERILIZATION AND INITIAL STERILIZATION ARE EXTRAORDINARILY IMPORTANT IN THIS. BUT THIS WAS FUNDAMENTALLY, THIS PART WAS FUNDAMENTALLY AN ENGINEERING EXERCISE. THE COMPONENT CAMERA SYSTEM INSIDE OF THIS WAS 510K CLEARED, SO THIS WAS AN EXAMPLE OF WHERE YOU ARE MODIFYING AN EXISTING DEVICE FOR YOUR NEW USES. FOR GENERAL ADVICE, THE APPROVAL STATUS OF REALLY OLD DRUGS DOES NOT PROVIDE ANY PRESENCE DENSE. YOU NEED -- PRECEDENCE. YOU NEED TO BE VERY CLEAR ABOUT THIS. YOU CANNOTCYTE INDOCYANINE GREEN AND GO TO ZIMAR'S GROUP AND SAY HI, I DID JUST EXACTLY WHAT INDOCYANINE GREEN DID IN 1922. THAT WON'T GET YOU ANYWHERE. YOU NEED TO BE WARY OF CONSULTANTS WHO GIVE YOU FIRM AND ABSOLUTE ADVICE ON HOW TO APPROACH A COMBO AS A DRUG OR A DEVICE. ANYBODY WHO TELLS YOU, OH, THIS IS ABSOLUTELY WHAT YOU MUST DO AND NOTHING ELSE, PROBABLY NOT A GOOD IDEA TO RELY ON THEM. CONSIDER IF YOU WANT TO COMPLETELY TIE YOUR DEVICE AND DRUG TOGETHER OR GENERALIZE BOTH OR EITHER. THIS IS A COMMERCIAL DECISION FREQUENTLY, BUT IT CAN BE IMPORTANT IN TERMS OF GETTING THEM OUT TO WHERE WE WANT THEM, WHICH IS TO THE PATIENTS. CONSIDER WHICH OF THE COMPONENTS PRESENTS THE LARGEST SAFETY RISK BECAUSE THAT'S THE ONE YOU NEED TO BE MOST AWARE OF. THIS IS WHAT WE'RE CONCERNED WITH HERE, ESPECIALLY IN THE EARLY STAGES OF THIS KIND OF DEVELOPMENT IS SAFETY. YOU DON'T WANT TO HURT ANYBODY. WHEN IN DOUBT, MEET WITH THE FDA DIVISION YOU THINK IS MOST RELEVANT, TELL THEM WHAT YOU INTEND TO DO, AND LISTEN TO THEIR INPUT. A PIECE OF ADVICE I FREQUENTLY GIVE PEOPLE WITH RESPECT TO THE FDA AND I SUSPECT THEY WILL AGREE WITH ME, WHICH IS YOU DO NOT GO IN AND GO, HI, WHAT SHOULD I DO? THEY WILL HAND YOU A COUPLE GUIDANCES AND SAY GO AWAY, OR NOT QUITE, BUT PRETTY CLOSE. YOU NEED TO LOOK AT WHAT YOU NEED TO DO FROM A SAFETY POINT OF VIEW AND AN EFFICACY POINT OF VIEW, YOU NEED TO UTION GOOD SCIENCE AND GOOD CLINICAL JUDGMENT, AND YOU NEED TO PROPOSE WHAT WILL BEST PROTECT PATIENTS AND DEVELOP YOUR DRUG AND YOUR DEVICE AND PRESENT THAT WITH GOOD SCIENCE AND GO FROM THERE. WHERE TO GET REGULATORY INFORMATION ABOUT APPROVED DRUGS AND CLEARED DEVICES. THIS IS SOMETHING WHERE YOU CAN'T CLEATLY GO BY ANALOGY BUT IT'S VERY IMPORTANT TO LOOK AT MORE RECENT THINGS TO SEE HOW THEY WERE APPROACHED BY THE FDA. THE FDA, LIKE ALL ORGANIZATIONS, EVOLVES. THEIR APPROACHES TOWARDS THINGS EVOLVE AS CHARACTERISTICS CHANGE. THE REGULATIONS GENERALLY DON'T CHANGE, BUT THE APPROACH TO THEM CAN. DEVICES AND BOTH OF THESE DATABASES HAVE A CHECK BOX FOR COMBINATION PRODUCTS. THERE'S A SEPARATE ONE FOR 510(K) CLEARED DEVICES AND FOR PMA CLEARED DEVICES. THERE'S ALSO A WHOLE BUNCH OF OTHER DATABASES BUT THESE ARE THE ONES THAT WAS FOCUSING ON HERE. SUMMARY STATEMENTS ARE AVAILABLE, THE SUPPLEMENTS ARE AVAILABLE, SO YOU CAN ESSENTIALLY SEE THE HISTORY OF CAMERA X HAS HAD FIVE SUPPLEMENTS OVER THE PAST EIGHT YEARS SOME OF WHICH LED TO CHANGES IN THE MANUALS AND INSTRUCTIONS, SOME OF WHICH DIDN'T. THE DRUGS, THE BEST PLACE TO GO IS DRUGS@FDA, IT'S ONE OF THE REALLY EXCELLENT DATABASES. YOU CAN TYPE IN PART OF THE NAME, YOU CAN TYPE IN A GENERIC NAME, YOU CAN TYPE IN A TRADE NAME AND THIS WILL BRING UP LINKS TO THE APPROVAL PAGES WHERE YOU CAN FIND THE SUMMARY BASIS OF APPROVAL AND LABELING. DRUGSATFDA. INCLUDING SUPPLEMENTS. OLD DRUGS MAY NOT HAVE EITHER A SUMMARY BASIS OF APPROVAL OR THE LABELING. YOU CAN GET THESE LABEL GZ AT DAILY MED, AGAIN, SAME WAY, YOU TYPE IN THE NAME. IT'S VERY IMPORTANT TO LOOK AT DRUG LABELING BECAUSE THAT'S WHAT THE FDA USES AS ITS PRIMARY I GUESS COMMUNICATION TO THE CLINICAL COMMUNITY IS THE LABEL. AND THAT'S ALL. QUESTIONS? COMMENTS? >> JOHN PINGLER FROM NOVADAQ. I WANTED TO CLARIFY, I THINK THE ORIGINAL SLY SYSTEM WAS CLEARED AS A COMBINATION PRODUCT. >> IT WAS, BUT IT WASN'T BOX CHECKED. WHEN YOU GO TO THE DATABASE, THE BOX FOR COMBINATION, IT WASN'T CHECKED. YEAH. SOY MEAN, PART OF WHAT -- SO I MEAN, PART OF WHAT PEOPLE AROUND HERE HAVE TO DO IS THEY HAVE TO FIGURE OUT HOW TO NAVIGATE THESE DATABASES, SOMETIMES THERE ARE GRICHES AND THINGS LEFT -- SOMETIMES THERE ARE GLITCHES AND THINGS LEFT OUT. >> NEIL OGDEN, THAT SPEAKS TO THE EVOLUTION OF THE FDA BECAUSE I THINK THE FIRST CLEARANCES FOR THAT DEVICE, THERE WAS NO BOX TO CHECK. >> CORRECT. >> SO WE DID EVOLVE ITALY ABIT AND STARTED TRACKING THOSE AND NOW THERE'S A BOX TO CHECK. >> THAT MAY BE IN ADVANCE OF THE OFFICE OF COMBINATION PRODUCTS AS WELL. SO I THINK WE HAVE A PANEL NOW? >> YES. I WOULD ASK THAT THE PANELISTS GO UP TO THE FRONT THERE IN THOSE CHAIRS. MIKE BOU VE E -- MIKE BOUVET WILL MODERATE. IT WOULD BE GREAT IF THE PANELISTS COULD STATE ONE AT A TIME AND STATE WHAT THEIR BACKGROUND AND AGENCY IS AND THE MODERATORS WILL BE NEIL OGDEN, LOU MARZELLA, BAMBI REYNOLDS, PAULA JACOBS, JOHN FENGLER, MIKE BOUVET WILL BE MODERATOR. AS MIKE DOES HIS ILLEGAL LAPTOP SWAP, IF PEOPLE COULD INTRODUCE THEMSELVES. SO I DON'T KNOW, LOU, DO YOU WANT TO START? DO YOU WANT TO START WITH INTRODUCING YOURSELF AND KIND OF GO DOWN THE ROW AS MIKE GETS THE SLIDES SET UP? >> GOOD MORNING, EVERYONE. I'M DELIGHTED TO BE HERE TO HAVE A PRODUCTIVE DISCUSSION ABOUT THESE PRODUCTS. MY NAME IS LOU MARZELLA, I'M THE DIRECTOR OF THE DIVISION OF MEDICAL IMAGING AT CD HE R AND WE'RE THE FOLKS THAT REGULATE A LOT OF THESE IMAGING PRODUCTS, DRUGS. YOU WILL HEAR FROM SOME OF OUR COLLEAGUES FROM CDRH BUT I WANTED TO EMPHASIZE ALSO THAT WE HAVE A COLLABORATIVE PROCESS FOR DEALING WITH THESE COMBINATION PRODUCTS SO THAT YOU DON'T HAVE TO GO TO MULTIPLE SHOPS. THIS IS A MESSAGE THAT I WANT TO GIVE FROM THE GET-GO THAT WE ARE INTERESTED, WE HAVE A LEAD CENTER FOR THESE PRODUCTS AND SO YOU HAVE, IF YOU WILL, A ONE-STOP SHOP PROCESS FOR DEALING WITH US. >> GOOD MORNING. MY NEEM IS NEIL OGDEN -- MY NAME IS NEIL OGDEN, I'M THE FOR GENERAL BRANCH DEVICES BRANCH ONE. THANK YOU FOR JOINING US TODAY. I WOULD LIKE TO REITERATE THAT WE DO HAVE AN OFFICE OF COMBINATION PRODUCTS THAT HELPS US DECIDE IF THERE'S A QUESTION, WHO THE LEAD CENTER IS AND THEN THAT LEAD CENTER WILL COORDINATE AND BASICALLY RUN THE REVIEW OF THE COMBINATION PRODUCT. >> GOOD MORNING. MY NAME IS JOHN FENGLER, I'M VICE PRESIDENT OF RESEARCH FOR NOVADAQ. YOU'VE HEARD ME SPEAK ABOUT THE SPY SYSTEM SO WE'RE VERY FAMILIAR WITH THE OFFICE OF COMBINATION PRODUCTS, AND I LOOK FORWARD TO A PRODUCTIVE DISCUSSION THIS MORNING. >> PAULA JACOBS. YOU'VE ALREADY HEARD FROM ME. I'M ASSOCIATE DIRECTOR IN THE DIVISION OF CANCER TREATMENT AND DIAGNOSIS IN THE NCI AND I RUN THE CANCER IMAGING PROGRAM, WHICH DEALS WITH A LOT OF THESE. >> BAMBI REYNOLDS, I'M WITH LIE CORE BIOSCIENCES, I'M A BUSINESS DEVELOPMENT ANALYST, PROPERTY MANAGER, WE DEVELOP AND MANUFACTURE SOME OF THE DYES THAT ARE BEING CON CONJUGATED TO SOME OF THESE CLINICAL TRIALS THAT DR. ROSENTHAL HAS DISCUSSED, LIE CORE IS ALSO INTERESTED -- LICOR IS ALSO INTERESTED IN MOVING ITS OWN PRODUCTS ARE THROUGH WHICH IS SIMILAR TO WHAT WE'LL BE DISCUSSING TODAY. >> Mike Bouvet, MD: I'M MIKE BOUVET, I'M A SURGEON AT UNIVERSITY OF CALIFORNIA SAN DIEGO AND EBEN ASKED ME TO MODERATE THE PANEL. IT'S A GREAT HONOR TO HAVE EVERYBODY FROM THE FDA AND INDUSTRY AND PAULA JACOBS AS WELL. WE'LL TALK ABOUT THE PRECEDENCE, WHAT PARALLELS CAN BE DRAWN WITH OTHER PROCEDURES OR AGENTS. SOME POTENTIAL TOPICS TO DISCUSS , CAN HERE, HISTORICAL REGULATORY ASPECTS OF EACH TECHNOLOGY, HOW ARE THESE IMAGING TECHNIQUES SIMILAR TO TARGETED MOLECULAR IMAGING TECHNOLOGY AND HOW HAPPENS THE FDA'S THINKING AAPPROVAL EVOLVED. I'LL GIVE A COUPLE CASES I'VE DONE IN THE OPERATING ROOM WITHIN THE LAST YEAR. I'VE BEEN DOING A LOT OF FLUORESCENCE IMAGING AND JUST FOR A SPRINGBOARD FOR IDEAS ABOUT WHAT WE CAN DISCUSS HERE. THIS WAS A LADY WHO CAME AND SAW ME IN CLINIC WHO HAD CUSHING'S SINNER DROAM, ONLY 27 YEARS OLD, HAS AN MRI THAT SHOWS A 5-CENTIMETER MASS IN THE LEFT ADRENAL GLAND. THIS IS AN MRI DONE WITH GADOLINIUM, IT'S A CONTRAST ENHANCED MRI AND THE INTERESTING THING ABOUT HER WAS THAT YOU COULD TELL THAT SOMETHING HAD CHANGED, SHE HAD GAINED A LOT OF WEIGHT, SHE HAD BUFFALO LUMP, SHE BROUGHT IN A DRIVER'S LICENSE PICTURE OF HER A YEAR AGO AND SHE WAS THIN. THIS TUMOR WAS OVERSECRETING CORTISOL. WE DECIDED TO DO A LAPAROSCOPIC ADRENALECTOMY ON HER AND WE WERE GOING TO USE INDOCYANINE GREEN TO HELP DEFINE THE MARGINS OF THE RESECTION AND AS WE HEARD FROM PAULA, INDOCYANINE GREEN HAS BEEN AROUND A LONG TIME, IT BINDS TO PLASMA PROTEINS, WHICH AMBUMINIMUM IS THE PRINCIPAL CARRIER, IT'S GOT A SHORT HALF-LIFE, AND IT'S REMOVED FROM THE CIRCULATION EXCLUSIVELY BY THE LIVER INTO BILE JUICE SO WE USE IT FOR LAPAROSCOPIC CHOLECYSECTOMY TO IDENTIFY THE BILE DUCTS. YOU HAVE TO ASK THE PATIENTS IF THEY HAVE ANY IODINE ALLERGIES OR ALLERGIES TO SHELF FISH. THAT WOULD BE A CONTRAINDICATION. WHEN YOU FLORIDA HE IS ET WITH THE RIGHT WAVELENGTH AROUND 800 IT WILL EXCITE AND EE MIGHTS AROUND 13 OR. SO A LITTLE BIT ABOUT THE REGULATORY HISTORY. IT WAS DEVELOPED BY THE KODAK RESEARCH LABS IN 1955 AND IT GOT FDA APPROVAL IN 1959 FOR HEPATIC FUNCTION TESTS IN CARDIOLOGY SO IT'S BEEN AROUND A LONG TIME AND IT WAS USED IN 1969 FOR RETINAL STUDIES IN OPHTHALMOLOGY. THERE'S SOME INTERESTING 510(K) CLEARANCE DATA WHICH YOU CAN GET OFF THE INTERNET THAT SHOWS THAT NOVADAQ SPY FLUORESCENT IMAGING SYSTEM OBTAINED THE FDA 510(K) CLEARANCE IN JANUARY 2005 FOR PLASTIC, MICROAND RECONSTRUCTIVE SURGERY AND LATER ON THE PINPOINT SYSTEM ALSO OBJECT TAIBD A PATENT IN 2008 AND NAFS AWARDED IN 2015 FOR USE OF IT WITH THEIR PINPOINT SYSTEM OF THE IT'S USED FOR OTHER SYSTEMS AS WELL. THESE ARE SOME OF THE FLUORESCENCE IMAGING SYSTEMS THAT ARE AVAILABLE BY NOVADAQ AND ALSO INTUITIVE SURGICAL, THE FIREFLY. FOR THIS CASE WE USED THE PINPOINT. THESE ARE SOME OF THE IMAGES WE OBTAINED DURING THE SURGERY. WHAT YOU CAN SEE HERE IS THE ADRENAL GLAND AND A LARGE TUMOR AND SOME OF THE VESSELS AND I JUST HAVE A REAL BRIEF LITTLE VIDEO THAT I THINK ILLUSTRATES THE CASE. YOU COULD SEE HOW LARGE SHE WAS, SHE HAD THESE ABDOMINAL STRIA, ALL BECAUSE SHE WAS CUSHING FROM THE CORTISOL OVERPRODUCTION BY THIS TUMOR. HERE IS THE TUMOR SEEN ON THE MRI. WHEN YOU GIVE THE ICG, YOU CAN INITIALLY SEE BLOOD VESSELS GOING INTO THE TUMOR. IT'S REALLY JUST A VASCULAR IMAGING AGENT. NOT NECESSARILY TUMOR SPECIFIC, ALTHOUGH SOME TUMORS DO TAKE UP ICG. AND YOU CAN ALSO SEE THE ADRENAL VEIN, WHICH GOES RIGHT INTO THE RENAL VEIN, AND DURING THE SURGERY WHEN WE DO IT LAPAROSCOPICALLY, WE WANT TO IDENTIFY THE BLOOD VESSELS AND THEN ONE OF THE KEY THINGS IS TO PUT SOME CLIPS ON THE ADRENAL VEIN SO THAT WOULD CONTROL THE OUTFLOW FROM THE TUMOR AND YOU CAN SEE WITH ICG, YOU CAN SEE THE ADRENAL VEIN NICELY. AND YOU'LL SEE ME PUTTING SOME CLIPS IN IN JUST A MINUTE HERE ON THAT VEIN. AGAIN, WITH THIS PINPOINT DEVICE, YOU CAN FLIP BETWEEN THE COLOR OVERLAY MODES OR YOU CAN GET THE BLACK AND WHITE MODE OR THERE'S ANOTHER COLOR SEGMENTAL FLOW MODE. THESE ARE HELPFUL AT DIFFERENT MODES FOR THE SURGEON TO SEE THE VASCULAR STRUCTURES AND PRESUMABLY MAKE THE SURGERY SAFER BECAUSE YOU CAN SEE EXACTLY WHAT YOU'RE DOING WHEN YOU'RE WORKING. SO HERE WE'RE JUST CLIPPING OFF THE VEIN. THEN AFTER THIS YOU CAN SEE THAT THE ADRENAL GLAND ITSELF HAS TAKEN UP SOME OF THE ICG AND THAT ACTUALLY HELPS THE SURGEON GO ALONG AND MAKE SURE THAT YOU'VE DONE A COMPLETE RESECTION BY SEEPING THE FLUORESCENCE THERE -- BY SEEING THE FLUORESCENCE THERE, AND YOU'RE NOT LEAVING ANY OF THE TUMOR OR THE ADRENAL BEHIND DURING THE CASE. SO WITH THAT -- SO JUST SOME QUESTIONS FOR THE PANEL TO START THE DISCUSSION. IS ICG SUFFICIENT OR ARE THERE BETTER FLUORESCENT PROBES THAT COULD HELP WITH INTRAOPERATIVE SURGICAL NAVIGATION? I DON'T KNOW IF ANYBODY WANTS TO ADDRESS THAT FIRST. THIS HAS BEEN AROUND A LONG TIME, SO HOW ABOUT -- >> WELL, I THINK EVERYBODY KNOWS THAT ICG IS A NONSPECIFIC DYE, AND IT CERTAINLY IS USEFUL IN VASCULAR IMAGING APPLICATIONS, AND YOU'VE MENTIONED THAT IT HAS SPECIFIC UPTAKE IN SOME FORMS OF TUMORS, BUT OBVIOUSLY THE INTENTION AND THE TOPIC OF INTEREST TO MOST PEOPLE HERE ARE THE DYES OR THE IMAGING AGENTS, IF YOU LIKE, THAT ARE SPECIFIC TO PATHOLOGY, AND SO I THINK THERE WOULDN'T BE THIS INTEREST IF ICG COULD ANSWER ALL THOSE QUESTIONS. >> AGAIN, THIS IS BAMBI REYNOLDS. I ALSO AGREE WITH JOHN. I THINK THIS IS A HUGE AREA OF OPPORTUNITY. I THINK ALL OF YOU KNOW WE HAVE ONE SPECIFIC DYE BUT I THINK AS WE RESEARCH ALL OF THESE PROBES, I THINK THERE'S ALL KINDS OF COMBINATIONS WE COULD DO FOR THE VARIOUS DIFFERENT DYES, BUT I THINK THAT'S WHY THIS CONVERSATION IS SO IMPORTANT BECAUSE IT'S NOT GOING TO BE ICG BASED. I THINK THERE'S GOING TO BE MULTIPLE DYES DEPENDING ON THE PROBE AND THE DEVICE AND THE APPLICATION, SO THIS IS A VERY IMPORTANT TOPIC TO NOT ONLY US ON THE PANEL, BUT IT'S A HUGE AREA, I THINK, THAT HAS YET TO BE DISCOVERED AS WELL. >> AND I THINK AS WE LEARN MORE ABOUT TUMOR BIOLOGY AND THE VARIOUS RECEPTORS THAT ARE AVAILABLE IN DIFFERENT TYPES OF HISTOLOGIES, THERE WILL BE A LOT MORE AND WE'LL HAVE TO AS A FIELD FIGURE OUT WHICH ARE THE MOST GENERALIZEABLE ONES TO GO AFTER FIRST BECAUSE I DON'T THINK THAT -- I COULD BE WRONG, BUT I DON'T THINK THE FIELD CAN SUPPORT 150 DIFFERENT NEW IMAGING AGENTS, EACH ONE DIRECTED TO A TUMOR THAT'S 3%, A TUMOR TARGET THAT'S 3% OF TUMORS, THAT YOU MIGHT ACTUALLY BE INTERESTED IN FROM A THERAPEUTIC POINT OF VIEW, BUT FROM AN IMAGING POINT OF VIEW, I'M NOT SURE YOU WOULD WANT FOR EXAMPLE AN AGENT DIRECTED TOWARDS -- I THINK THIS WILL BE INITIALLY AN EXPLOSION OF RESEARCH BUT I THINK IT NEEDS TO BE NARROW #-D DOWN FAIRLY QUICKLY. >> I'M CURIOUS TO KNOW WHAT THE PANEL THINKS ABOUT THE SURGERY THAT MIKE JUST PRESENTED AND SOME OF THE CASES THAT I PRESENTED WHERE SURGEONS ARE USING NONSPECIFIC FLUORESCENT ENHANCEMENT TO PROVIDE ACTIONABLE DATA THAT THEY USE. SO THE EXAMPLE THAT MIKE GAVE WAS HE'S USING FLUORESCENCE IN ORDER TO DEFINE ROUGHLY THE EDGES OF A TUMOR. IT'S NOT THE ONLY THING THAT HE'S USING OR THE INFORMATION HE'S USING, JUST LIKE THE SURGEONS WHO DURING MRI GUIDED RESECTION USE NONSPECIFIC VASCULAR ENHANCEMENT. I GUESS MY QUESTION IS, IS THAT A PRECEDENCE FOR ENHANCEMENT LEADING TO ACTIONABLE INFORMATION? IS THAT A SUFFICIENT PRECEDENT THAT WE CAN USE AS WE GO FORWARD WITH THESE AGENTS? >> I THINK THAT -- I'LL GET BACK TO YOUR QUESTION IN A SECOND, BUT I JUST WANTED TO EXPAND ON WHAT PAULA WAS SAYING IN TERMS OF PRODUCT DEVELOPMENT. I KNOW THAT THIS GROUP IS HIGHLY FOCUSED ON SURGICAL APPLICATIONS, BUT ONE NEEDS TO THINK A LITTLE BIT OUT OF THE BOX. SO ONE NEEDS TO TRY TO MAKE A CLINICAL DEVELOPMENT AS EFFICIENT AS POSSIBLE, SO FOR INSTANCE, IF THERE WAS AN AGENT THAT WAS TARGETING SPECIFIC CANCER CELLS, IT WOULD HAVE CLEAR APPLICATIONS FOR DIAGNOSTIC USES, NEVERMIND THE INTRIF -- NEVERMIND THE INTRIF USE. SO I -- NEVERMIND THE INTRAOPERATIVE USE. SO I WILL BE MAKING THIS POINT LATER ON, BUT IN TERMS OF THINKING ABOUT PRODUCT DEVELOPMENT, YOU NEED TO START WITH ENLARGING YOUR PERSPECTIVE. THE QUESTION THAT WAS BEING ASKED IN TERMS OF PRECEDENCE, I WOULD USE PAULA'S SORT OF RULE, I WILL CALL IT THE PAULA JACOBS RULE. SO LOOK AT THE FDA LABEL. SO IF THE FDA LABEL FOR GADOLINIUM CONTRAST BASED AGENTS DOES NOT INCLUDE AN INDICATION FOR INTRAOPERATIVE MANAGEMENT OF, YOU KNOW, THE SPECIFIC TUMOR, THEN IT MEANS THAT IT'S NOT FDA APPROVED FOR THIS USE. SO IT COULD BE IN CLINICAL USE, BUT THE FDA HAS NEVER REVIEWED THE DATA. SO WE WOULD NOT VIEW IT AS A PRECEDENT. THE OTHER POINT THAT I WANTED TO MAKE WAS THAT IN THE CONTEXT OF DRUGS, AS PAULA ALSO WAS SAYING, WE DON'T HAVE A SORT OF AN EQUIVALENCE FOR NEW MOLECULAR ENTITIES. WE HAVE IT FOR GENERIC DRUGS. SO YOU NEED TO START WITH WHAT IS THE PRECEDENT, AND WE DO NOT YET HAVE A PRECEDENT FOR THE USE OF AN INTRAOPERATIVE DEVICE THAT WOULD -- AND DRUG THAT WOULD HELP IN THE RESECTION OF BRAIN TUMORS. >> SO WE STARTED WITH VASCULAR AGENTS, AND I WONDER IF WE CAN CONTINUE THAT DISCUSSION A LITTLE BIT. THAT WOULD BE A GENERALIZEABLE AGENT THAT MANY PEOPLE ARE INTERESTED IN. SO MIKE AND BAMBI, WHAT HAVE YOU LEARNED ABOUT USING ICG? WHAT HAVE YOU LEARNED ABOUT IT AS A VASCULAR AGENT? WHAT WOULD YOU LIKE IN THE NEXT GENERATION OF VASCULAR AGENTS, AND WHAT'S CURRENTLY ON THE HORIZON THAT WE CAN ANTICIPATE SEEING IN THE CLINIC? >> I'LL JUST GIVE YOU A COUPLE OF INSIGHTS. ICG IS VERY RAPID, SO WHEN YOU INJECT IT, YOU KNOW, IT WILL STICK AROUND FOR A FEW MINUTES AND THEN IT GETS CLEARED. THAT'S A GOOD THING I THINK SOMETIMES, BUT YOU HAVE TO USE IT MULTIPLE TIMES SOMETIMES DURING THE CASE AS WELL. SO MAYBE A VASCULAR AGENT THAT IF WE HAD A VARIETY OF THINGS, A VASCULAR AGENT THAT STUCK AROUND A LITTLE LONGER SO THE SURGEON COULD CONTINUE THE DISSECTION WITHOUT HAVING TO GIVE REPEATED DOSES, THAT MIGHT BE ONE THING. THE OTHER THING IS IT'S REALLY, AS WAS MENTIONED BEFORE, IT'S NONSPECIFIC, SO I HAVE A CASE OF A PARATHYROID HE CANHE CAN COME MY -- PARATHYROIDECTOMY, WHICH I WILL SHOW LATER, THE IT LIGHTS UP NICELY, BUT IT'S ALSO NEXT TO THE THYROID, SO DEPENDING ON WHICH ORGAN YOU'RE TRYING TO REMOVE, SOMEHOW IF WE HAD A MORE SPECIFIC AGENT FOR WHATEVER THE PURPOSE WAS, THAT WOULD BE BETTER AS WELL. BAMBI, DO YOU HAVE ANYTHING TO ADD? >> I DON'T WANT TO SHARE A WHOLE LOT, BUT WE ALSO SEE SPECIFICITY AS BEING THE AREA OF INTEREST, ALSO LOOKING AT OTHER STRUCTURAL IDENTIFICATION AS SOMETHING THAT WE'RE INTERESTED IN AS WELL. SO OTHERWISE, I CAN'T SAY A WHOLE LOT MORE. >> ALTHOUGH ONE THING THAT MAY COME UP IS THAT YOU COULD USE A VASCULAR AGENT AND THEN A TUMOR-SPECIFIC AGENT OF A DIFFERENT WAVELENGTH AND THAT WOULD BE KIND OF A COMBINATION THING THAT MIGHT MAKE IT REALLY HELPFUL FOR SURGEONS. >> SINCE EBEN AND OTHERS ARE WORK WITH ANTIBODIES THAT LABEL THE TUMOR, WHY NOT USE AN ANTI-CD31 ANTIBODY THAT WOULD LIGHT UP THE VASCULATURE AND BE SOMEWHAT PERSISTENT AND ALLOW YOU TO SEE IT OVER A PERIOD OF TIME? ARE THERE REGULATORY HURDLES THERE FOR ANTIBODIES THAT WOULD LIGHT UP NORMAL CELLS, ENDOTHELIUM? AND DOES ANYBODY KNOW ON THE PANEL OF WHAT AGENTS ARE ON THE HORIZON AS A VASCULAR LABEL? BESIDES ICG. >> TO ADDRESS THE REGULATORY QUESTION, WE WOULD HIGHLY ENCOURAGE THAT APPROACH SO THAT -- AND I THINK A NUMBER OF COMPANIES ARE INTERESTED IN THAT APPROACH. IF YOU HAVE, FRINGS, A THEY ARE -- IF YOU HAVE, FOR INSTANCE, A THERAPEUTIC FOR CANCER, IT MAY BE VERY HELPFUL TO RADIO LABEL THAT ANTIBODY AND USE IT, FOR INSTANCE, FOR TUMOR STAGING OR FOR DETECTION OF RECURRENCE OF TUMOR. SO THAT IS SOMETHING THAT WE WOULD HIGHLY ENCOURAGE TO TRY TO DEVELOP WHAT WE CALL COMPANION DIAGNOSTICS, IT'S SOMETHING WE WOULD ENCOURAGE. WE NEED TO START THINKING MORE IF WE WANT TO BE PRODUCTIVE, NOT AS CLINICIANS, BUT AS SCIENTISTS, OR CLINICIANS SCIENTISTS, IN OTHER WORDS, WE NEED TO START THINKING WHAT WOULD I BE ABLE, WHAT DO I NEED TO DO TO DEMONSTRATE THAT THIS PARTICULAR PRODUCT OR THIS PARTICULAR TECHNOLOGY ADDS VALUE TO WHAT I'M DOING. SO IT'S CLEAR THAT THERE'S A TREMENDOUS NEED. IT'S CLEAR THAT THERE'S A TREMENDOUS AMOUNT OF OPPORTUNITIES. BUT AS DRUG DEVELOPERS, ONE NEEDS TO START WITH, YOU KNOW, WHAT ARE THE POTENTIAL APPLICATIONS AND WHAT IS THE SPECIFIC PATIENT POPULATION IN WHICH THIS DRUG IS GOING TO BE USED AND HOW WILL I OBJECTIVELY DEMONSTRATE IN A SCIENTIFICALLY VALID MANNER THAT WHATEVER I AM DOING ON TOP OF THE STANDARD CARE ADDS VALUE. SO WE NEED TO START WITH THAT FROM THE GET-GO TO DETERMINE WHETHER, YOU KNOW, THE CLINICAL DEVELOPMENT APPROACH IS GOING TO BE VIABLE. >> IF I CAN ASK ONE QUICK QUESTION. >> FOR THE FDA PANELISTS, WHAT'S THE FUNDAMENTAL PHILOSOPHICAL DIFFERENCE WHICH MAKES THE DEVELOPMENT OF A NEW PET AGENT, NEW PET SCAN ERROR A NEW MRI AGENT, MRI SCANNER, DIFFERENT THAN THE DEVELOPMENT OF A NEW OPTICAL AGENT IN AN OPTICAL IMAGER? IT SEEMS LIKE THE MRI IN THE PET CASE DID NOT INVOLVE DRUG DEVICE COMBINATION DEVELOPMENT AND STILL DOESN'T. >> THAT'S A VERY GOOD QUESTION. WHAT THE FDA REGULATES IS DRUG MARKETING OF NEW DRUG OR MARKETING OF DEVICES. WE DO NOT REGULATE CLINICAL PRACTICE. SO THE MRI IS A CLEARED DEVICE, SO ANY PHYSICIAN CAN USE THE MRI DEVICE IN ANY MANNER THAT HE WOULD LIKE TO USE IT. THE ONLY LEGAL RESTRICTIONS WOULD BE THAT EVEN IF THE FDA IS NOT INVOLVED, IF A CLINICIAN WANTS TO DO A CLINICAL STUDY THAT INVOLVES HUMAN PATIENTS, THAT HE NEEDS TO GET IRB APPROVAL, AND HE MAY NEED TO GET APPROVAL FROM THE FDA FOR THAT STUDY TO PROCEED. SO WE NEED TO MAKE A CLEAR DISTINCTION BETWEEN CLINICAL PRACTICE AND MARKETING OF DRUGS AND DEVICES. THERE ARE LEGAL REQUIREMENTS FOR WHAT SOMEONE NEEDS TO DO BEFORE THEY CAN MARKET A DRUG OR A DEVICE. HOWEVER, ONCE THAT DRUG OR DEVICE IS MARKETED, THEN IT FALLS UNDER THE PURVIEW OF MEDICAL PRACTICE, SO A MEDICAL PRACTITIONER CAN USE A PRODUCT IN ANY WAY THAT THEY CHOOSE. HOWEVER, A COMPANY CAN NOT MAKE A CLAIM FOR A SPECIFIC USE OF A DEVICE WHICH HAS NOT BEEN CLEARED BY THE FDA. SO FOR INSTANCE, IF WHOEVER MAKES THAT DEVICE SORT OF MAKES A CLAIM THAT HAS NOT BEEN REVIEWED BY THE FDA, THAT THAT WOULD BE AN ILLEGAL PROCESS. >> MY NEW PET AGENT RIGHT TODAY, I COME UP WITH ONE, IT'S NOT GOING TO BE APPROVED ONLY ON A SEMANS SCAN, FDA WOULD APPROVE IT AS A DRUG BECAUSE THERE ARE LOTS OF SCAN ERPZ OUT THERE, WE ALL KNOW THEY'RE QUITE DIFFERENT. >> YES, I THINK THERE'S A NUMBER OF OPTIONS THAT A COMPANY CAN HAVE, YOU KNOW. YOU CAN DEVELOP SOMETHING AS A COMBINATION PRODUCT, YOU CAN DEVELOP IT FOR USE WITH MULTIPLE DEVICES. WHAT THE FDA IS INTERESTED IN IS DATA THAT SUPPORTS THE INTERCHANGE ABILITY OF THE USE OF THE DRUG WITH THE USE OF THE DEVICE. SO JUST TO GIVE YOU ARE A SILLY EXAMPLE, YOU WOULDN'T USE FDAG WITH MRI SCANNER AND FDA DOESN'T NEED TO CONTROL THAT. WE HAVE SPECIFIC EXAMPLES WHERE WE ARE REALLY INTERESTED IN THE DRUG IF TWO STANDPOINTS. I ALWAYS KEEP GETTING REMINDED OF THIS, ONE IS IN TERMS OF SAFETY, THE QUALITY OF THE DRUG IN TERMS OF SAFETY AND EFFICACY IS REALLY CRITICAL. THAT'S HOWE THE FDA GOT STARTED, TO ENSURE THAT PRODUCTS THAT WERE MARKETED WERE POTENT, THEY WERE SAFE, THEY WERE CLEAN SO WE'RE DEALING WITH THIS RIGHT NOW WHERE A SPECIFIC MANUFACTURING EQUIPMENT, A SPECIFIC DEVICE WILL PRODUCE SOMETHING THAT GOES INTO THE MANUFACTURE OF A DRUG, AND THE PRODUCT THAT COMES OUT OF THIS MANUFACTURING DEVICE IS VERY SPECIFIC. IT HAS DIFFERENT INGREDIENTS. AND IT MATTERS IN TERMS OF ENSURING THAT THE FINAL DRUG PRODUCTS THAT YOU GET, YOU KNOW, MEETS THE SPECIFICATIONS THAT YOU NEED. SO IN THE CASE OF SCANNERS, WE KNOW THAT GADOLINIUM CONTRAST WORKS WITH ANY MRI SCANNER, SO WE DON'T NEED TO SPECIFY. IF WE THOUGHT THAT THERE WAS A SAFETY OR EFFICACY ISSUE, WE WOULD BE SPECIFYING. ALSO MANUFACTURERS DO HAVE THE OPTION IF THEY WANT FOR COMMERCIAL REASONS TO TIE A DRUG TO A SPECIFIC DEVICE THAT THEY OWN. SO THERE'S A NUMBER OF COMMERCIAL REASONS, A NUMBER OF SAFETY AND EFFICACY REASONS THAT DETERMINE WHETHER OR NOT THERE IS CROSS-LABELING BETWEEN A DRUG AND A DEVICE. >> I'LL MAKE A COMMENT THERE. ONLY IF YOU SPECIFY THAT YOUR DRUG MUST BE USED WITH A SPECIFIC DEVICE, THAT THAT APPLIES. IF THE FDA HAS CLEARED FIVE PET DEVICES AS BEING SUBSTANTIALLY EQUIVALENT, THEY'RE SUBSTANTIALLY EQUIVALENT AND YOU CAN USE THEM INTERCHANGEABLY. THIS IS NOT YET THE CASE FOR MANY OF THE DEVICES THAT WE'RE TALKING ABOUT HERE THAT ARE USED INTRAOPERATIVELY. IT MAY WELL BE THE CASE. THE HANDHELD GAMMA COUNTERS THAT ARE USED FOR SENTINEL NODE, THEY'RE NOT SPETION FIED. YOU CAN USE -- THEY'RE NOT SPECIFIED. YOU CAN USE ANY DEVICE THAT'S BEEN CLEARED. I WILL ECHO LOU THAT MANY TIMES THIS IS A COMMERCIAL DECISION RATHER THAN A REGULATORY OR EVEN A SCIENTIFIC DECISION. YOU MAY FOR COMMERCIAL REASONS WANT TO TIE HAD. YOU MAY WANT TO SPECIFY WITH YOUR DEVICE THAT THE USER -- AND YOU CAN USUALLY ENGINEER IT SO IT WORKS THIS WAY, THE USER CAN ONLY BUY THE DRUG FROM YOU, IT'S SET UP IT WORKS IN A CERTAIN PLACE AND SO FORTH. THAT DOESN'T NECESSARILY MEAN THAT'S REQUIRED SCIENTIFICALLY. >> TO GIVE YOU A TRIVIAL EXAMPLE, YOU KNOW, WE DON'T THINK OF THESE COMPONENTS AS MEDICAL DEVICES, BUT, YOU KNOW, IF YOU'RE GOING TO INJECT A PET DRUG, YOU'RE GOING TO HAVE TO USE A NUMBER OF DEVICES. YOU NEED TO USE AN ALCOHOL SWAB, YOU NEED TO USE A SYRINGE. WELL, SOME MANUFACTURERS DECIDE TO PRODUCE KITS SO THAT FOR CONVENIENCE SAKE YOU HAVE YOUR DRUG, YOU HAVE THE SWAB, YOU HAVE, YOU KNOW, THERE'S A SURGICAL PROCEDURE INVOLVED. SO THERE ARE A NUMBER OF PERMUTATIONS. SO EVERYTHING THAT THE FDA DOES IS DATA DRIVEN. SO IF THERE'S NO SAFETY OR EFFICACY CONCERNS, IF A SPECIFIC DRUG CAN WORK WITH A SPECIFIC DEVICE, THEN THERE'S NO REASON TO TIE THE TWO TOGETHER. >> CAN I JUST FOLLOW UP ON THIS? JIM BASILION. CASE WESTERN. I'M NOT FULLY UNDERSTANDING THIS. YOU'RE SAYING IF YOU HAVE WE HAVE A FLUORESCENT OPTICAL AGENT IS PROVED, THAT YOU CAN ONLY USE IT WITH A CAMERA PRODUCT THAT IT'S TESTED WITH AND CAN'T INTERCHANGE CAMERA PRODUCTS CLINICALLY BECAUSE THE REPRODUCIBILITY OF THOSE DEVICES IS UNKNOWN OR YOU CAN CHANGE CAMERA PRODUCTS INDISCRIMINATELY? >> YOU CAN. IF THE CAMERAS ARE ALL CLEARED, YOU CAN USE ANY CLEARED CAMERA THAT WORKS. RIGHT? >> SO TYPICALLY WHAT WOULD HAPPEN WOULD BE THAT DURING THE IND PROCESS, YOU WOULD PROVIDE US THE INFORMATION AND WE WOULD NOT -- WE ARE NOT DEVICE EXPERT, WE WOULD GO TO OUR FRIENDLY DEVICE CONSULTANT AND THEY WOULD SAY THIS IS CLEARED FOR THIS USE, IT MEETS THE SPECIFICATION, IT'S FINE, OR THEY COULD SAY NO, THIS RAISES NEW SAFETY AND EFFICACY ISSUES, WE WANT TO TAKE A LOOK AT IT. SOME ADDITIONAL DATA MAY NEED TO BE PROVIDED IN TERMS OF ENGINEERING DATA OR IT COULD GO ALL THE WAY UP TO ACTUAL TESTING. SO IT'S DEPENDENT ON WHAT EXPERIENCE, WHAT DATA THE FDA HAS LOOKED AT AND IF THERE'S NO SAFETY OR EFFICACY ISSUES, THEN YOU DON'T NEED TO REINVENT THE WHEEL. >> DO YOU AGREE WITH THAT, NEIL? IS THAT -- WHAT PAULA'S STATEMENT WAS? >> IN GENERAL, YES, I AGREE WITH THAT. LET'S LOOK AT PHOTODYNAMIC THERAPY AS AN EXAFERL. THOSE CAME ON THE MARKET BACK IN THE '90S SOME OF THEM AND THEY WERE COMBINATION PRODUCTS BACK THEN BUT WE DIDN'T HAVE THAT DESIGNATION SO WE HAD AN NDA AND THEN WE HAD A PMA TO GO WITH IT AND THAT PMA WAS THE LIGHT SOURCE TO ACTIVATE THE PHOTOFERON PRODUCTS. OTHER COMPANIES WANTED TO CELLULITE PRODUCTS TO ACTIVATE PHOTO FERON, THEY CAME IN WITH THEIR OWN PMA OR PMA SUPPLEMENT, WE REVIEWED THOSE TWIESES AND SAID YES YOU'RE PRODUCING THE SAME ACTIVATION LIGHT, YOU CAN ACTIVATE PROTOFERON AS WELL AS THE PREVIOUS PMA, YES, YOU CAN GO ON THE PROTRACTOR. THE ORIGINAL APPROVAL WAS NOT FOR ANY LIGHT SOURCE THAT CAN PRODUCE 630-NANOMETER LIGHT AT 120-MILLIMETER WATTS AT 6 CENTIMETERS SQUARED, IT WAS THIS WATT THAT CAN PRODUCE THIS LIGHT AT THIS ENERGY. IF THE ORIGINAL APPROVAL HAD BEEN FOR ANY LIGHT SOURCE THAT CAN PRODUCE THIS, THEN THE AGENCY MAY HAVE HAD A DIFFERENT OUTLOOK ON WHAT THE NEXT ONE CAN BE, SO IT REALLY DEPENDS ON WHAT COMPANIES COME TO US WITH, WHAT EVIDENCE THEY HAVE TO SUPPORT THAT COMBINATION AND ITS PERFORMANCE AND THEN WE'LL TAKE A LOOK AT IT AND SEE WHERE WE CAN GO FROM THERE. AND AGAIN, IT'S A MARKETING DECISION, WHETHER YOU WANT IT NARROW AND JUST ONE DEVICE TO GO WITH YOUR DRUG OR IF IT'S BROAD, WE CAN WORK EITHER WAY. >> ACTUALLY, I'M SURE I'M NOT SAYING ANYTHING NEW. THERE ARE DIFFERENT COMMERCIAL INTERESTS. SO IT'S NOT AS THOUGH THE FDA CAN FORCE A DEVICE MANUFACTURER TO CROSS-LABEL A DRUG. IT HAS TO BE A MUTUAL AGREEMENT. SO IT'S BASED ON PERCEPTION OF RISK, IT'S BASED ON PERCEPTION OF MARKET SHARE, SO, YOU KNOW, IN A LOT OF CASES WE'VE ACTUALLY SEEN SITUATIONS WHERE THE DRUG MANUFACTURER IS CONCERNED ABOUT LINKING THEIR DRUG TO ANOTHER DRUG OR ANOTHER SPECIFIC DEVICE IF THEY DON'T SEE A COMMERCIAL BENEFIT, AND ALL THEY SEE IS POTENTIAL RISK, YOU KNOW, THEY WOULD NEVER DO THIS. WE TYPICALLY ALSO WOULD ASK, IF WE HAD SOME EVIDENCE THAT A PIECE OF MANUFACTURING EQUIPMENT OR EVEN A DEVICE OR AN APPROVED DRUG WAS NEEDED FOR THE SAFE AND EFFECTIVE USE OF THE PRODUCT, WE DON'T HAVE AUTHORITY TO REQUIRE THAT. WE WOULD HAVE THE APPLICANT TO GO AND ASK PERMISSION FROM IN THIS CASE THAT I'M THINKING ABOUT WOULD BE THE DEVICE MANUFACTURER TO ALLOW THAT INFORMATION TO BE PUT IN THE LABEL BECAUSE, AGAIN, WE THINK THAT THAT INFORMATION IS NEEDED FOR THE SAFE AND EFFECTIVE USE OF THE DRUG. >> I WAS INTRIGUED BY THIS TERM SUBSTANTIALLY EQUIVALENT. I DIDN'T INTRODUCE MYSELF EARLIER. CHRIS CONTAG FROM STANFORD. FROM AN INSTRUMENTATION MANUFACTURING PERSPECTIVE, YOU NEVER WANT TO BE SUBSTANTIALLY EQUIVALENT, YOU ALWAYS WANT TO BE BETTER THAN THE OTHER DEVICES OUT THERE, SO WHEN A VENDOR COMES TO YOU WITH A PMA AND IS LOOKING ESSENTIALLY FOR SUBSTANTIALLY EQUIVALENT BUT YET THEY SAY THEIR DEVICE IS BETTER, WHAT DEFINES SUBSTANTIALLY EQUIVALENT IN THE CASE OF OP TI CAL INSTRUMENTS? >> SO ONE CLARIFICATION IS THAT PMA'S ARE NOT SUBSTANTIAL EQUIVALENTS. THOSE ARE SAFE AND EFFECTIVE. SO THE 510(K) PARADIGM IS, TECH TIP CLIR IT'S A TECHNICAL COMPARISON THAT DETERMINES SUBSTANTIAL EQUIVALENCE. THE DEVICE THAT'S THE PREDICATE THAT'S ALREADY FDA CLEARED AND APPROVED AND OUT THERE, SORRY, IT SHOULD BE CLEARED, YOU WOULD MAKE A COMPARISON TO THAT DEVICE AND THE PERFORMANCE. SO YOU SHOULD BE AS GOOD AS THAT PREDICATE DEVICE AND TYPICALLY COMPANIES WANT TO BE BETTER THAN OR OFFER OTHER FEATURES THAT THE PREDICATE DOESN'T HAVE SO WE'LL ASSESS THOSE FOR SUBSTANTIAL EQUIVALENCE SAFE AND EFFECTIVE AND GO FROM THERE. >> TO FOLLOW UP ON THIS, I'M FROM THE TECHNICAL UNIVERSITY OF MUNICH. IF THERE'S A DEVICE THAT CAN ESTABLISH EQUIVALENCY, SAY RUF A PET DEVICE MUCH MORE SENSE SENSITIVE. YOU HAVE A DRUG THAT DOES NEW THINGS. IT GOES AWAY FROM JUST A COMMERCIAL INTEREST BECAUSE THE DEVICE NOW BECAUSE OF ITS BETTER PERFORMANCE DOES BETTER THINGS. SO HOW DO YOU ADDRESS SOMETHING LIKE THIS? >> SO AGAIN, THEN YOU'RE GETTING INTO THE COMPLEXITIES OF DOES THIS NEW PERFORMANCE SORT OF ALTER THE STANDARD OF CARE IN THE CURRENT PRACTICE OF MEDICINE? AND IF IT DOES, THEN WE HAVE TO ASK QUESTIONS ABOUT THAT AND IS THAT ALTERING OF THE CURRENT STANDARD OF CARE, IS THAT GOING TO BENEFIT THE PATIENTS? IS THAT SAFE AND EFFECTIVE? SO YOU GET INTO QUESTIONS OF, SO THE PREDICATE COULDN'T DO THOSE THINGS. SO NOW YOU HAVE, IN OUR MINDS, IT'S FAIR TO ASK, WELL, WE DON'T HAVE ANY, LET'S SAY, EVIDENCE OF HOW YOU'RE GOING TO USE THAT INFORMATION IN THE PRACTICE OF MEDICINE. IS THAT GOING TO BE SAFE AND EFFECTIVE FOR THE TREATMENT OF PATIENTS? WE HAVE CLINICIANS THAT WORK FOR US. WE HAVE SCIENTISTS. AND WE ASSESS THOSE QUESTIONS. AND HOPEFULLY WHEN A SPONSOR COMES TO US AND THEY HAVE THIS GREAT ENHANCEMENT, THEY WILL HAVE SOME EVIDENCE TO SUPPORT THE UTILITY OF THESE ENHANCED FEATURES. THEY'RE NOT JUST GOING TO SAY HERE, FDA, WHAT DO YOU THINK? WE'RE GOING TO SAY, WAIT A MINUTE, THIS IS A NEW PARADIGM. WHY ARE YOU GIVING US THIS? WHERE IS THE EVIDENCE? >> WE HAVE ABOUT TEN MINUTES LEFT, AND I THINK JONATHAN SORGER HAD QUESTIONS. IT WOULD BE NICE TO GET TO THOSE QUESTIONS. >> I WANTED TO ADD THAT IT'S VERY SIMPLE FOR DRUGS. IF THE DRUGS ARE PAST THE EXCLUSIVITY, THERE ARE SPECIFIC STANDARDS BY WHICH YOU CAN ESTABLISH COMPARABILITY SO YOU DON'T HAVE TO DO CLINICAL TRIALS ALL OVER AGAIN. ALL YOU HAVE TO DO IS TO SHOW THAT THE DRUG IS PHARMACOLOGICALLY EQUIVALENT IN TERMS OF BIODISTRIBUTION. >> I ACTUAL HAVE TWO QUESTIONS, BUT I WILL ASK ONE NOW AND ONE LATER. THIS IS PHIL LAU FROM PURDUE UNIVERSITY. SO IF ONE HAS A DRUG THAT ILLUMINATES THE TUMOR VERY WELL AND THERE ARE SEVERAL DEVICES THAT WOULD LIKE TO BE ABLE TO USE THAT DRUG AND ADVERTISE IT, WHO DETERMINES WHETHER THEY CAN LIST THEIR DEVICE WITH THE DRUG? DOES THAT HAVE TO COME -- CAN THEY SHOW EQUIVALENCE AND THEN ADVERTISE THAT WITHOUT APPROVAL FROM THE DRUG COMPANY? >> NO. IF THE DRUG IS NECESSARY TO IMAGE THE TUMOR, THE CLAIM WOULD HAVE TO BE IN THE DRUG LABEL. >> SO IF THEY WANT TO USE THAT DRUG AND WOULD LIKE TO CLAIM THEIR ABILITY TO IMAGE TUMORS WITH THIS PARTICULAR DRUG THAT MAY BE SPECTACULAR AND HIGHLIGHT -- >> RIGHT. THE DEVICE MANUFACTURER DOES NOT OWN THE DRUG. THEY WOULD HAVE TO TALK TO THE OWNER OF THE DRUG. IF THE DRUG PASSES EXCLUSIVITY, THEN THE DEVICE MANUFACTURER MAY CHOOSE TO MANUFACTURE THAT SAME DRUG, GET AN ANDA, A GENERIC DRUG APPROVAL, THEN THEY CAN DEVELOP THEIR OWN LABEL FOR THE DRUG. >> IF THE DRUG IS ON PATENT AND IS -- >> THEN THE DRUG MANUFACTURER OWNS THE DRUG AND OWNS THE MARKETING AND OWNS THE LABEL. EVEN THE FDA DOESN'T OWN THE LABEL. THE DRUG MANUFACTURER OWNS THE LABEL. >> AND IF THE DRUG MAKER WANTED TO SHOW EQUIVALENCE, IS THAT AN ELABORATE PHASE II OR PHASE IV COLLIN -- IS THAT AN ELABORATE PHASE 3 OR PHASE 4 CLINICAL TRIAL? >> WE DO NOT HAVE A 510(K) CLEARANCE. ALL OF THE DRUGS NEED TO BE SHOWN TO BE CLINICALLY BENEFICIAL, SO THE ONLY MARKETING BASIS IS EITHER A NEW DRUG APPLICATION OR A BIOLOGIC LICENSE APPLICATION. >> OKAY. BUT IF ONE WANTS TO SAY, OKAY, IN ADDITION TO HAMMER X WOULD CAISH CAMERA X WOULD LIKE TO BE ABLE TO LIST ON OUR LABEL CAMERA Y AND CAMERA C, THE CLINICAL TRIALS DEMONSTRATED FOR EQUIVALENCE, HOW ELABORATE ARE THEY? >> THEY WOULD BE HANDLED BY THE DEVICE FOLKS. WE DON'T -- FOR INSTANCE, WITH THE EXAMPLE OF THE CONTRAST AGENTS, WE DON'T DO CROSS-LABELING. WE DON'T SPECIFY WHICH -- >> I UNDERSTAND. BUT I'M ASKING NOT SO MUCH THE QUESTION OF WHO HANDLES IT, BUT HOW INVOLVED. WE SAW EARLIER 500 PATIENTS, 100 PATIENTS. HOW DIFFICULT IS IT TO DEMONSTRATE EQUIVALENCE? >> WELL, THAT'S AN OPEN HYPHENED QUESTION. THE DEVIL -- THAT'S AN OPEN ENDED QUESTION. THE DEVIL IS IN THE DETAILS. I'LL TALK ABOUT THIS LATER AND DR. PATRICIA LOVE WILL TALK ABOUT IT MORE WHEN SHE TALKS ABOUT THE OFFICE OF COMBINATION PRODUCTS, BUT WE'RE TRYING TO HAVE A SINGLE APPLICATION FOR A COMBINATION PRODUCT. SO LET'S SAY YOU HAVE AN NDA FOR A COMBINATION PRODUCT, IT CLUFERS THE DEVICE -- IT INCLUDES THE DEVICE IN THE NDA, SO THERE'S NOT A SEPARATE PMA FOR THE DEVICE. SO NOW THE NDA OWNER, WHOEVER THAT IS, IT COULD BE THE DEVICE OR THE DRUG COMPANY, BUT WHOEVER OWNS THE COMBINATION PRODUCT, THEY WANT TO NOW HAVE ANOTHER DEVICE ACTIVATE THEIR DRUG. SO THEY WOULD COME IN WITH A SUPPLEMENT TO THE NDA. I BELIEVE YOU CALL THEM SUPPLEMENTS. SO THEN THAT WOULD GO INTO THE CENTER FOR DRUGS BECAUSE IT'S AN NDA AND THEY WOULD CONSULT WITH US, THE DEVICE FOLKS, AND WE WOULD REVIEW THAT NEW DEVICE TO ACTIVATE THAT DRUG IN THE COMBINATION PRODUCT. SO THEN THE COMBINATION WOULD BE THE DRUG AND TWO DEVICES TO ACTIVATE IT. >> (AWAY FROM MIC). >> IT FITS EXACTLY THE SAME OUTPUT OF THE DEVICE AND FUNCTIONS VERY SIMILARLY. I DON'T SEE WHY WE WOULD NEED A LOT OF CLINICAL DATA TO SUPPORT ITS SAFETY AND EFFICACY. >> LET ME MAKE ANOTHER COMMENT, WHICH IS THAT AS PAULA WAS SAYING IN THE INTRODUCTORY COMMENTS, THAT IN THIS PARTICULAR CONTEXT, WE ARE REALLY LOOKING FOR PATIENT OUTCOMES. DECISIONS ARE BEING MANAGED WHICH HAVE IMPORTANT IMPLICATIONS, YOU KNOW. IT COULD BE LIFE SAVING, IT COULD BE LIFE-THREATENING. SO THERE NEEDS TO BE CLINICAL DATA. YOU COULD NOT, YOU KNOW, DO EQUIVALENCE FOR THESE COMBINATION PRODUCTS. SO THE NUMBERS ARE NOT ARBITRARY. THE NUMBERS HAVE TO DO WITH WHAT DO YOU NEED TO DO TO DO A SCIENTIFICALLY STATISTICALLY POWER STUDY TO SHOW THAT THIS PROCEDURE ADDED ONTO THE STANDARD SURGICAL MANAGEMENT ADDS VALUE AND IT DOESN'T CAUSE HARM. >> I'LL ALSO MAKE ONE COMMENT HERE, WHICH IS ONE OF THE THINGS YOU HAVEN'T MENTIONED, YOU'RE TALKING ABOUT AN EXISTING DRUG. IF THAT DRUG LABEL DOES NOT CALL OUT AN EXPLICIT DEVICE, THE RULES ARE TOTALLY DIFFERENT. IF THE DRUG LABEL SAYS, LIKE CYSVIEW DOES, IT SAYS YOU WILL USE THIS WITH KARL STORZ, BLAH, BLAH, BLAH, THE ONLY THING YOU CAN DO IS GO TO THE OWNER OF CYSVIEW AND SAY I HAVE ONE TUBE, CAN YOU WORK WITH MINE AND WHAT DO WE NEED TO DO? BUT IF IT DOESN'T CALL IT OUT, THEN IF YOUR DEVICE CAN BE CLEARED FOR THE SAME ENGINEERING CHARACTERISTICS, YOUR DEVICE IS CLEARED. >> I'LL ASK MY QUESTION VERY QUICKLY BECAUSE IT TIES IN TO EVERYONE'S COMMENTS. BACK TO OUR OLD FRIEND ICG. JONATHAN SORGER. WE KNOW THE HISTORY. SAY THOUSANDS OF SURGEONS START USING ICG OFF LABEL IN A MANNER WHICH IS NOT APPROVED, SAY THE NCC GUIDELINES START RECOMMENDING IT BE USED IN THAT OFF LABEL MANNER. WE DO NOT MARKET, WE CANNOT MARKET THAT INDICATION. WE DO NOT OWN THE DRUG. IT PUTS THE DEVICE MAKERS IN STRANGE SITUATIONS. IF I WERE TO FILE FOR AN ANDA, IT WOULD BE ON MY SPECIFIC SYSTEM, DR. FENGLER WOULD NOT BE ABLE TO USE IT ON HIS SYSTEM, STORZ WOULD NOT BE ABLE TO USE IT ON HIS SYSTEM, IT DISBT SEEM RIGHT FOR A NONCANCER SITUATION, SAY LYMPH NODE SITUATION, WE WOULD MAKE A DEAL WITH A DRUG MAKE AND HER GET IT APPROVED FOR OUR DEVICE SPECIFICALLY BECAUSE WE ARE INVESTING MONEY. IT SEEMENTZ LIKE A WASTE OF RESOURCES TO ME, BUT IS THAT CORRECT? >> WE HAVE AN EXPERT IN COMBINATION PRODUCTS, BUT MY PRELIMINARY GUESS WOULD BE YES, THAT THAT COULD BE A COMMERCIAL INCENTIVE FOR MAKING THAT WORK, FOR RECOUPING THE INVESTMENT, BECAUSE IF THE DRUG ACQUIRES A NEW INDICATION, TO GET A GENERIC PRODUCT APPROVED, YOU HAVE TO BE COMPLETELY CONSISTENT WITH THE LABEL OF THE APPROVED DRUG. SO IF YOU DO ADDITIONAL STUDIES, THEN YOU GET EXCLUSIVITY. I THINK IT'S ABOUT THREE YEARS OR SO. SO YOU COULD LEVERAGE THE DEVICE WITH THE DRUG AND BE ABLE TO MARKET IT WITH EXCLUSIVITY. BUT HOLD ONTO THAT QUESTION. WE HAVE THE EXPERT IN THE BACK OF THE ROOM, AND THERE WILL BE A FULL HOUR ON THAT TOPIC. >> IF WE DID NOT OPT TO DO THAT, WE WOULD JUST LET IT GO OFF LABEL AND NOT PROMOTE IT AND WE WOULD BE LEGALLY OKAY. >> YES. YES. >> I THINK WE'RE PRETTY MUCH OUT OF TIME. I WANT TO MAKE SURE THAT WE HAVE A COUPLE MINUTES TO CHANGE OVER. >> I JUST WANT TO THANK ALL THE PANELISTS. THANK YOU VERY MUCH. >> ARE WE READY TO CONTINUE, EBEN? GREAT. MY NAME IS BOB IN ORDER STROVMENT I'M A BRANCH CHIEF HERE IN THE CANCER -- MY NAME IS BOB NORDSTROM, I'M A BRANCH CHIEF HERE IN IMAGE GUIDED INTERVENTIONS AND MY FUNCTION HERE HAS BEEN STATED TO BE AN OVERVIEW OF DEVICES WHICH MEANS THAT I'M NOT GOING TO TELL YOU ANYTHING YOU DON'T ALREADY KNOW. LET ME REMIND OURSELVES OF WHERE WE ARE. WE'RE TALKING TODAY ABOUT THE INTERSECTION OF TWO PARTICULAR TECHNOLOGIES. WE HAVE THE DEVICES, OF COURSE, AND WE ARE TALKING ALSO ABOUT THE AGENTS. THE NEXT FEW MINUTES WILL BE TAKEN UP WITH LOOKING AT THE DEVICES THEMSELVES AND SOME OF THE THINGS THAT ARE GOING ON INSIDE THOSE DEVICES. LET ME JUST REMIND US THAT WHAT WE'RE TALKING ABOUT ARE THOSE THINGS THAT AUGMENT THE VISION DURING SURGERY. WHAT DO WE MEAN BY THAT? WELL, THERE ARE TWO BASIC AREAS THAT COME TO MIND. FIRST OF ALL IS OF COURSE EXPANDING THE WAVELENGTH DOMAIN OF VISIBLE IMAGING, AND PRIMARILY THESE DEVICES ARE GOING THROUGH TO THE NEAR INFRARED. THERE'S A NUMBER OF ADVANTAGES OF THAT, PRIMARILY BECAUSE IT INCREASES THE DEPTH OF PENETRATION WITHIN TISSUE. BUT THERE'S ALSO ANOTHER DIMENSION THAT THESE DEVICES ARE OFFERING AND THAT IS TO INCREASE THE CONTRAST AMONG DIFFERENT TISSUE TYPES, AND WE'VE LOOKED ALREADY, WHAT MIKE SHOWED US WAS SOME AUGMENTATION OF TUMORS AND THAT SORT OF THING. FLUORESCENCE IS THE PRIMARY MODE FOR DOING THAT, AND I REMIND US THAT WE DO HAVE EXOGENOUS AS WELL AS ENDOGENOUS OPPORTUNITIES THERE WITH FLUORESCENCE. BASICALLY WITH THE TARGETED DYES AND FLOOR FORS. WE -- AND FLUOROPH ORES. WE ALSO HAVE THE OPPORTUNITY TO DO BOTH. WE'VE SEEN SOME NEAR INFRARED FLUORESCENCE IMAGING OCCUPIES BOTH THESE STAGES IN WHAT THE DEVICES DO. A COUPLE DIFFERENT KINDS OF DEVICES. EVERYBODY HAS BEEN PUTTING UP THEIR DEVICES ON THE SCREEN, SO I WILL GO AHEAD AND DO THE SAME THING. THEY CAN BE AS SIMPLE AS FILTERED EYE LOUPES WITH SPECIALTY LAMPS IN THE SURGICAL SUITE. THESE ARE OFTEN OVERLOOKED AS DEVICES BUT THEY ARE. WE HAVE LAPAROSCOPIC DEVICES AS UP AND COMING AREA. I HAD TO INCLUDE COLPOSCOPES AND THOSE SORTS OF THINGS BECAUSE THE DEVICE OVER THERE AT THE FAR END IS THE ONE THAT I HELPED TO CREATE A LONG TIME AGO AND ONE OF THE THINGS THAT PAULA MENTIONED IS THAT THESE DEVICES ARE ALL BECOMING ROBOTIC IN THEIR FUNCTION. I FIND THIS WAS A VERY USEFUL REFERENCE SEVERAL YEARS AGO AND I KEEP IT SORT OF ON HAND TO KIND OF REMIND MYSELF OF WHAT'S GOING ON IN THE DEVICE AREA. AND IT OFFERS A NUMBER OF OTHER OPPORTUNITIES. YOU CAN SEE A NUMBER OF THESE DEVICES THAT ARE AVAILABLE IN THE SURGICAL SUITE. IF WE START TO UNPACK WHAT'S IN THESE DEVICES, YOU SEE THAT EVERYTHING FALLS INTO BASIC CATEGORIES. THERE'S ALWAYS A LIGHT SOURCE OF SOME KIND THAT CAN BE ANYTHING FROM AN LED TO A LASER, THERE'S DETECTORS INVOLVED IN EVERYTHING FROM PHOTOADIODES TO VERY COMPLEX PMT'S AND THERE'S ALWAYS SOME SORT OF OPTICAL TRAIN THAT GEFTSZ THE LIGHT FROM POINT A TO POINT B AND BACK AGAIN SO THOSE ARE THE KINDS OF THINGS WE'RE TALKING ABOUT WHEN WE'RE UNPACKING THESE DEVICES THE SELECTION OF COURSE IF YOU'RE A DEVICE MANUFACTURER LIKE I USED TO BE, THE SELECTION OF THESE DEVICES DEPENDS ON THE MISSION OF THE OPTICAL DEVICE ITSELF AND IF WE LOOK CONVERSELY OF COURSE THE IMAGING AGENT THAT YOU SELECT, IF YOU'RE GOING TO DO IT THAT WAY, HAS TO BE COMPATIBLE WITH ALL OF THE CHARACTERISTICS IN THE DEVICE. NOW, A COUPLE OF THESE DEVICES ARE INDICATED HERE AND THE SMALL PRINT IS THERE TO SHOW YOU THAT THESE MANUFACTURERS TYPICALLY GIVE YOU PARAMETERS SUCH AS THE EXCITATION WAVELENGTH, IF IT'S FLUORESCENCE, THEY TELL YOU FIELD OF VIEW, THEY TELL YOU ALL SORTS OF VERY INTERESTING THINGS, WHAT THEY DON'T TELL YOU IN THESE SORTS OF ARTICLES IS THE PARTICULAR AGENT THAT THEY'VE SELECTED TO USE IF THEY HAVE ONE SELECTED. BUT IF YOU WANT TO SELECT ONE, AN AGENT, THEN YOU LOOK AT THE PARAMETERS OF THE DEVICE AND SEE IF THAT AGENT WOULD BE APPROPRIATE. THESE PARTICULAR DEVICES ARE ONES THAT I SINGLED OUT THAT ACTUALLY CALL ON ICG AS A FLUORESCENT INDICATOR. SO THEY HAVE SPECIFIED THOSE. NOW, IF WE'RE UNPACKING THE DEVICE AND LOOKING INSIDE, TYPICALLY THERE'S TWO STYLES OF DEVICE THAT WE HAVE TO LOOK AT. THERE ARE THOSE THAT I CALL DUAL CHANNEL DEVICES, THAT IS, THE TRANSMISSION FEATURES OF THE DEVICE ARE COMPLETELY SEPARATE FROM THE RECEPTION, AND I JUST INDICATE HERE VERY QUICKLY A SOURCE THAT SOMEHOW IS COLLECTED, THE OPTICS ARE COLLECTED, SENT OVER TO THE TARGET, IT MAY BE A TISSUE OF SOME KIND, AND THEN ON A COMPLETELY SEPARATE CHANNEL, THE RETURN LIGHT GETS BACK TO THE DETECTOR OF SOME SORT. NOW, THAT HAS SOME ADVANTAGES, THERE'S VERY LITTLE, THERE'S NO CROSSTALK BETWEEN THE TRANSMISSION AND THE RECEPTION AND THAT'S VERY CONVENIENT FOR USING LESS EXPENSIVE DETECTORS AND THAT SORT OF THING. AND THE OPTICS CAN BE TAILORED FOR THE SPECIFIC FUNCTION, THAT IS, FOR THE TRANSMISSION FUNCTION OR FOR THE RECEPTION FUNCTION. THERE ARE SOME DISADVANTAGES TO THIS. OFTENTIMES YOU'RE USING DUPLICATE OPTICAL COMPONENTS IN THE DEVICE, SO THERE MAY BE SOME INCREASED COST. AND THE DEVICE SIZE MIGHT SUFFER SOMEWHAT BECAUSE OF THE ADDED COMPONENTS THAT ARE INSIDE THESE DEVICES. BUT AGAIN, THE SELECTION OF THE AGENTS THAT WOULD BE USED FOR A PARTICULAR DEVICE DEPENDS ON THE OPTICAL PROPERTIES THAT YOU SELECTED BOTH IN TRANSMISSION AND IN RECEPTION. AND AGAIN, CONVERSELY, THE SELECTION OF THE DEVICE COMPONENT DEPENDS ON WHAT YOUR FINAL OPPORTUNITY IS. IF WE GO TO A SINGLE, A COMMON CHANNEL DEVICE, WE HAVE TO FIGURE OUT SOME WAY OF COMPACTING ALL THOSE OPTICAL COMPONENTS SO THAT THEY SERVE THE FUNCTION OF BOTH TRANSMISSION AND RECEPTION, WE HAVE TO COMBINE THE BEAMS TOGETHER, WE HAVE TO USE COMMON PATH OPTICS TO GET TO AND FROM THE TARGET, AND THESE HAVE OF COURSE A NUMBER OF ADVANTAGES AND DISADVANTAGES AS WELL. IT REDUCES THE SIZE PERHAPS AND THERE'S A POSSIBLE COST SAVINGS. SOMETIMES THE POSSIBILITY OF PUTTING BOTH THE TRANSMISSION AND THE RECEIVER OPTICS TOGETHER IS MORE EXPENSIVE THAN USING THE TWO COMPONENTS SEPARATELY. I SHOW A SIMPLE BEAM SPLITTER HERE AS PUTTING THEM TOGETHER, BUT THERE'S AN AWFUL LOT OF CREATIVE WAYS OF DOING THAT. DISADVANTAGE IS OF COURSE ONE OF THE BIGGEST DISADVANTAGES IS THERE'S GOING TO BE CROSS-TALK BETWEEN THE TRANSMISSION, THE SOURCE AND THE DETECTOR IF YOU'RE NOT CAREFUL. THIS IS WHERE FILTER MANUFACTURERS MAKING OD5'S AND GREATER OPTICS MAKE THEIR MONEY BECAUSE WE'VE TRIED TO BLOCK THE TRANSMISSION FROM THE RECEPTION AND THAT SORT OF THING. BUT IT CAN BE AN ADVANTAGE. AND TAILORING OPTICS, IF THERE'S A SEPARATE TRANSMISSION FUNCTION YOU WANT TO ILLUMINATE BROAD FIELD OF VIEW BUT YOU WANT TO COLLECT A VERY NARROW AREA, IT'S VERY DIFFICULT TO DO THAT TOGETHER. BUT THESE ARE THE KINDS OF THINGS THAT PLAY INTO THE DEVICE ITSELF AND HOW THE DEVICE WORKS. NOW, AS AN EXAMPLE OF WHAT I'M TRYING TO SAY HERE, WE'RE FAMILIAR WITH THE EXCITATION FLUORESCENCE KIND OF CHARTS. YOUR ILLUMINATION BANDWIDTH WOULD BE OVER HERE IN THE BLUE, AND YOUR EXCITATION BANDWIDTH -- I'M SORRY, YOUR RECEIVER BANDWIDTH WOULD BE OVER HERE IN THE RED. IF WE'RE USING COMMON OPTICS, OF COURSE, YOU HAVE TO COVER BOTH OF THESE AT THE SAME TIME AND YOU HAVE TO FIGURE OUT HOW TO ILLUMINATE, AND THAT CAN CAUSE PROBLEMS WHEN YOU'RE LOOKING AT HOW, SAY, AN AGENT MIGHT WORK IN THIS WHOLE SCHEME OF THINGS. SO LET ME JUST CONCLUDE REAL QUICKLY BY SAYING THAT THESE DEVICES ARE MEANT TO EXPAND OUR VISUAL FIELD, OUR VISUAL WAVELENGTH FIELD OR TO AUGMENT CONTRAST AND EXOGENOUS AGENTS OF COURSE ARE NEEDED FOR THAT. I WANT TO JUST END BY SAYING THAT THERE ARE POSSIBILITIES WHERE WE CAN USE NOT ONLY THE OPTICAL METHODS BUT WE CAN USE OTHER METHODS AND WE TALKED ABOUT OTHER METHODS, MR, CT, WE CAN COMBINE THOSE VERY SUCCESSFULLY INTO IMAGING SUITES THAT MAY GIVE US SOME ADDED OPPORTUNITIES. AND ALSO I WANT TO END BY REMINDING US THAT WE CAN HAVE VERY ACTIVE OPTICAL OPPORTUNITIES THAT ARE COMPLETELY WITHOUT THE EXOGENOUS TISSUES. WE JUST FINISHED A WHITE PAPER AND A COUPLE OF US FINISHED THIS WHITE PAPER ON LABEL-FREE OPTICAL TECHNIQUES, AND I JUST WANT TO REMIND YOU THAT THOSE SORTS OF THINGS EXIST IN THIS WORLD AS WELL. AND WITH THAT, I'M GOING TO TURN IT OVER TO NEIL BECAUSE HE'S REALLY THE MAIN ATTRACTION FOR THIS PART OF THE TALK. >> Neil Ogden, MS: GOOD MORNING. THANK YOU FOR THIS OPPORTUNITY. I WOULD LIKE TO SAY IT'S NICE TO SEE MANY OF YOU AGAIN. I MET A LOT OF YOU IN 2013 AT THE WORLD MOLECULAR IMAGING CONGRESS AND I MET SOME OF YOU AT THE NATIONAL INSTITUTES OF SCANNERS AND TECHNOLOGY MEETING A COUPLE YEARS AGO, TALKING ABOUT IMAGING AND TRYING TO GET EVERYBODY TO WORK ON THE SAME PAGES. SO I'VE BEEN WORKING WITH THE FDA FOR ABOUT 25 YEARS NOW. IT SAYS DME BECAUSE I'M A BIOMEDICAL ENGINEER BY TRAINING AND I'M MOST COMFORTABLE WITH ENGINEERING TYPE ANALYSES AND TECHNICAL COMPARISONS BUT I'VE BEEN DOING CLINICAL TRIAL DEVELOPMENT AND PROTOCOL DEVELOPMENT AND ANALYSIS FOR THOSE 25 YEARS, SO I'M PRETTY COMFORTABLE WITH THAT TOO. CON CONFLICTS. I DON'T HAVE ANY. DISCLAIMER. I DON'T SET POLICY FOR THE AGENCY. I WORK WITH THE AGENCY, AND WE WORK WITH DEVELOPING POLICIES WHEN NECESSARY. SO WHAT HAVE WE DONE? SO THIS IS MY SLIDE I LIKE TO SHOW ABOUT WHAT THE FDA LOOKS LIKE FROM THE OUTSIDE. YOU CAN SORT OF SEE THINGS GOING ON IN DIFFERENT ROOMS, BUT IT'S NOT REALLY CLEAR. SO THIS IS WHY WE COME OUT AND TRY TO TALK TO FOLKS AND EXPLAIN WHAT WE'RE DOING. SO THERE'S A BUNCH OF CENTERS, AND I'M FROM THE CENTER FOR DEVICES AND RADIOLOGIC HEALTH AND LOU MARZELLA AND OTHERS ARE FROM THE CENTER FOR DEVICES AND THERE ARE SOME FOLKS FROM THE CENTER FOR BIOLOGICS, AND WE HAVE THIS NEW COMBINATION PRODUCTS SYSTEM WHERE WE COLLABORATE WHERE A LEAD CENTER IS IDENTIFIED AND THEN TEAMS ARE BUILT ACROSS THE CENTERS TO ADDRESS THE ISSUES OF THE COMBINATION PRODUCT ASK WE REVIEW THEM TOGETHER. SO IT'S AN EVOLVING PROCESS. WE'RE LEARNING AS WE GO AS WELL. SO I'LL SHOW SOME PICTURES. WE TALKED A LOT ABOUT ICG. THERE IS A DEVICE THAT'S INDICATED FOR USE FOR LOOKING AT VASCULAR FLOW IN THE HANDS. SO IT'S NOT GERMANE PARTICULARLY FOR TUMORS, BUT IT IS ONE OF THE CLEARANCES THAT ICG HAS. SO THIS IS JUST SOME IMAGING OF SOME MUSCLE TISSUE. THIS IS SOME HEART CELLS. THIS IS MORE OF INTEREST, THIS IS A BRAIN TUMOR CASE WITH A FLUORESCING AGENT IN IT, AND THEN OF COURSE THE NEWER STUFF IS ANTIBODIES. SO I WOULD LIKE TO TALK ABOUT, WE'VE HEARD A LOT, AND THANK YOU TO PAULA AND TO BETSY AND YOU FOLKS, I REALLY APPRECIATE THE EARLIER TALKS, WE'VE HEARD A LOT ABOUT ICG CLEARANCES ASK DEVICES AND I'LL JUST RUN THROUGH -- AND DEVICES AND I'LL JUST RUN THROUGH SEVERAL OF THEM. THEY STARTED OFF WITH INTRAOPERATIVE VISUAL ASSESSMENT OF CORONARY ARE BYPASS GRAPHS USING ICG, THEY WENT ON TO SAY BLOOD FLOW AND RELATED TISSUE PERFUSION DURING CARDIOVASCULAR PROCEDURES SO IT GOT A LITTLE BROADER. THEN WE WENT ON TO ADJUNCTIVE METHOD FOR EVALUATION OF TISSUE PERFUSION AND RELATED TISSUE TRANSFER CIRCULATION IN TISSUE AND PREFLAPS, USING IN MICROAND RECONSTRUCTIVE SURGERY. THEN WE WENT ON FOR VISUAL ASSESSMENT OF BLOOD FLOW, AND INDICATIVE, RELATED TO TISSUE TRANSFER CIRCULATION IN IMPLANTED AND TO VISUALIZE BLOOD FLOW INDICATIVE OF PERFUSION OF DONOR IMPLANT PRIOR TO TRANSPLANTATION AND TO PROVIDE INDICATION OF ORGAN FUNCTION AFTER TRANSPLANTATION. AGAIN, IT'S GETTING MORE SPECIFIC. THESE ARE COMBINATION PRODUCTS. SO THIS LABELING GOES WITH THE DEVICE PLUS ICG. THIS LABELING DOES NOT ALTER THE ICG LABELING. SO I'LL TALK A LITTLE BIT MORE ABOUT THAT LATER. DR. LOVE WILL TALK ABOUT IT MORE AS WELL. SHE'S MORE OF AN EXPERT IN THAT. AS THOSE OF US ENGAGE IN THIS BECOME MORE EXPERTISE BECAUSE WE HAVE TO DEAL WITH IT FREQUENTLY AND MORE FREQUENTLY. OTHER INDICATIONS FOR COMBINATION PRODUCTS WITH ICG. VISUAL ASSESSMENT OF VESSELS, BLOOD FLOW AND RELATED TISSUE PERFUSION IN NEAR INFRARED IMAGING, DURING MINIMALLY INVASIVE SURGERY. VISUAL ASSESSMENT OF VESSELS, BLOOD FLOW AND RELATED TISSUE PERFUSION WITH NEAR INFRARED FLUORESCENCE IMAGING DURING MINIMALLY INVASIVE ROBOTIC SURGERY. NOW WE HAVE THE ROBOTS INVOLVED AND THEY'RE USING ICG AS WELL AND WE HAVE A REPRESENTATIVE FROM INTUITIVE HERE. FOR USE IN DIAGNOSTIC AND OPERATIVE ARTHROSCOPIC AND ENDOSCOPIC PROCEDURES TO PROVIDE ILLUMINATION AND VISUALIZATION OF AN INTERIOR CAVITY OF THE BODY THROUGH EITHER A NATURAL OR SURGICAL OPENING. NOW YOU HAVE LAPAROSCOPY, ENDOSCOPY, THIS SYSTEM CAN BE USED IN COMBINATION WITH ICG FOR THOSE VARIOUS THINGS. MOVING ON, WE HAVE INTENDED TO ALLOW CONFOCAL LASER IMAGING OF THE INTERNAL MICROSTRUCTURE OF TISSUES IN THE ANATOMICAL TRACT, ENABLES SURGEONS TO PERFORM MINIMALLY INVASIVE SURGERY USING STANDARD ENDOSCOPIC VISIBLE LIGHT AS WELL AS VISUAL ASSESSMENT OF VESSELS, BLOOD FLOW AND RELATED TISSUE PERFUSION. NOW YOU HAVE CONFOCAL WITH ANATOMICAL TRACT. ANOTHER USE FOR A COMBINATION PRODUCTS. NOW WE HAVE THE DA VINCI COMBINATION USE, TALKING ABOUT VISUAL ASSESSMENT OF VESSELS, BLOOD FLOW, RELATED TISSUE PERFUSION, AT LEAST IN MAJOR EXTRAHEPATIC BILE DUCTS. YOU CAN SEE THERE'S A VARIETY OF INDICATIONS FOR USE FOR COMBINATION PRODUCTS. WHEN THESE DEVICES CAME IN, THESE COMBINATION PRODUCTS CAME IN, WE CONTACTED OUR CO-WORKERS IN THE CENTER FOR DRUGS AND SAID DO YOU HAVE ANY ISSUES WITH THIS SYSTEM USING THE ICG IN THIS MANNER, SINCE WE ALL KNOW ICG HAS BEEN AROUND FOR 50 YEARS, THEY WERE USING DOSING RECOMMENDATIONS THAT WERE THE SAME AS THE APPROVAL FOR THE ICG, SO THE CENTER FOR DRUGS CONSULT CAME BACK AND SAID THEY HAVE NO SAFETY ISSUES, IT'S ICG, THEY'RE USING THE DOSING ON LABEL, NOT AN ISSUE. SO THOSE DEVICES WENT OUT AS A COMBINATION PACKAGE AND HAVE BEEN CLEARED THROUGH THE 510(K) PROCESS. WHAT DO WE WANT TO DO? WE WANT TO TRY TO HELP FOLKS GET THROUGH THE REGULATORY PATHWAY, GET THEIR DEVICES TRANSLATED FROM THE BENCH TO THE CLINIC, THAT'S WHY WE'RE HERE. WE'RE INTERESTED IN THAT. WE WANT TO TRY TO HELP YOU THROUGH THE PROCESS. SO THESE ARE SOME OF THE QUESTIONS THAT I WAS ASKED TO TRY TO ANSWER. SO I WILL TRY TO WALK THROUGH SOME OF THESE, NOT SPECIFICALLY ONE AT A TIME, BUT YOU CAN SEE WHAT SOME OF THE INTERESTS ARE. SO WHAT IMAGING CLINICAL STRATEGIES? WHAT INFORMATION WE WANT REALLY DEPENDS ON WHAT YOU WANT TO DO. SO YOU WANT A GENERAL VISUALIZATION ALONE, WE'RE NOT REALLY FOCUSING ON THAT HERE TODAY. SPECIFIC DISEASE DETECTION. SO IS THAT YOU'RE GOING TO DIAGNOSE A DISEASE OR ARE YOU GOING TO JUST IDENTIFY SPECIFIC CELL TYPES FOR INTRAOPERATIVE PROCEDURE? AND TYPICALLY THESE ARE COMBINATION PRODUCTS, BUT WE HAVE HAD DEVICES THAT ARE INTERESTED IN LOOKING AT AUTOFLUORESCENCE SO THERE IS NO COMBINATION WITH THOSE DEVICES. SO AGAIN, THE DEVICE INDICATION FOR THE IMAGING SPECIFIC DISEASES. SO THE INDICATION FOR USE FOR THE SYSTEM IS GOING TO REALLY DRIVE THE INFORMATIONAL NEEDS. AGAIN, IF YOU WANT TO SAY THIS COMBINATION PRODUCT IS FOR IDENTIFYING AND EXCISING GLIAL BLASTOMAS IN BRAIN SURGERY, THAT'S VERY SPECIFIC, WE WOULD WANT TO SEE INFORMATION SPECIFIC FOR USE IN THAT. IF YOU WANT TO SAY THE SYSTEM IS SPECIFIC FOR IDENTIFYING BLOOD FLOW, THAT'S A DIFFERENT DATASET WE'RE INTERESTED IN SEEING. IT REALLY DEPENDS ON WHAT YOU WANT TO DO AND HOW YOU WANT TO DEVELOP YOUR PRODUCT. SO AGAIN, I'M TALKING ABOUT THE SAME SORT OF THING. IS IT MARGIN DETECTION? WHEN IS THAT MARGIN DETECTION -- WHEN IS WHERE IS MARGIN DETECTION OCCURRING? IS IT PREOPERATIVELY, IS IT INTRAOPERATIVELY, IS IT DURING THE OPERATION BUT AFTER EXCISION, CHECKING FOR MARGINS, IS IT POSTOP, CHECKING FOR MARGINS, DID YOU GET IT ALL? SO DEPENDING ON IF YOU WANT TO SPECIFICALLY IDENTIFY HOW TO USE YOUR SYSTEM, THAT WILL DRIVE THE DATA REQUIREMENTS THAT WE'RE INTERESTED IN. AGAIN, AS I MENTIONED BEFORE, THANKS FOR THE QUESTION, IS IT GOING TO CHANGE THE PRACTICE OF MEDICINE? IF IT IS, WHAT EVIDENCE DO YOU HAVE THAT THAT'S A SAFE AND EFFECTIVE THING TO DO? SO AGAIN, COMBINATION PRODUCTS, THESE ARE ONE OF OUR MOST CHALLENGING REVIEWS JUST BECAUSE OF THE LAYERS OF ISSUES THAT WE HAVE TO DEAL WITH. WE HAVE TO DEAL WITH THE DRUG SIDE, WE HAVE TO DEAL WITH THE DEVICE SIDE. TYPICALLY THE DEVICE PART OF THE REVIEW IS THE SIMPLER JUST BECAUSE I THINK THAT WAY, I'M AN ENGINEER, I'M FAMILIAR WITH DEVICES, HOW THEY WORK, HOW TO ASSESS THEM, AND I RELY ON OUR FOLKS IN DRUGS FOR REVIEWING THE DRUG SIDE. SO AGAIN, IS THERE A PREDICATE DEVICE? IT MAKES THE TECHNICAL COMPARISON EASIER BECAUSE WE ALREADY HAVE A SYSTEM WE'VE REVIEWED AND WE'VE SAID IS OKAY, IS READY TO GO TO MARKET, IT'S SUBSTANTIALLY EQUIVALENT, IT'S SAFE AND EFFECTIVE. SO WE CAN BORROW FROM THAT PREVIOUS EXPERIENCE AND LEVERAGE THAT INFORMATION TO ASSESS AND EVALUATE NEW TECHNOLOGY. WE DON'T WANT TO REINVENT THE WHEEL IF WE DON'T HAVE TO. IT'S A LOT OF WORK. REGULATORY PATHWAY EXPERIENCE. SO ESTABLISHED DRUG. PAULA ALREADY WENT OVER A LOT OF THIS, SO THERE'S NOT MUCH NEW HERE. I DID MENTION CO-PACKAGING. DR. LOVE CAN TALK MORE ABOUT THAT. TYPICALLY WHAT THAT IS IS WHEN YOU HAVE A COMBINATION PRODUCT AND YOU HAVE AN APPROVED DRUG AND THE COMBINATION PRODUCT IS INDICATED FOR USE IN A WAY THAT IS SORT OF NOT IN THE DRUG APPROVAL. THE EXAMPLES I GAVE EARLIER. ICG IS NOT APPROVED FOR LOOKING AT THOSE THINGS THAT WERE ON THOSE INDICATIONS FOR USE. BUT THE COMBINATION PRODUCTS CAN BE IF IT'S CO-PACKAGED, AND CO-PACKAGING MEANS THAT THE ORIGINAL DRUG LABEL GOES INTO THE LABELING FOR THE SYSTEM AND SO THE SYSTEM ITSELF, THE CO-PACKAGE, IS NOT RAE LAID ON THE DRUG. MY SIMPLE WAY OF NOT EXPLAINING IT. DR. LOVE CAN EXPLAIN IT BETTER PROBABLY. IF WE'RE NOT SURE WHO SHOULD BE LEAD CENTER, THERE'S THE REQUEST FOR DESIGNATION. THIS IS REVIEWED BY OUR OFFICE OF COMBINATION PRODUCTS, AND WHAT HAPPENS IS AN RFD COMES INTO THE AGENCY, IT GOES TO THE OFFICE OF COMBINATION PRODUCTS, THEY WILL ASSIGN LEGAL REVIEWERS AND THEN THEY WILL DECIDE WHICH CENTERS NEED TO BE CONSULTED ON WHICH CENTER NEEDS TO BE THE PRIMARY MODE OF ACTION. TYPICALLY THEY'LL SENT OUT AND IT WILL BE FUNNELED TO THE EXPERT TITION IN THAT AREA, THEY'LL RIGHT WHY A REVIEW OF WHAT THEY THING IS THE EXPERIENCE. THAT GOES BACK TO THE OFFICE OF COMBINATION PRODUCTS AND THEN MAKE A DETERMINATION OF WHO THE LEAD CENTER IS. SO HERE IS THEY HAVE A GUIDANCE DOCUMENT, HERE IS THE WEB ADDRESS, THAT'S HOW YOU FILE AN RFD. SO THIS GETS TO EBEN'S QUESTION EARLIER. HE SAID SO THERE IS A BODY OF EXPERIENCE AND SOMEBODY HAS BEEN DOING ICG, TUMOR EXCISION FOR FIVE YEARS, THEY HAVE 500 CASES S THAT ENOUGH EVIDENCE TO GET A CLEAR ANSWER AND APPROVAL? SO I DON'T KNOW. THE DEVIL IS IN THE DETAILS AS ALWAYS. BUT WE NEED INFORMATION TO MAKE OUR DECISIONS, SO WHAT DRIVES OUR THINGS, DEVICE LABELING, PERFORMANCE SPECIFICATIONS, VALID SCIENTIFIC EVIDENCE AND A CASE SERIES WOULD BE VALID SCIENTIFIC EVIDENCE. SO WE'RE CERTAINLY WILLING TO LOOK AT THAT. IF YOU CAN MATCH THE PATIENTS AND THERE'S ENOUGH BASIC SCIENCE THERE TO SAY THIS IS ENOUGH BODY OF EVIDENCE TO MOVE FORWARD, THEN YOU CAN DO THAT. BUT IF THERE'S NOT, WE MAY HAVE ADDITIONAL QUESTIONS. WE WOULD LIKE TO KNOW THE TISSUE EFFECTS OF YOUR COMBINATION PRODUCT. WE WOULD LIKE TO KNOW THE MECHANISM OF ACTION THAT'S NOT NECESSARY BUT IT CERTAINLY HELPS US UNDERSTAND AND REVIEW THE PRODUCTS, AND CERTAINLY CLINICAL OUTCOMES IS IMPORTANT. SO THIS IS JUST A REGULATION THAT TALKS ABOUT VALID SCIENTIFIC EVIDENCE AND IT'S ANYTHING FROM WELL CONTROLLED, CONCURRENT CONTROLLED STUDIES, ALL THE WAY DOWN TO SIGNIFICANT HUMAN EXPERIENCE WITH A MARKETED DEVICE AND SO WE WILL ACCEPT ALL OF THAT AND WE'LL REVIEW IT. WE PREFER TO HAVE WELL CONTROLLED INVESTIGATIONS, BUT WE WILL CERTAINLY ACCEPT OTHER THINGS. JUST AS ANOTHER POINT, SO PHANTOMS. I MENTIONED SOME PREVIOUS MEETINGS WHERE FAN ATOMS WERE DEFINITELY DISCUSSED. I THINK FROM AN ENGINEERING POINT OF VIEW, I THINK PHANTOMS WOULD BE AN IMPORTANT WAY TO MOVE FORWARD AS FAR AS UNDERSTANDING PERFORMANCE OF DEVICES AND ALSO HAVING COMPARISON BETWEEN DEVICES. IF WE HAD A VALIDATED PHANTOM FOR OPTICAL IMAGING, THAT WOULD BE GREAT BECAUSE THE AGENCY COULD USE IT, INDUSTRY COULD USE IT TO COMPARE THEIR DEVICE IS GET PERFORMANCE DATA AND JOSH PFEFER WILL BE SETTING ON OUR UNANIMOUSLY A FEW MINUTES AND HE'S AN EXPERT ON PHANTOM DEVELOPMENT AND HE'S HERE. SO I MENTIONED I WAS AT A ARE MEETING AND AGAIN STANDARDIZATION WOULD BE NICE AS WELL. IT'S ANOTHER TOOL WE COULD ALL USE TO HELP US UNDERSTAND IMAGING, IMAGING QUAWMENT. RIGHT NOW -- IMAGING QUALITY. RIGHT NOW THERE'S STILL A WIDE VARIETY OF IMAGES COMING FORWARD AND IT'S ALWAYS A CHALLENGE TO TRY TO COMPARE APPLES AND ORANGES, SO IT WOULD BE NICE TO HAVE IMAGING CALIBRATION AND PERFORMANCE EVALUATION, UNDERSTANDING IMAGE QUALITIES, NUMBER OF PIXELS, COLOR RENDERING, OPTICAL IMAGE SIZE, RESOLUTION, CONTRAST, PRECISION, WHAT KIND OF SYSTEM ARE YOU USE TO GO CAPTURE THE IMAGE. THAT CAN VARY AS WELL, AND WHAT KIND OF IMAGES ARE THEY, AND ALSO THE IMAGE CREATION. HAS IT BEEN PHOTO SHOPPED OR ALTERED IN ANY WAY AND IF SO DID THAT MAKE THE INFORMATION LESS VALUABLE IN SOME WAY OR DID IT MAKE IT MORE VALUABLE? IT COULD GO EITHER DIRECTION. BUT WE NEED TO UNDERSTAND THAT AND ALL BE ON THE SAME PAGE SO WE'RE TALKING THE SAME LANGUAGE. I'M NOT GOING TO GO OVER THE SUMMARY COMMENTS. THAT'S PRETTY MUCH WHAT I WANTED TO SAY AND AGAIN THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> MAYBE WE SHOULD HAVE OUR PANEL COME UP AGAIN AND PROBABLY INTRODUCE THEMSELVES AGAIN JUST TO MAKE SURE THAT THE FOLKS VIEWING THE WEBCAST AS WELL AS FOR FOLKS THAT HAVE JOINED US. DR. POGUE WILL BE MODERATING AS WELL. IF YOU ARE GOING TO BE PRESENTING LATER IN THE DAY, WE ARE ASKING FOLKS TO ADD THEIR SLIDES TO THE COMPUTER AT THE BREAK RATHER THAN BRING YOUR LAPTOPS UP JUST TO REDUCE THE TIME. ALSO WE'RE INTERESTED IN CAPTURING THE SLIDES AND MAKING THEM PUBLICLY AVAILABLE. WHILE WE'RE GETTING SET UP, MAYBE, LAURA, YOU WANT TO START BY INTRODUCING YOURSELF, THEN WE'LL GO JACOB. >> I'M LAURA MARCU FROM UC DAVIS, I'M A PROFESSOR IN BIOMEDICAL ENGINEERING AND I HAVE A JOINT APPOINTMENT IN NEUROLOGICAL SURGERY AND MY WORK IS RELATED TO LIFETIME TECHNIQUES AND INTRAOPERATIVE VARIATION OF SURGICAL MARGINS. JUST ONE COMPONENT. I'M COMING FROM THE WORLD OF DEVICE WITH NO DRUG, LABEL-FREE. >> HI. I'M AN GILLENWATER FROM MD ANDERSON, I'M WORK WITH AGENTS FOR ORAL CANCER SP PRECANCER. >> I'M JOHN FRANGIONI, I WAS AT HARVARD FOR OVER 30 YEARS, AND INTERESTS IN GUIDED SURGERIES AND FLUORESCENCE. >> I SPOKE EARLIER. -- FROM MUNICH. >> I'M BOB NORDSTROM AND MY REASON FOR BEING HERE REALLY IS BECAUSE MY PAST LIFE IN INDUSTRY, I WENT THROUGH THE PMA APPROVAL PROCESS SEVERAL YEARS AGO, SO I'VE SEEN WHAT IT'S LIKE >> CHRIS CONTAG, PROFESSOR OF PEDIATRICS AT STANFORD STANFORD UNIVERSITY. WE DEVELOP INSTRUMENTS, IMAGING AGENTS AND STUDY THE BIOLOGY AND ALE NUMBER OF OUR PATENTS HAVE BEEN LICENSED AT STANFORD AND OTHERS FOR COMMERCIALIZATION. >> NEIL OGDEN, BRANCH CHIEF, GENERAL SURGERY DEVICES BRANCH 1. >> JOSH PFEFER, LABORATORY LEADER FOR OPTICAL DEVICES IN CDRH AND MY GROUP PROVIDES SUPPORT FOR FOLKS LIKE NEIL AND HIS GROUP AND OTHER REGULATORY STAFF REVIEWERS AND OTHER DIVISIONS, FOR EXAMPLE, FOLKS WHO LOOK AT ORAL CANCER AND OB-GYN AND THE CYSVIEW DEVICE AND CYSVIEW AND PDP DEVICE. MY LAB ALSO PERFORMS RESEARCH ON THINGS LIKE PHANTOMS AND LOOKING AT THE MECHANISMS OF THESE TECHNOLOGIES AS WELL AS SAFETY ISSUES. >> MY NAME IS BRIAN POGUE. I'M AT DARTMOUTH COLLEGE IN NEW HAMPSHIRE, I'M WE LOOK AT CLINICAL TRIALS FOR FLUORESCENCE GUIDED SURGERY. THIS HAS BEEN TERRIFIC. I THINK WE'VE COVERED A LOT OF THE HARDWARE ISSUES ALREADY. THIS PANEL WILL DISCUSS THAT. ONE ISSUE THAT COMES UP A LOT AND HAS BEEN MENTIONED IS CAN WE DECOUPLE DEVICES THERE PAGHTSZ USING -- DECOUPLE DEVICES FROM AGENTS USING PET AND CT, AS GUIDE PEOPLE, IT WILL HELP ADVANCE THE FIELD BECAUSE IT WOULD ALLOW US TO EXPLORE NEW AGENTS AND DECOUPLE THEM. SO THAT'S I THINK A VERY COMMON THEME AND WE'LL DISCUSS THAT A LOT. THE ISSUE, THOUGH, AND THIS IS KIND OF THE GORILLA IN THE ROOM IN THE OPTICS WORLD, IS THAT THERE ARE ORDERS OF MAGNITUDE VARIATIONS IN SIGNAL LEVELS AND I THINK THAT IS THE ONE THING THAT IS DIFFICULT TO DRAW ANALOGY TO IN CT AND PET. THINGS LIKE WHEN YOU LOOK AT THE DEVICE VARIETY, THERE'S CONFOCAL SYSTEMS, THERE'S SURGICAL MICROSCOPY SYSTEMS, ENDOSCOPIC, LAPAROSCOPIC, THEY ACTUALLY VARY BY AT LEAST A FACTOR OF 100 IN TERMS OF THEIR FIELD SIZE. ENORMOUS DYNAMIC RANGE DIFFERENCES BETWEEN DIFFERENT TYPES OF AGENTS. VASCULAR AGENTS ARE MILLIMOLAR, TYPICALLY CONCENTRATION, ENZYMES ARE TYPICALLY MICROMOLAR CONCENTRATION, RECEPTORS NANOMOLAR, WE'RE TALKING SIX ORDER OF MAGNITUDE, THAT'S A BIG DEAL, THAT IS CERTAINLY NOT WHAT'S SEEN IN THE PET AND CT WORLD. WAVELENGTH VARIATIONS WAS MENTIONED BUT EASILY CAN CHANGE THINGS BY AN ORDER OF MAGNITUDE. PERFORMANCE WITH ROOM LIGHTS ON VERSUS NOT. IT'S A BIG DEAL, EASILY A FACTOR OF 10 BETWEEN BACKGROUND SENSITIVITY. VARIATION WITH DISTANCE CAN EASILY VARY THE INTENSITY PATTERN BY A FACTOR OF 100. RECOGNITION OF BIOLOGICAL VARIABILITY AND SPATIAL PATTERNS TO CAPTURE IS AN IMPORTANT FEATURE. DEPTH SENSING. ALMOST EVERY PANEL I'VE BEEN ON THIS CERTAINLY COMES UP THAT PHYSICIANS WOULD LIKE TO SENSE BELOW THE SURFACE. IT'S A HARD BUT ACHIEVABLE ISSUE, BUT IT LEADS YOU DOWN A DIFFERENT TECHNOLOGY PATH. THEN I THINK THE MOST IMPORTANT THING THAT WAS JUST MENTIONED IS IF WE REALLY DO WANT TO DO THIS AND RECOGNIZING ALL THESE THINGS, CAN WE COME UP WITH PERFORMANCE STANDARDS ORPHAN ATOMS THAT CAN -- STANDARDS OR FAN ATOMS THAT CAN HELP US DO THIS SO WE CAN HAVE A SET OF APPROVED DEVICES THAT DIFFERENT AGENTS COULD BE TRIED WITH? SO THAT CERTAINLY WOULD HELP ADVANCE THE FIELD IN OUR GROUP LAST SLIDE WE LOOKED AT WHAT IS THE IDEAL SYSTEM. MANY PEOPLE WANT AND NEED REALTIME OPERATION WITH WHITE LIGHT AND FLUORESCENCE OVERLAY. SEAMLESS OPERATION WITH THE ROOM LIGHTS ON. HIGH SENSITIVITY, MEANING GETTING DOWN THE MICROMOLAR AND NANOMOLAR RANGE. QUANTITATIVE OR PATTERN RECOGNITION CAPABILITIES TO REALLY AUGMENT WHAT THE SURGEON DOES. AND THEN ERG NONE MIX OF -- AND THEN ERGONOMICS OF USE, BECAUSE UNLIKE PET, CT, THESE ARE TOOLS USED IN REALTIME AND INSTANTANEOUS DECISIONS ARE MADE WITH THEM SO THE ERGONOMICS HAVE A HUGE FACTOR. DWE ALE SURVEY OF ALL THE DIFFERENT -- WE DID A SURVEY OF ALL THE DIFFERENT DEVICES OUT THERE. IT'S SURPRISING REALLY VERY FEW OR ALMOST NONE OF THE FDA APPROVED DEVICES CAN FIT THIS BILL FROM A DEVELOPER/RESEARCHER STANDPOINT SO IT SHOWS THAT THE FIELD IS REALLY IN A STATE OF FLUX RIGHT NOW. LET ME BACK UP A SECOND AND PERHAPS ASK THE PANEL I GUESS WHERE DO WE SEE THE MOST COMPELLING POTENTIAL TO DECOUPLE DEVICES AND AGENTS? DOES ANYBODY WANT TO TACKLE THAT QUESTION? JOHN, YOU'VE ALWAYS GOT -- >> I WILL JUST SAY I THINK THE STANDARD, WE AGREE THAT STANDARDS ARE VERY IMPORTANT BUT IT OPENS UP A SLIPPERY SLOPE, IN TERM OF THE CHEMISTRY, WE CAN ALTER EXCITATION WAVELENGTH AND STOKE SHIFTS IN 10 TO 20-NANOMETER INCREMENTS FROM 7 THOWN 900 SO HOW DO YOU DEVELOP A PHANTOM OR SET OF STANDARDS BECAUSE YOU CAN HAVE A FLUOROPHORE THAT EXCITES AT 690 AND EMITS AT 800 OR YOU CAN HAVE ONE THAT EXCITES AT 780 AND EMITS AT 800. I THINK IT WILL BE VERY DIFFICULT TO DEVELOP SUCH STANDARDS AND IT MAY HAVE THE OPPOSITE EFFECT OF WHAT YOU WANT WHICH IS TO CONSTRAIN THE CHEMISTRY IN SUCH A WAY THAT WOULD BE UNCOMFORTABLE. SO I THINK THAT THE POWER OF FLUORESCENCE AT LEAST IN THE CHEMISTRY MAKES IT RATHER DIFFICULT TO THINK ABOUT STANDARDS THAT COULD BE APPLIED UNIFORMLY. >> I CAN ADDRESS SOME OF THOSE ISSUES ACTUALLY. I THINK ACTUALLY IF YOU LOOK AT THE STANDARDS FOR OTHER ESTABLISHED MEDICAL IMAGING MODALITIES WHERE THEY USE CONTRAST AGENTS, THERE HAVE BEEN FAN ATOMS THAT HAVE BEEN DEVELOPED AND INCORPORATED INTO THESE GUIDANCE DOCUMENTS OR STANDARDS WHERE YOU ACTUAL HAVE A PHANTOM THAT HAS INCLUSION INSIDE IT THAT CAN BE FILLED WITH A SPECIFIC CONTRAST AGENT SO YOU CAN ACTUALLY TEST A SPECIFIC DEVICE USING A SPECIFIC CONTRAST AGENT AND SWITCH OUT THE CONTRAST AGENT IF YOU WANT TO LOOK AT MULTIPLE ONES. IT'S RELATIVELY EASY ALSO TO MAKE A SOLID PHANTOM WHERE YOU DOPE IT WITH ONE FLUOROPHORES OR ANOTHER FLUOROPHORES AND JUST SWITCH FAN ATOMS. >> MAYBE I CAN FOLLOW UP ON THAT SINCE WE STARTED WITH STANDARDIZATION AND FAN ATOMS. WE'RE PUTTING TOGETHER A VERY SIMILAR LIST OF WHAT IS AN IDEAL PHANTOM. SO IT SHOULD BE SOLID, IT SHOULD HAVE DYNAMIC RANGES. TYPICALLY FAN ATOMS IN THE FIELD HAS LOOKED AT ONE OR TWO PARAMETERS, THEY HAVE LOOKD AT SENSITIVITY AND MAYBE PERFORMANCE WITH DEPTH BUT OF COURSE IF YOU HAVE CAMERAS, YOU HAVE A LARGE FEEL OF VIEW SO YOU CAN FIT A LOT OF FAN ATOMS UNDER ONE -- PHANTOMS UNDER ONE FIELD OF VIEW. WE'VE BEEN TALKING ABOUT WITH OTHER PEOPLE IN THE COMMUNITY TO HAVE PHANTOMS YOU CAN TEST MULTIPLE PARAMETERS SIMULTANEOUSLY AT LEAST GIVING SOME UNDERSTANDING OF WHAT ARE THE DIFFERENCES AND WHAT WE SHOULD BE LOOKING AT AT EXACTLY ESTABLISHING THOSE OPTIMAL SMGZ THAT YOU HAD IN YOUR NEXT SLIDE AND THIS COULD EVEN INCLUDE HAVING QUANTUM DOTS WITH DIFFERENT SPECTRAL RANGES SO EVEN THIS COULD BE INTEGRATED IF IT'S FELT THAT THIS IS AN IMPORTANT THING TO TEST. I THINK AS A COMMUNITY WE HAVE NOT DECIDED WHAT ARE THE PARAMETERS WE NEED TO TEST FOR. I THINK SENSITIVITY WE ALL AGREE BUT THERE ARE MANY OTHER PARAMETERS. BUT I THINK IF WE ALSO REACH A PHANTOM THAT CAN BE USED AS A STANDARD ACROSS THE COMMUNITY, THAT WILL HELP US AND HELP THE DIALOGUE AND IT WILL HELP ALSO APPROVALS WITH THE FDA. >> I SHOULD SAY THERE HAS BEEN A WORKING GROUP OF US, ACTUALLY BASS -- ACTUALLY VASILA STARTED IT, THERE'S AIR SOCIETY GROUND SWELL BUT REALLY NOT A PROFESSIONAL SOCIETY GOVERNANCE AT ALL. IT'S JUST MORE GROUPS OF RESEARCHERS COMING TOGETHER ON THIS ISSUE. JOSH? >> SO CERTAINLY THE IDEA OF HAVING SANG HE WILL PHANTOM THAT YOU COULD -- SINGLE PHANTOM THAT YOU COULD PERFORM MULTIPLE TESTING FOR SINGLE QUALITY CHARACTERISTICS WOULD BE GREAT. A POTENTIAL PROBLEM WOULD BE THAT YOU MIGHT ACTUALLY GET VARIATIONS IN PERFORMANCE ACROSS THE FIELD OF VIEW OF A DEVICE SO ONE OF THE MOST PRIMARY OR INITIAL THINGS YOU HAVE TO TEST FOR IS KIND OF A UNIFORMITY. BUT THERE ARE A WIDE RANGE OF IMAGE QUALITY CHARACTERISTICS THAT IF YOU LOOK AT THE PRIOR LITERATURE AND STANDARDS FOR ESTABLISHED MEDICAL IMAGING MODALITIES YOU CAN FIND THINGS LIKE SPATIAL RESOLUTION, UNIFORMITY DISTORTION, FIELD OF VIEW SENSITIVITY, LINEARITY, NOISE, THERE'S A WHOLE LIST, SO CERTAINLY THEN YOU ALSO GET TO KIND OF MORE TASK-BASED CHARACTERISTICS LIKE LOW CONTRAST DETECTACT OR CONTRAST DETAIL ANALYSIS OR SPATIAL MEASUREMENT ACCURACY. SO THERE'S A NEED TO CERTAINLY KIND OF WHITTLE THESE DOWN TO WHAT ARE THE REAL KEY CHARACTERISTICS FOR ANY SPECIFIC DEVICE. THEN IT ALSO MAY VARY FOR A SPECIFIC DEVICE WHETHER YOU'RE DOING THIS TO ESTABLISH KIND OF A PRELIMINARY LEVEL OF SENSITIVITY FOR PRECLINICAL TEST BEFORE GOING INTO CLINICAL TESTING FOR THE FIRST TIME VERSUS IF YOU'RE TRYING TO ACTUAL ESTABLISH EQUIVALENCE TO A PREDICATE DEVICE VERSUS IF YOU'RE USING THESE FAN ATOMS TO PERFORM CALIBRATION -- THESE PHANTOMS TO PERFORM CALIBRATION OR MANUFACTURING QUALITY CONTROL OR EVALUATE PERFORMANCE VARIATIONSES IN TIME DURING CLINICAL USE. SO THERE'S A VARIETY OF DIFFERENT CONSIDERATIONS BOTH IN TERMS OF THE PHANTOMS AND HOW THEY'RE USED. >> ONE OF THE PROBLEMS OF COURSE WE HAVE WITH PHANTOMS IN GENERAL IS THAT WE NEED STANDARDS FOR THE PHANTOMS AND THAT'S OFTEN THE DIFFICULT THING TO DO WHEN WE'RE TALKING ABOUT THE TYPE OF INSTRUMENT. IT IS ENCOURAGING TO NOTE THAT THERE ARE COMMERCIAL COMPANIES THAT ARE PUTTING OUT PHANTOMS FOR LIMITED USE BUT THEY'VE GONE TO THE POINT NOW WHERE YOU CAN ACTUALLY, A COMPANY IN CAN DARKS YOU KNOW, THAT'S ACTUALLY -- IN CANADA THAT'S ACTUALLY PRODUCING COMMERCIAL PHANTOMS AND I'VE SEEN THEIR FACILITY TO THE EXTENT THAT THEIR QUALITY CONTROL IS EXCELLENT. SO WE'RE STARTING TO GET SOME OPPORTUNITY TO SEE SOME PHANTOMS THAT HAVE REPRODUCIBILITY OVER THE LONG RUN. >> I CAN FOLLOW UP AGAIN. CERTAINLY THIS IDEA THAT A COMPANY, IT WOULD BE GREAT TO HAVE COMPANIES THAT ARE MAKING THESE PHANTOMS BECAUSE IF YOU LOOK AT CT, MRI, ULTRASOUND, THERE ARE COMPANIES THAT MAKE GREAT PHANTOMS THAT ARE USED FOR STANDARDIZATION, FOR PERFORMANCE ASSESSMENT OF DIFFERENT ULTRASOUND DEVICES, FOR EXAMPLE, YOU CAN JUST GO OUT AND BUY IT AND YOU HAVE A REALLY NICE, WELL-CHARACTERIZED COMMONLY USED PHANTOM AND YOU CAN COMPARE IT TO THE MEASUREMENTS THAT SOMEONE ELSE HAS PERFORMED ON THE OTHER SIDE OF THE WORLD. BUT CERTAINLY WE HAVE A WAYS TO GO TO GET TO THAT POINT IN OPTICS, UNFORTUNATELY. >> IF WE COULD ASK NEIL, SO IF THERE WERE AN ESTABLISHED SORT OF STANDARD, COULD A COMPANY COME IN TO DO A PMA PROCESS BASED ON QUALIFICATION OR VERIFICATION BASED ON THE STANDARD? >> SO LIKE I MENTIONED, WE'RE INTERESTED IN ANY VALID SCIENTIFIC EVIDENCE. SO IF THERE WERE THIS VALIDATED STANDARD AND WE COULD UNDERSTAND THAT VALIDATION, WHICH I THINK WE CAN, WE'VE GOT SOME GOOD SCIENTISTS THAT WORK FOR US AND CLINICIANS, AND I THINK IT WOULD BE PART OF THE PACKAGE OF INFORMATION. SO WE LEVERAGE STANDARDS ALL THE TIME, AND WE HAVE A WHOLE STANDARDS PROGRAM. WE RECOGNIZE STANDARDS. SO THERE ARE STANDARDS THAT ARE FDA RECOGNIZED. IF THERE WAS SUCH A STANDARD, I WOULD ENCOURAGE THAT IT WOULD GO THROUGH THAT PROCESS AND I COULD INITIATE THAT PROCESS THROUGH THE AGENCY AND WE WOULD GET IT RECOGNIZED AS VALID AND HELPFUL FOR US. SO CERTAINLY I WOULD ENCOURAGE IT AND THAT'S ONE REASON I THINK I'M INTERESTED IN STANDARDS DEVELOPMENT BECAUSE IT'S SOMETHING WE ALREADY DO IS USE STANDARDS IN OUR REVIEW PROCESS AND IT HELPS US. >> ONE PATTERN I'VE SEEN RECENTLY AND EBEN HAS DONE THIS VERY NICELY I THINK IS LOOK AT FLUORESCENT CONTRAST AGENTS OUT OF THE BODY, ONCE THE TISSUE HAS BEEN RESECTED AND THAT SEEMS LIKE A MUCH EASIER PATHWAY TO GETTING DEVICES THROUGH FDA. BUT IT'S STILL USING THAT INFORMATION FOR SURGICAL DECISION-MAKING. RIGHT? SO I GUESS WHAT'S THE NUANCE THERE IN TERMS OF GETTING APPROVAL? CAN SOMEBODY GET APPROVAL FOR DETECTION ONLY? OR WOULD THAT BE -- >> SO THERE'S NO LIMIT ON WHAT A SPONSOR CAN APPLY FOR AS FAR AS THEIR INDICATION FOR USE OF LABELING, SO IF THEY BELIEVE THERE'S A MARKET AND THERE'S A UTILITY FOR IT, THEY CAN APPLY FOR IT. I WOULDN'T WANT TO RESTRICT ANYBODY. I THINK THAT'S BAD FOR THE WHOLE COMMUNITY. BUT AGAIN, WHETHER IT'S IN SITU, IT'S DURING SURGERY OR POSTSURGERY, IT REALLY KIND OF DEPENDS ON HOW YOU'RE GOING TO USE THAT INFORMATION. IF IT'S INTRAOPERATIVE INFORMATION AND IT'S GOING ON PROVIDE FEEDBACK FOR THE SURGEON TO DO THE NEXT THING, THEN I THINK THERE'S A HIGHER LEVEL OF SCRUTINY BECAUSE THAT DIRECTLY AFFECTS PATIENT CARE AND THE PATIENT OUTCOMES FROM THAT PROCEDURE. SO ONE EXAMPLE IS NOT MY FAVORITE EXAMPLE BUT DU MEDICAL DOESN'T USE OPTICAL I AM MANGING BUT IT ENTER GATES A SPECIMEN REMOVED FROM A PATIENT, A BREAST TUMOR R INTERROGATE THE MARGIN AND LOOKS AT WHETHER IT FINDS ANYTHING SUSPICIOUS. IT'S INTRAOPERATIVE AND WENT THROUGH THE PMA MARKET AND CURRENTLY ON THE MARKET. >> IS THAT VIEWED AS A CLASSES 2? >> CLASS 3. >> CLASS 3 BECAUSE IT'S INFLUENCING THE SURGICAL DECISION PROCESS. >> RIGHT. >> I JUST WANTED TO FOLLOW UP AGAIN ON THE SHORT DISCUSSION ABOUT STANDARDS. THERE ACTUALLY IS OR HAS BEEN A STANDARD THAT WAS DEVELOPED BY IC OR ISO RECENTLY OR AN INITIAL DOCUMENT, IT WASN'T A FINAL STANDARD, FOR PHOTODIAGNOSIS AND PHOTODIKE THERAPY AND IT DIDN'T SPECIFICALLY -- AND PHOTODYNAMIC THERAPY AND IT DIDN'T SPECIFICALLY ADDRESS CONTRAST ENHANCED DEVICES BUT CERTAINLY HAVE G HAVING MORE INPUT FROM INDUSTRY AND ACADEMIA ON THAT STANDARD AND OTHER STANDARDS MOVING FORWARD WOULD BE VERY USEFUL. >> MAYBE LAURA, I CAN GET TO YOU COMMENT. YOU I THINK SPEARHEAD THIS HAD WORKSHOP WITH BOB ON LABEL-FREE OPTICAL IMAGING AND TECHNOLOGY AND OBVIOUSLY THAT'S THE EASIEST WAY TO DECOUPLE THE AGENT IS TO NOT HAVE AN AGENT, BUT DO YOU WANT TO COMMENT ABOUT WHERE THAT WORKSHOP ENDED AND WHAT YOU SEE HAPPENING GOING FORWARD FROM THAT WORKSHOP? >> THE IDEA IS TO UNDERSTAND THE CHALLENGES WHICH ARE FACED BY THE DEVICES WHICH IS LABEL-FREE AND WE ORGANIZED THE WORKSHOP LAST SEPTEMBER, AND WE WENT OVER THE CHALLENGES RELATED TO THE REGULATORY AS SPECTSZ AND STANDARDIZATION WHICH IS COVERED BRIEFLY NOW. BOB WAS ALSO PART OF THIS MEETING. WE EMPHASIZE ADVANTAGES OF USING LABEL-FREE TECHNIQUES VERSUS USING CONTRAST AGENTS, WHICH ARE SOMEHOW OBVIOUS IN A SENSE THAT YOU DON'T HAVE TO USE A DRUG, THEREFORE, YOU DON'T HAVE TO GIVE PHARMACODYNAMICS, ALSO YOU DON'T HAVE TO GO THROUGH THIS VERY CUMBERSOME PATHWAY FOR FDA APPROVAL. AT THE SAME TIME, YOU LOSE SPECIFICITY AND THIS IS WHAT WE HAVE TO BALANCE BETWEEN THE TWO WORLDS. TR THERE IS ALSO A RANGE OF DEVICES THAT CAN USE OUR TECHNOLOGIES AND EACH OF THEM WILL HAVE DIFFERENT CHALLENGING. SOME OF THEM ARE RELATED TO SPECTROSCOPY, SOME OF THEM ARE MORE IMAGING OR CLASSICAL IMAGING AND THERE'S A NEW TERMINOLOGY I LEARNED MORE RECENTLY LOOKING AT HORIZONTAL TECHNIQUES VERSUS VERTICAL TECHNIQUES, SO RELATED TO THAT. AND THIS IS SOMETHING THAT ALSO HAS TO UNDERSTAND HOW THEY CAN COMPLEMENT EACH OTHER. IT'S ALSO A QUESTION OF, AGAIN, STANDARDS, A QUESTION OF SAFETY, DIFFERENT LIGHT SOURCES AND THERE IS NO STANDARDIZATION IN TERMS OF WHAT IS THE LIGHT RADIATION THAT IS PERMEATED. CURRENTLY MOST OF THE REGULATIONS ARE DONE FOR EYE OR SKIN BUT NOT FOR INTERNAL ORGANS. SO WE NEED TO HAVE AN UNDERSTANDING OR STUDIES THAT ARE VIGOROUSLY DONE IN TERMS OF WHAT IS SAFE AND WHAT IS NOT SAFE AND THIS STUDY HAS TO BE DONE IN VIVO, IN ANIMAL MODELS, THEREFORE, OUR STUDY WILL BE PROBABLY VERY EXPENSIVE. SO IN BRIEF I THINK THE MAIN CHALLENGE IS RELATED TO REGULATORY PATHWAY, WITH AGAIN LIGHT EXPOSURE AND ALSO STANDARDIZATION. THIS WAS KIND OF THE CONCLUSION. BUT OVERALL, I THINK THERE ARE ADVANTAGES USING THE LABEL-FREE TECHNIQUE VERSUS A CONTRAST AGENT IN TERMS OF FDA APPROVALS AND PROBABLY SAFETY OVERALL. LIMITED TOXICITY. >> IT'S TIME FOR QUESTIONS. >> COULD I ASK LAWYER A QUESTION? LAWYER REMARKS I'M OVER HERE. SO THE CHALLENGE WITH INTRINSIC OPTICAL CONTRAST IS OF COURSE SIGNAL TO NOISE AND SPEED OF DATA ACQUISITION. DO YOU WANT ON ADDRESS THAT WITH REGARD TO USING LABELS JUST AS PART OF YOUR OVERVIEW? >> YES. DIFFERENT TECHNIQUES WILL HAVE DIFFERENT SPACE. YOU LOOK UP OCT, SPACE IS NOT A PROBLEM ANY LONGER, BUT PROBABLY IF YOU LOOK AT REFLECTOR SPECTROSCOPY, THAT'S A DIFFERENT BALL GAME. FLUORESCENCE ALSO CAN BE DONE VERY FAST THESE DAYS. THE QUESTION IS AGAIN IF YOU WANT TO LOOK AT THE STRUCTURE AND YOU HAVE TO HAVE A DEPTH RESOLVE TECHNIQUE, THEN YOU HAVE TO SCAN, THEREFORE, IT'S A QUESTION OF TIME. IF IT'S A SURFACE TECHNIQUE, HORIZONTAL TECHNIQUE, THEN YOU CAN STILL IMAGE, AND HOWEVER YOU DON'T HAVE A DEPTH RESOLVE INFORMATION. SO THE ADVANTAGE OF LABEL-FREE OR ONE MEASUREMENT YOU CAN RESOLVE MANY FLUOROPHORES OR MANY CONTRAST MECHANISMS IN TISSUE, WHEREAS WITH A CONTRAST AGENT IT'S VERY TARGETED AND YOU ARE JUST LOOKING AT ONE PART OF THE PICTURE. SO IT DEPENDS ON WHAT YOU WOULD LIKE TO SEE, WHAT THE SPEED HAS TO BE IMPROVED OR IT'S NOT A DRAW BACK. >> SO THE CASE OF INTRINSIC CONTRAST, YOU PROBABLY WOULD LIKE TO INCLUDE AS PART OF THE PERFORMANCE CHARACTERISTICS HOW QUICKLY YOU CAN SCAN A SQUARE CENTIMETER OR A CUBIC CENTIMETER AND GET THE RELEVANT INFORMATION BECAUSE WITH THE LABEL TECHNIQUES, THAT'S USUALLY NOT A CONSIDERATION BECAUSE THEY'RE GENERALLY PRETTY FAST AND YOU'RE SCANNING, YOU KNOW, MANY SQUARE CENTIMETERS IN A FEW SECONDS OR MAYBE LARGE FIELDS OF VIEW, SO WITH THE INTRINSIC OPTICAL PROPERTIES, YOU MIGHT WANT WANT TO HAVE A PARAMETER FOR HOW QUICKLY YOU CAN SCAN A CERTAIN -- IF YOU'RE DOING IT HORIZONTALLY, CERTAIN SURFACE AREA OR IF YOU'RE DOING IT IN DEPTH, CUBIC VOLUME. AND THAT MIGHT BE AN INTERESTING CHARACTERISTIC TO BUILD INTO THE PHANTOMS FOR INTRINSIC OPTICAL CONTRAST. >> LET ME JUST SHIFT THINGS A SLIGHTLY DIFFERENT DIRECTION. JOHN, MAYBE I CAN GET YOU TO COMMENT. THE COMMENT FROM JOHN SORGER HERE MADE ME REALIZE A COMPANY HAS NO MOTIVATION TO DECOUPLE A DRUG FROM THE DEVICE IF YOU'VE INVESTED A LOT OF TIME AND ENERGY IN IT. THE GOAL WOULD BE TO YOU TOOLY COUPLE THEM SO THAT -- WOULD BE TO ACTUALLY COUPLE THEM SO THAT YOU CAN PROFIT FROM THAT AND RECOUP THE COST THAT YOU'VE INVESTED IN THEM. MY IMPRESSION IS GOING FORWARD THAT WILL PROBABLY BE THE STATUS QUO FOR MANY COMPANY IS HAVING A COUPLED DRUG DEVICE. DO YOU SEE THAT BEING THE CASE? >> I THINK IT'S SO DEPENDENT ON THE COMPANY AND WHAT THEIR STRATEGIC GOALS ARE AND WHAT THEIR ULTIMATE GOALS ARE BUT IT REALLY COMES DOWN TO SAFETY. A LOT OF THIS IS WHEN YOU COUPLE A DEVICE AND A DRUG, YOU'VE GONE THROUGH RIGOROUS TESTING AND THAT YOU CAN MAKE A CLAIM ABOUT SAFETY AND AT THE END OF THE DAIF THAT'S WHAT WE ALL WANT TO MAKE SURE THOSE DEVICE AND DRUGS USED TOGETHER ARE SAFE AND EFFECTIVE. I THINK IT'S A VERY COMPLEX ISSUE BUT AT THE END OF THE DAY THAT'S WHAT EVERYBODY IS LOOKING FOR. >> I MEAN, IT'S A VERY GOOD POINT THAT WAS BROUGHT UP. IF HE WANTS TO GO TO ONE SPECIFIC DEVICE COMPANY, HE NEEDS TO SAY HERE IS THE SENSITIVITY, HERE IS WHAT YOU NEED TO BE TIEBL DETECT FOR OVARIAN CANCER -- NEED TO BE ABLE TO DETECT FOR OVARIAN CANCER OR WHATEVER. IF EMG, YOU NEED TO GIVE ME THAT SPEC. IF HE WANTS TO PUBLISH THAT SPEC, WE NEED TO KEEP THE CLINICAL EVIDENCE IN CHECK. IF HE WANTS TO GO TO ONE COMPANY AND GET A JOINT APPROVAL, IT'S WHERE THE BUSINESS DECISION REALLY IMPORTANT. I WANT TO PUSH US AWAY FROM SAYING MAKE PHANTOMS AND SHOW WE COULD GET THE BEST SENSITIVITY THAT WE COULD DO BECAUSE WE'LL BUILD DEVICES THAT AREN'T MANUFACTURABLE AT SCALE AND WE REALLY WANT TO MEET THE CLINICAL NEED FOR EACH OF THESE AGENTS. >> MAY I ADD THIS. WE HAVE DISCUSSED IT INDIVIDUALLY THIS THING, BUT THERE IS ALSO A DIFFERENT WAY TO LOOK AT IT BECAUSE RIGHT NOW WE DON'T KNOW WHAT IS THE CLINICAL SPEC. SO IN A WAY, IT IS DIFFICULT FOR SOMEBODY THAT HAS A LABEL TO GO AND SAY THIS IS THE SENSITIVITY ARE I -- THIS IS THE SENSITIVITY I WANT YOU TO DETECT. THE REALITY IS THAT THE MORE SENSITIVE YOU ARE, THE MORE THINGS YOU WILL POTENTIALLY SEE AND ONLY IN RETROSPECT YOU CAN DEFINE, OH, THAT SHOULD HAVE BEEN MY SPECIFIC THING LIKE THIS BECAUSE IN A WAY, THE LESS SIGNAL YOU SEE, THE LESS NUMBER OF CELLS YOU SEE. SO IN A WAY IS THERE REALLY A LIMIT TOO. SO I THINK THIS IS A DISCUSSION THAT CAN ACTUALLY BE HELPED BY PHANTOMS, AT LEAST TO UNDERSTAND WHERE WE ARE. IT'S NOT, THE PHANTOM IS NOT GOING ON DEFINE ANYTHING IN ANY ABSOLUTE TERM. I DON'T THINK SO, AT LEAST AT THE FIRST PHASE. BUT AT LEAST IT WILL DEFINE WHERE WE ARE AS A FIELD AND WHERE DIFFERENT SYSTEMS ARE. >> RECENTLY WE JUST DID A REVIEW OF DIFFERENT SYSTEMS. WE'RE HOPING TO PUBLISH IT. BUT SYSTEMS VARY BY ORDERS OF MAGNITUDE, FOUR, FIVE ORDERS OF MAGNITUDE AND SENSITIVITY. IF YOU THINK ABOUT THAT, SOMEBODY COULD EASILY START A CLINICAL TRIAL WITH THE WRONG DEVICE AND NOT SEE WHAT THEY'RE HOPING TO SEE AND HAVE A FAILED CLINICAL TRIAL AND REALLY HAMPER AND DESTROY THE FIELD AS A WHOLE. >> WE PUT AN IDEA OUT AND OBSCURE BECAUSE OBVIOUSLY NOBODY READ IT PAPER ABOUT TEN YEARS AGO ON, YOU KNOW, ICG EQUIVALENCE AND THE THING IS THAT TO KIND OF JUMP START THIS WHOLE IDEA OF THE PHANTOMS, WE ALL HAVE THE ABILITY TO TEST EACH OTHER'S SYSTEMS TODAY BECAUSE IF YOU DEFINE EX-TINGE COEFFICIENT QUANTUM YIELD AND PATH LENGTH, THEN YOU'VE REALLY DEFINED ALL THE OPTICAL PROPERTIES SO DO WE HAVE A DRUG THAT WE CAN ALL BELIEVE IN? WELL, YEAH, ICG IS AVAILABLE AS A USP THAT YOU CAN BUY FROM SEVERAL MANUFACTURERS AND HAS A USP LABEL IT'S MET CERTAIN MANUFACTURING AND PERFORMANCE SPECIFICATIONS. SO RIGHT NOW YOU CAN BUY FROM FISHER, A HEMATOCRIT TUBE, IF IT'S A CLINICAL HEE MET CREDIT TUBE, IT'S DEFINED AS A SYSTEM AND PATH LENGTH, YOU HAVE VOLUME, PATH LENGTH, EX-TICK SHUN COEFFICIENT AND QUANTUM LEAD AND THEN REALLY IT'S CHEMICAL ENVIRONMENT. ICG WHICH IS VERY UNABLE IN AQUEOUS ENVIRONMENTS AND VERY STABLE IN DMSO. BY BUYING USCG AND PUTTING IT IN DMSO AND TAKING IT UP IN A CAPILLARY TUBE, WE HAVE A VERY STANDARD SYSTEM, IT'S A PLUS OR MINUS 5% SYSTEM THAT WE COULD ALL BE TESTING SO IF WE WANT TO ANSWER THE FIRST QUESTION WHICH IS HOW DO THESE TEN OR TWELVE SYSTEMS OUT THERE COMPARE FROM A PERFORMANCE, IT'S A TRUE PERFORMANCE METRIC, YOU KNOW, WE CAN DO THAT TODAY AS A FIELD AND WE DON'T HAVE TO DO COMPLEX PHANTOMS OR ANYTHING ELSE. I WOULD LOVE TO SEE THAT DONE BUT I HAVEN'T SEEN IT YET. >> A QUESTION FOR PEOPLE TO CONSIDER AS WE GO FORWARD, IS THERE A ROLE FOR SOCIETIES, FOR THE NCI, FOR THE FDA IN COLLABORATING IN MAKING PROBABLY NOT ONE PHANTOM BUT AN ENTIRE FAMILY OF THEM TO BE LOOKED AT FOR CERTAIN THINGS LIKE THIS, OR ARE WE NOT READY YET? I'M NOT MAKING A CONCLUSION, I'M SAYING IT'S SOMETHING WE SHOULD THINK ABOUT, BECAUSE PUTTING TOGETHER COLLABORATIONS, THERE'S A LOT OF PEOPLE, ALL THE SOCIETIES ARE INTERESTED IN THIS, SPIE, WMIS, IS IT TIME TO START LOOKING AT THIS OR NOT? >> I THINK IT IS BECAUSE WE STARTED ONE, BUT HAVING SAID THAT, THE IDEAL SOCIETY DISBT EXIST. >> THAT'S WHY YOU NEED A CONSORTIUM. >> I SHOULD SAY WE HAVE A WORKING GROUP TO THE AMERICAN ASSOCIATION OF PHYSICISTS IN MEDICINE THAT IS PROBABLY NOT THE RIGHT GROUP, THEY TEND TO BE RADIATION PHYSICISTS, BUT THEY HAVE A VERY WELL FORMULATED MECHANISM TO PUBLISH THESE THINGS TO ACCRUED INDICATE THEM, TO REVIEW THEM -- TO ADJUDICATE THEM, TO REVIEW THEM, SO THEY HAVE THE SOCIETY PATHWAY TO CREATE VERY FORMAL DOCUMENTS SO THAT'S WHY WE DID IT BUT THE WMIS OR MORE OPTICALLY RELEVANT SOCIETIES ARE PROBABLY THE RIGHT CONDUITS, BUT THEY DON'T HAVE THE HISTORY OF MAKING GOVERNMENT GUIDANCE DOCUMENTS LIKE THIS. >> I WAS GLAD TO HEAR THAT THERE ARE COMPANIES INTERESTED IN MAKING PHANTOMS BECAUSE THEY HAVE THE RIGHT SELECTIVE PRESSURE TO DEVELOP THE PHANTOMS THAT ARE STANDARDIZED AND HAVE PERFORMANCE CHARACTERISTICS BECAUSE IF THEY MAKE A PHANTOM THAT DOESN'T WORK, IT'S NOT GOING ON SELL, SO THEY HAVE TO MAKE ONE THAT'S IDEALLY SUITED FOR EACH APPLICATION. I THINK THE CONSORTIUM IS A GREAT IDEA FOR SOCIETIES, FDA, NCI, TO DEVELOP THE GUIDELINES, BUT I THINK IT REALLY NEEDS TO BE A COMMERCIAL ENTITY THAT DEVELOPS THESE THINGS BECAUSE OTHERWISE IT'S NOT GOING TO BE USED AND IT'S NOT GOING TO BE AS WELL DEVELOPED. >> AGAIN, A WORD OF CAUTION THAT BECAUSE OF THE CHEMISTRY IN THE INFRARED FLUORESCENCE IMAGING AND VARIATIONS IN THE CHEMISTRY, I THINK PHANTOMS REALLY SHOULD JUST BE UP TO THE DEVICE MANUFACTURER OR THE DRUG OR COMBO OR WHATEVER TO DEFINE THE PHANTOM. IT WOULD BE VERY DANGEROUS TO TRY TO PUT TOGETHER GENERAL PHANTOMS BECAUSE IT'S NOT GOING ON FIT WITH EVERY APPLICATION. I LOVE THE IDEA OF THE FILLABLE PHANTOM BECAUSE THAT GETS AROUND THAT, BUT WE HAVE TO REMEMBER THAT THIS IS A UNIQUE CHEMISTRY. IT'S NOT IODINE CONTRAST. THIS IS THE ABILITY TO CONTROL ALMOST EVERY PARAMETER, EXCITATION, YOU KNOW, THE SPECTRUM, SPECTRAL PARAMETERS, QUANTUM YIELD, EVERYTHING ELSE. IT'S VERY DIFFERENT. >> NUCLEAR MEDICINE TYPE PHANTOMS ARE A CLOSER ANALOGY. EBEN? >> I WANT TO MAKE ONE COMMENT ABOUT PHANTOMS AND OPTICAL IMAGING AND COMPARISON WITH THE OTHER METHODS. MRI, CT, PET, PHOTO ACOUSTIC AND ULTRASOUND HAVE VERY LITTLE ENVIRONMENTAL BACKGROUND. THEIR USAGE SITUATION IS CONTROLLED IN THE INSTRUMENT. AS BRIAN POINTED OUT, THE USAGE SCENARIO FOR OPTICAL IS GOING TO BE DIFFERENT IF IT'S ENDOSCOPIC, IN WHICH CASE THE ENVIRONMENT IS GENERALLY DARK, VERSUS BEING USED IN AN OPERATIVE THEATER IN WHICH CASE YOU HAVE ROOM LIGHTS AND THE SENSITIVITY A CAMERA OR ANY OPTICAL SYSTEM AT LOW LIGHT IS DIFFERENCE THAN THE SENSITIVITY AT HIGH LIGHT BECAUSE THE NOISE SOURCES ARE DIFFERENT. AT HIGH LIGHT YOU HAVE FIXED PATTERN NOISE AT LOW LIGHT YOU HAVE READ NOISE AND OTHER THING. IT'S VERY EASY TO MAKE A GREAT PHANTOM BUT UNLESS YOU ALSO CONSIDER THE USAGE SITUATION AND THE SURGICAL LIETSZ WHICH MAY BE HALOGEN OR LED, YOU CAN GET VERY DIFFERENT RESULTS FOR THE CONCLUSIONS. >> RIGHT. THAT'S WHY STANDARDS USUALLY THEY DO NOT JUST CONFINE THE PHANTOM BUT THEY DEFINE THE -- DON'T JUST DEFINE THE PHANTOM BUT THEY DEFINE THE MEASUREMENT. SO PERHAPS THE LIGHTING CONDITIONS WOULD BE FOR CERTAIN APPLICATIONS BE A REAL KEY CRITERIA TO INCLUDE. >> ARE WE OUT OF TIME? WE'RE OUT OF TIME. OKAY. COFFEE BREAK IS RIGHT NOW, I BELIEVE. THEN WE'LL RECONVENE IN 15 MINUTES. >> THANK YOU. I'M PETE CHOYKE FROM THE INTRAMURAL PROGRAM, MOLECULAR IMAGING PROGRAM. THIS IS THE TARGETING AND DETECTION SECTION, AND I'M TALKING ABOUT CLASSES OF AGENTS. FOR MANY OF YOU THIS WILL BE QUITE A REVIEW. THE CHALLENGE IS TO DETECT SMALL TUMORS ON THE EPITHELIAL SURFACES, ET CETERA, AND IT CAN BE USED, THESE AGENTS CAN BE USED FOR SCREENING PURPOSES AND FOR, AS MOST OF THE SUBJECT TODAY, OPT CLI ENHANCED SURGERY OR ENDOSCOPY. WE'RE LOOKING AT A VA RIEFT DIFFERENT KINDS OF STRUCTURES LIKE LYMPHATIC VESSELS, LEAKAGE OF VESSELS, SNOADZ, LYMPHATIC DRAINAGE, VASCULARITY OF GRAFTS, LEAKAGE FROM VESSELS, ET CETERA. NO MATTER WHAT WE'RE LOOKING AT, WE ALWAYS HAVE A GOAL WHICH IS TO HAVE TO HAVE THE TARGET BE VERY BRIGHT AND THE BACKGROUND BE RELATIVELY LOW SO WE CAN HAVE VERY GOOD SENSITIVITY FOR DETECTING WHATEVER IT IS WE WANT TO DETECT. THERE ARE TWO MAJOR CLASSES OF THESE AGENTS, NONTARGETED PROBES WE'VE DISCUSSED A BIT THIS MORNING STARTING WITH SMALL MOLECULE AGENTS AND THESE ARE BASICALLY THE DYES THEMSELVES THAT CLEAR VERY RAPIDLY THROUGH THE KIDNEY. THERE ARE AGENTS LIKE ICG THAT ARE SMALL BUT BY VIRTUE OF THE FACT THAT THEY BIND PROTEIN IN THE BLOOD THEY BECOME MACROAGGREGATES THAT CLEAR MORE SLOWLY AND THUS BECOME BLOOD POOL AGENTS AND THERE ARE OTHER EXAMPLES LIKE THAT, THEN THIS YEAR NAN OH PARTICLES LIKE DENDROMERS AND LIPOSOAMS, YOU CAN LOAD A LOT OF OPTICAL FLUOROPHORES ON A SINGLE PROBE, THEY CAN CARRY THINGS LIKE DRUGS OR OTHER KINDS OF MARKERS SO YOU CAN HAVE BOTH OPTICAL AGENT AND A RADIOACTIVE AGENT IN THE SAME PARTICLE BUT THEY CARRY A PRICE AND THAT'S OF THEIR BIODISTRIBUTION, VERY SLOW CLEARANCE FROM THE BACKGROUND AND MAYBE VERY POOR ELIMINATION FROM THE BODY ITSELF. THE OTHER BIG CLASS OF THESE AGENTS ARE TARGETED IMAGING PROBES THAT TYPICALLY HAVE A SIGNALLING MOITY, IN THIS CASE I CALL IT OPTICAL VEHICLE, TARGETING LIGAND. FIRST THE SIGNALLING MOIETY, WE DEAL WITH VISIBLE FLUOROPHORES THAT ARE DESIGNED TO BE VERY SENSITIVE TO THE HUMAN EYE SO WE DON'T NEED CAMERAS. ICG AND THE ILLUSTRATION FROM THIS MORNING WAS VERY GOOD IN SHOWING THE GREENISH COLOR OF THE DYE. GREEN FOR INSTANCE IS VERY SENSITIVE FOR THE HUMAN EYE. NO CAMERA NEEDED. OR WE CAN GO WITH NEAR INFRARED FLUOROPHORES THAT HAVE THE BENEFIT OF BETTER TISSUE PENETRATION BUT DO REQUIRE A FLUORESCENCE CAMERA TO DETECT THEM. SO THOSE ARE THE MAJOR CLASSES. OF COURSE, WITHIN THAT WE HAVE TWO OTHER CLASSES, THOSE THAT ARE ALWAYS ON FLUOROPHORES AND HERE IS JUST A THEORETICAL EXAMPLE OF ONE THAT, SAY, AVIDIN-FITC OR FLUORESCEIN AND THE TRICK THERE IS IT WILL BIND TO SOME PART OF A CELL AND THERE WILL BE A LOT OF SIGNAL ON THE CELL BUT THERE'S CLEARLY A LOT OF BACKGROUND AT THE SAME TIME. SO THAT'S NOT GOOD. SO YOU NEED TO WAIT UNTIL THE UNBOUND MATERIAL HAS CLEARED IN THIS CASE THROUGH THE PERITONEUM INTO THE LIVER AND THEN YOU GET A TOLERABLE TARGET TO BACKGROUND RATIO BUT YOU'RE ALWAYS FIGHTING THE BACKGROUND SIGNAL FROM YOUR UNBOUND AGENT. SO THE OTHER CLASS OF FLUOROPHORES THAT CAN BE EITHER IN THE VISIBLE RANGE OR THE NEAR INFRARED RANGE ARE ACTIVATABLE, SO THEY COME IN COMPLETELY NONFLUORESCENT BUT ONLY BECOME FLUORESCENT WHEN THEY BOUND THEIR TARGET. SO IN THIS CASE, SAME KIND OF THING USING A GAMMA GLUTAMINATE HMRG, IT TURNS ON IN THE PRESENCE OF ENZYME, THE BACKGROUND IS DARK. CR REQUIRES THE PRESENCE OF THIS ENZYME. SO THERE ARE CONDITIONS THAT MAKE THIS WORK. BUT AT THE END OF THE DAY YOU GET EXTREMELY HIGH TARGETED BACKGROUND RATIOS WHICH MEANS YOU CAN DETECT SMALLER AND SMALLER AMOUNTS OF DISEASE. SO FOR ACTIVATABLE, THERE ARE NUMB REDUCE MECHANISMS OF ACTIVATION. IT'S DIFFICULT ON COVER THIS WHOLE FIELD AND PROBABLY NOT A GOOD IDEA. BUT ENZYMATIC CLEAVAGE IS ONE OF THE MOST POPULAR. THERE ARE PHOTOCHEMICAL SWITCHES, FRET, DIMER FORMATION, CAGES THAT CONTAIN THE OPTICAL FLUOROPHORE AND RELEASE IT, QUENCH AND GO DEQUENCHING, PH SENSITIVITY AND ACTUALLY THE LIST IS JUST PARTIAL. SO LET'S TALK ABOUT THE VEHICLE AND TARGETING PART OF ALL THIS AS ANOTHER PART OF THE TARGETED AGENT. SO THIS IS VERY, VERY IMPORTANT. ONCE AGAIN WE HAVE SMALL, INTERMEDIATE AND LARGE MOLECULES TO CONSIDER, AND WHAT WE REALLY NEED TO KEEP IN MIND HERE IS THAT AS WE CHANGE THE CARRIER MOLECULE THAT IS THE COMBINATION OF THE VEHICLE AND THE TARGET, WE CHANGE THE ABILITY OF THE TARGETING LIGAND TO FIND ITS TARGET BECAUSE YOU START TO INFLUENCE THE PHARMACOKINETICS OF THE ENTIRE STRUCTURE. SO CERTAINLY FOR SMALL MOLECULES YOU CAN GET WHERE YOU WANT TO BECAUSE YOU HIT THE TARGET AND THEN THERE'S CLEARANCE OF THE MOIETY. SO THAT'S A FAVORABLE SITUATION, BUT YOU DON'T GET MUCH OOM PH FROM A SMALL MOLECULE. YOU CAN ONLY PUT ON ONE OR TWO FLUOROPHORES ON THAT. SO THAT'S THE DISADVANTAGE. SO YOU CAN GO TO MACROMOLECULES, FOR INSTANCE, ANTIBODIES, WHICH ARE A NATURAL MACROMOLECULE AND THEY HAVE ALE SLOWER CLEARANCE, THE ADVANTAGE IS THAT YOU CAN PUT MULTIPLE FLUOROPHORES ON THEM BUT YOU'RE FIGHTING THE BACKGROUND CLEARANCE UNLESS YOU HAVE AN ACTIVATABLE FORM OF THE AGENT IN WHICH CASE YOU CAN GET RID OF THAT AND AGAIN THE NANOPARTICLE, THAT I'VE BEEN IN AND OUT OF LOVE WITH NANOPARTICLES AND I HOPE THAT I CAN SORT OF CONVEY MY AMBIGUITY AND MY AMBIVALENCE TOWARDS THEM. THEY'RE POLYVALENT, SO THAT GIVES YOU EVER A LOT OF PLACES TO CONNECT FLUOROPHORES, BUT THEY'RE VERY SLOW IN CLEARANCE AND CAN HOLD UP IN PARTICULAR ORGANS, MAKING REGULATORY ISSUES VERY, VERY SIGNIFICANT. AND OF COURSE THERE'S A HUGE RANGE OF POTENTIAL NANOPARTICLES RANGING FROM THESE CARBON NANO TUBES THROUGH DENDRIMERS, QUANTUM DOTS, ET CETERA, THAT YOU'RE ALL FAMILIAR WITH. SO I JUST WANT TO REITERATE THIS POINT THAT THE SIZE OF THE CARRIER MOLECULE MAKES A BIG DIFFERENCE IN THE BIODISTRIBUTION AND THE CLEARANCE AND THE ABILITY OF THE WHOLE MOLECULE TO PENETRATE INTO THE TUMOR OR TISSUE, THE AFFINITIES AND THE SIGNAL TO NOISE. SO IT'S NOT TRUE THAT YOU CAN JUST PUT ON ANYTHING, ANY KIND OF CARRIER AND NOT CHANGE THINGS. SO FINALLY, IN MY CLASSES OF AGENTS, ROUTES OF ADMINISTRATION. YOU HAVE INTRAVENOUS OR SYSTEMICALLY ADMINISTERED AGENTS TYPICALLY ADMINISTERED RIGHT BEFORE USE OR, SAY, 24 HOURS BEFORE USE. THEN THERE'S A LARGE CATEGORY OF INTRACAVITARY, WHICH IS VERY PROMISING, SAY PERITONEUM AS A CAVITY OR THE BLADDER AS A CAVITY WHERE YOU CAN INSTILL IT WITHOUT INCURRING THE WHOLE SYSTEMIC LOAD OF THE AGENT, AND THERE ARE TOXICITY ISSUES THAT ARE THEREFORE A LITTLE MORE LIMITED. THEY'RE NOT ELIMINATED BUT THEY'RE MORE LIMITED BECAUSE THERE'S ALWAYS SOME DEGREE OF ABSORPTION FROM MANY OF THESE CAVITIES SYSTEMICALLY. SO YOU CAN'T IGNORE T BUT YOU CAN UTILIZE THE VARIOUS CAVITIES. NOW, THE BLADDER DOESN'T TEND TO ABSORB THESE AGENTS VERY WELL SO IT TENDS TO KEEP IT AS A BALLOON. THE PERITONEUM IS EXCELLENT AT LETTING SMALL TO MEDIUM SIZED MOLECULES THROUGH, SO YOU CAN GET FAVORABLE TARGETED BACKGROUNDS. THEN I FEEL SORT OF VERY PROMISING METHOD IS THE TOPICAL APPLICATION DURING THE PROCEDURE. SO THE OPERATOR, WHETHER IT BE AN ENDOSCOPIST OR SURGEON SPRAYS THE AGENT ON OR APPLIES IT IN SOME MANNER, PAINTS IT, FOR INSTANCE, AND IT'S TOPICAL WITH VERY LOW SYSTEMIC ABSORPTION BUT GIVES THEM A REALTIME SORT OF ADJUVANT HELP DURING THE PROCEDURE THAT THEY'RE DOING. AND THEN IT DISAPPEARS. SO THIS IS JUST BASICALLY A SUMMARY OF THE TALK. AS WE DESIGN A SURGICAL OPTICAL PROBE, WE WANT TO DECIDE WHETHER OUR PROBLEM IS ON THE SURFACE OR IT'S DEEP TO THE SURFACE, SO THAT WILL INFLUENCE THE PROBE THAT WE PUT ON. HOW MUCH DO WE NEED SENSITIVITY? BECAUSE IF WE NEED A LOT OF SENSITIVITY FOR A MICROFOCI OF DISEASE, THEN WE SHOULD BE THINKING ABOUT ACTIVATABLE RATHER THAN ANNALS ON PROBE, SO THAT'S NEXT QUESTION. DO YOU NEED IT TO BE SHORT ACTING OR LONG ACTING? IF IT'S SHORT ACTING, PREFER A SMALL MOLECULE. IF IT'S SOMETHING THAT YOU NEED OVER A PERIOD OF HOURS, YOU'LL NEED SOMETHING THAT DOESN'T CLEAR THAT FAST, SO A MACROMOLECULE OR A NANO PARTICLE. THEN OF COURSE I THINK EXTREMELY IMPORTANT TO ALL OF THIS EXTERNAL TO THE TECHNICAL DISCUSSION IS WORK FLOW. HOW ARE SURGEONS OR ENDOSCOPIST TION GOING TO EMBRACE THIS? IS IT GOING TO INTERFERE AND SLOW THEM DOWN DURING AN OPERATION OR SPEED THEM UP AND GET THEM BETTER OPERATION? THAT'S CRITICAL TO THE SUCCESS OF THESE. OFTENTIMES DRUG DESIGNERRERS LEAVE OUT THE END USER BUT THE END USER IS CRITICAL TO THE SUCCESS AND WE REALLY NEED TO THINK ABOUT THESE METHODS OF ADMINISTRATION. I WANTED TO GIVE AN ILLUSTRATION OF ONE AGENT WE DEVELOPED JUST TO SHOW YOU THAT I HAVE SKIN IN THIS GAME, OVARIAN CANCER, BIG PROBLEM, PERITONEAL METASTASES, WE CAME UP WITH AN ACTIVATABLE PROBE, BETA -- GLU-TAMYLTRANSFERASE PROBE, THE MOVIE ISN'T WORKING, BUT IT WOULD HAVE SHOWN YOU THAT THE AGENT IS CONVERTED INTO AN IT CAN ACTIVATED FORM AND INTERNALIZED AND ACCUMULATE IN THE CELL DURING MINUTES, YOU CAN SPRAY THIS PROBE ON AND WITHIN 30 SECONDS GOIN SEE WHERE THE TUMOR FOCI ARE AGAINST A BACKGROUND THAT'S BLACK AND HERE ARE SOME EXAMPLES OF UNPROCESSED IMAGES IN A MOUSE WITH PERITONEAL METASTASES AND YOU CAN ACTUALLY USE THE ACTIVATION IN A DYNAMIC MODE TO INCREASE THE SENSITIVITY EVEN FURTHER BECAUSE ONE OF THE FEATURES THAT WE CAME TO UNDERSTAND IS THAT THERE ARE ACTUALLY POOLS OF FLUID IN A PERITONEUM THAT CAN DILUTE THE AGENT SO WHEN YOU PUT IT IN, YOU SAY OH, THIS IS GREAT, IT'S TEST RIGHT CONCENTRATION, UNTIL YOU REALIZE THAT THERE ARE POOLS THAT DILUTE IT TENFOLD, IN WHICH CASE YOU NEED TO GET THE SIGNAL OUT IN OTHER WAYS AND THE DYNAMIC MODES WILL BE HELPFUL IN THAT. SO THAT'S WHAT I WANTED TO SAY. I BASICALLY WON'T GO OVER IT AGAIN IN THE INTEREST OF TIME, BUT THINK ABOUT THE OPTICAL BEACON AND THINK ABOUT THE CARRIER AND IF IT'S TARGETED THINK ABOUT THE TARGETING MOLECULES AND THESE NEEDS TO BE, THESE ARE INDIVIDUAL COMPONENTS THAT NEED TO BE COMBINED. IT'S COMPLEX CHEMISTRY AND FROM A REGULATORY POINT OF VIEW IT IS THESE VARIOUS COMPONENTS CAUSE ISSUES, AND WITH THAT I'LL STOP AND TAKE ANY QUESTIONS. OR YIELD TO THE DIRECTION OF OUR LEADER. >> GOOD MORNING. MY NAME IS ADEBAYO LANIYONU. THE TOPIC OF MY TALK THIS MORNING IS ON SAFETY AND TOXICITY ASSESSMENT OF NEW MOLECULE ENTITIES AND MODIFIED EXISTING AGENTS. FIRST WE ARE SEEING A LOT OF AGENTS THAT HAVE BEEN USED AND MODIFIED FOR OPTICAL IMAGING. THE TOPIC OF MY TALK. NONCLINICAL STUDIES NEEDED TO SUPPORT CLINICAL INVESTIGATIONS UNDER IND FOR APT CAL IMAGING COMBINATION PRODUCTS. AND NONCLINICAL PERSPECTIVES ON OPTICAL IMAGING AGENTS COMBINATION PRODUCTS, AND POE STAKEHOLDERS. I WILL NOT BE ADDRESSING THE TOXICITIES -- THE DEVICE TOXICITIES BECAUSE THESE ARE DREASED BY OUR CDRH COUNTERPARTS. THE GOAL OF INVESTIGATIONS IS IDEALLY INVESTIGATION FOR THESE TYPE OF COMPOUNDS, IDENTIFICATION OF TARGET ORGANS, CHARACTERIZATION OF PHARMACOLOGY AND TOXICOLOGY AND ALSO SPECIFIC OUTCOMES, THIS WOULD BE TO ENABLE THE SELECTION OF INITIAL STARTING DOSE, DOSE ESCALATION SCHEME, TO ADDRESS THE MONITORING SCHEMES, AND HE IS SPECIAL TOLL ALLOW NONE CLINICAL STUDIES TO BE TAILORED TO MEET THE NEEDS OF THE CLASS OF AGENTS. I SAW THE STUDY THAT PAULA WAS SHOWING, THAT PROBABLY STARTED MANY, MANY YEARS AGO BEFORE THE FINAL APPROVAL, AND I'M VERY SURE -- SO THE KIND OF FLUOROPHORES THAT WE'LL BE SEEING. I NEED TO MENTION SOMETHING ABOUT THIS BECAUSE SOMETIMES THIS IS JUST RELATED TO -- THE PHARMACOLOGY MIGHT BE DIFFERENT. SOME WORK-UP PRIOR TO HUMAN STUDIES. SOMETIMES WE SEE APLEUFD AND NONAPPROVED DYE -- WE SEE APPROVED AND NONAPPROVED DYES ARE COMBINED WITH NEW MOLECULAR ENTITY, AND APPROVED SMALL MOLECULE BUY LOGICS. I REALIZE THE QUESTION WAS ASKED EARLIER THIS MORNING ABOUT IF YOU ARE COMBINING A BIOLOGIC WITH AN PROVED OR ONE PROVED DYE, THE DIFFERENCE, AND I WILL ADDRESS THAT. SO ALSO SOME ENZYME ACTIVATED PRODUCTS, RELATED TO SOME OF THAT. THE NANOPARTICLES, GOLD, SILICA AND IRON OXIDE. THE CONCEPT IS SELF-EVIDENT. SOME OF THESE PRODUCTS ARE ALREADY APPROVED, START WITH THE DYE OR A LINKER IN BETWEEN, AND THEREFORE, NONCLINICAL REQUIREMENTS HAVE TO BE TAILORED TO MEET THE NEEDS FOR THE LEVEL OF DEVELOPMENT. WHAT MAY NOT BE OBVIOUS IS THAT WE ACTUALLY HAVE A GREAT AMOUNT OF FLEXIBILITY IN WHAT WE DO ASK FOR. BUT THIS IS NOT OFTEN UTILIZED BY SPONSORS. SOMETIMES IT MAY BE LACK OF AWARENESS, AND WE TRULY ENCOURAGE YOU TO ENGAGE US. OFTENTIMES SOME OF THE SPONSORS DELIBERATELY DO NOT WANT TO COME AND MEET WITH US SIMPLY BECAUSE THEY ASSUME THAT IF THEY DO, WE'LL SIMPLY GIVE THEM A LAUNDRY LIST OF THINGS TO DO. [LAUGHTER] THIS IS A VERY IMPORTANT POINT. THAT IS FAR FROM BEING WHAT WE DO. AS PUBLIC SERVANTS, WE ALSO HAVE A STAKE IN ASSURING, IN A TIMELY, VERY EFFICIENT MANNER. SO WE ENCOURAGE A DIALOGUE, WE ENCOURAGE YOU TO COME AND SPEAK WITH US, SIMPLY BECAUSE WE ACTUALLY BELIEVE THAT THERE IS VALUE IN INTERACTIONS WITH THE FDA. IF YOU DETERMINE THAT NONCLINICAL PHARMACOLOGISTS ARE NOT NEEDED, AT ANY STAGE OF DEVELOPMENT AND PROVIDES ADEQUATE JUSTIFICATION, FDA IS PREPARED TO GRANT A WAIVER. SO APPEAL TO THE SENSE OF TIME AND WE'LL AND DO THE STUDIES. TALK TO GO VARIOUS SEGMENTS, NOT ASSESSMENT OF NEW MOLECULAR ENTITIES. RECOMMENDED STUDIES. SO OPTICAL IMAGING IND, THIS WILL INCLUDE PROOF OF CONCEPT STUDIES, AND THIS TRULY WOULD HAVE HAPPENED ANYWAY WHETHER YOU ARE DEVELOPING THIS WITH THE INTENTION OF MARKETING OR SIMPLY BECAUSE OF YOUR LOVE OF SCIENCE, THESE ARE THE KIND OF STUDIES YOU WOULD PUBLISH IN JOURNALS ANYWAY, BUY ADISTRIBUTION AND SO ON -- BIODISTRIBUTION AND SO ON, AND THEN YOU NEED SAFETY PHARMACOLOGY STUDIES, MAJOR ORGANS AND ORGAN SYSTEMS, TK SPAISH PK, AND EXPANDED SINGLE DOSE STUDIES, MAY BE COMBINED FOR COST EFFICIENCY. AND SPECIAL TOXICOLOGY FOR THE TOXICITY, ROUTE IR TAN SI, BLOOD COME PAT -- ROUTE IRRITANCY, BLOOD COMPATIBILITY. SO THE STUDIES THAT ARE REQUIRED PRIOR TO PHASE 2, SHORT-TERM REPEAT DOSE TOXICITY STUDY, GENOTOXICITY STUDIES, REQUEST FOR WAIVER OF REPRODUCTIVE AND DEVELOPMENTAL TOXICITY STUDIES IF APPLICABLE. SOMETIMES WHEN YOU SEE, YOU MUST DO THIS, YOU MUST DO THIS, THINK ABOUT THAT AGAIN. IT COSTS YOU NOTHING TO ASK US QUESTIONS ANYWAY. I GIVE YOU A RECENT EXAMPLE. A WAIVER OF STUDIES, WHICH WE GRANTED, AND THEN THE PACKAGE, YOU ARE ASKING US WHETHER IT WOULD BE OKAY FOR THEM TO DO A REPROCESS STUDY IN TWO SPECIES, CONCURRENTLY OR PRIOR TO THEIR STUDY, AND WE ALSO REMIND THEM THAT WE HAVE ALREADY GRANTED YOU A WAIVER, THAT YOU'RE DOING IT TO CONDUCT THE STUDY ANYWAY. NOW MOVING ON TO ASSESSMENT OF MODIFIED AGENTS. TO SAVE TIME AND RESOURCES, WE STRONGLY ADVICE THAT SPONSORS COMMUNICATE WITH THE AGENCY PRIOR TO STUDY INITIATION. BECAUSE YOU MAY ACTUALLY NOT BE REQUIRED NEW CLINICAL STUDIES. MODIFY EXISTING AGENTS,. STUDY YOU'VE DONE ANYWAY. REQUIRE BRIDGING TOXICITY STUDIES. IF ISSUES WITH DYE OR OTHER COMPONENTS, YOU CAN REQUEST A LETTER OF AUTHORIZATION TO REFERENCE NONCLINICAL STUDIES FROM OTHER SPONSORS. AND BOTH NCI AND NIH, REALLY THE NONCLINICAL STUDIES THAT HAVE BEEN DONE. BECAUSE THEY'RE PUBLIC ANYWAY, YOU CAN APPROVE THE APPLICATION. BIOLOGICAL OPTICAL IMAGING. FROM MY EXPERIENCE, MOST OF THESE WERE PREVIOUSLY INVESTIGATED EITHER AS APPROVED THERAPEUTIC BUY LOGICS OR AS INVESTIGATIONAL THERAPEUTIC BUY LOGICS AT ADVANCED STAGES OF DEVELOPMENT, AND MOST ARE RELATIVELY WELL CHARACTERIZED AND MAY REQUIRE FUROR NO NEW STUDIES FOR YOU TO BEGIN -- AND MAY REQUIRE NO NEW STUDIES FOR YOU TO BEGIN. YOU SAVE TIME ON THE LONG RUN IN YOUR DEVELOPMENT OF PLAN. YOU ARE CHANGING THE ROUTE, DOSE OR POPULATION CHANGE FOR APPROVED AGENTS. THIS IS A CASE-BY-CASE BASIS AND WE STRONGLY ENCOURAGE EARLY COMMUNICATION AND DIALOGUE WITH THE REVIEW DIVISION. I'M HOPING THAT THE OUTCOME, THAT YOU COMMUNICATE WITH THE REVIEW DIVISION TO OPTIMIZE NONCLINICAL PROGRAM AND A FLEXIBLE APPROACH THAT ALLOWS INNOVATIVE PRODUCTS TO MOVE SAFELY AND QUICKLY THROUGH NONCLINICAL DEVELOPMENT. THESE ARE SOME OF THE PERTINENT GUIDANCES THAT YOU MAY FIND HERE. THANK YOU AND I HAVE MY E-MAIL ADDRESSES AND MY TELEPHONE NUMBER SHOULD YOU NEED TO CONTACT ME. >> WE HAVE A COUPLE MINUTES FOR QUESTIONS. >> THANK YOU VERY MUCH FOR THE OVERVIEW. ON SLIDE 10 YOU MENTION REPEATING A DOSE TOXICITY STUDY. IS THAT FOR AN AGENT THAT WILL BE ADMINISTERED MANY TIMES IN THE LIFE OR FOR A SINGLE USE AGENT? >> SOMETIMES -- IT DEPENDS. ACTUALLY THE PART OF THIS PRESENTATION IS THAT SOMETIMES BECAUSE OF THE FIRST PK OF THE PRODUCT, CORRECT ME IF I'M WRONG, THAT THERE MIGHT BE OCCASIONS DURING SURGERY WHERE THE PK DOSES MIGHT HAVE BEEN GIVEN. I WAS ALMOST TEMPTED TO ASK WHETHER WHEN GIVEN THOSE REPEATED DOSES, USING THE APPROVED DOSE, BECAUSE IF YOU ARE REPEATING YOUR DOSE FOUR TIMES DURING SURGERY -- >> WITH I CRI -- >> WITH ICG A LOT. >> THAT'S AN ANALOGY THAT MIGHT BE APPLICABLE. IT MIGHT NOT BE TO THE SAME INSTANCE, BUT IN ESSENCE, YOU WANT TO SAY WHAT TOXICITY YOU CAN GET BY REPEATING THE INSULT. IT MAY NOT BE -- AT THE MINIMAL IT ALLOWS YOU TO IDENTIFY POSSIBLE TOXICITY, BECAUSE YOU ARE GET THE SPECTRUM OF TOXICITY THAT YOU SEE AND THAT MAY VARY. THEN YOU REPEAT IT AND ACTUALLY IT AGAIN CAN BE TAILORED TO THE NEEDS. WE ARE NOT TALKING ABOUT ABOUT A MONTH PROBABLY. >> MOST OF US ARE DOING A 14 DAY TOXICITY STUDY FOR THESE AGENT, SO IF YOU DO SINGLE SURGERY I HOPE IT WOULDN'T GO PAST 14 DAYS. >> NO, IF DEPENDING ON THE COMPOUND, WE ENCOURAGE YOU TO DO SUFFICIENT STUDY. >> THANKS. >> IF YOU HAVE AN IMAGING AGENT THAT CONSISTS OF A TARGETING AND A DYE SAY LICOR OR SOMETHING AND YOU GO THROUGH THE NONCLINICAL STUDY SO IT WOULD BE SAFE AND THEN YOU WANTED TO SWITCH THE TARGETING MOIETY, WHETHER FOR TARGET OR THE SAME TARGET BUT SLIGHTLY BIOCHEMICAL, HOW MUCH OF THE NONCLINICAL STUDY DO YOU NEED TO REPEAT? >> FAMILIARITY AND UNDERSTANDING OF THIS CLASS IS ALSO INVOLVING ALONGSIDE, AND SOMETIMES SAY NCI, NIH OR EVEN A CONSORTIUM OF COMPANIES COME TOGETHER AND CONNECT THE DYE AND SO ON, DEPENDING ON WHAT YOU ARE CHANGING, IF IT IS -- FIRST OF ALL, IT DEPENDS ON THE DOSE. IF YOU ARE DEALING WITH A MICRODOSE, THE CHANGE IS VERY MINIMAL, AND THOSE CHANGES WILL BE EVALUATED NOT BY PHARMACOLOGY AND COUNTERPARTS, YOU CAN LEVERAGE AND I ENCOURAGE YOU TO LEVERAGE WHAT YOU'VE CONDUCTED AND THAT IS WHERE THE CASES OF A BRIDGE STUDY MIGHT BE USEFUL AND ADDED COMMUNICATION WITH THE AGENCY WOULD ALSO BE USEFUL. >> SO IN OPTICAL IMAGING WE VERY RARELY CAN DO MICRODOSING BECAUSE THE SENSITIVITY OF OUR INSTRUMENTS IS NOT AT THE SAME LEVEL OF A PET. WHAT ABOUT IN THE NONMICRODOSING REGIME? >> WHAT YOU ARE TALKING ABOUT, MICRODOSE OR NOT, IT CAN STILL BE LEVERAGED TO A LARGE EXTENT, AND I AGREE WITH THAT, YOU SHOULD BRING ALL THE DETAIL YOU HAVE AND NOT BE DEEMED YOUR DEVELOPMENT -- >> LET'S MOVE ON TO THE NEXT SPEAKER, PLEASE. I WOULD REQUEST THAT PEOPLE ASKING QUESTIONS INTRODUCE THEMSELVES PARTICULARLY IF THEY HAVE NOT INTRODUCED THEMSELVES BEFORE. IT WOULD BE HELPFUL FOR BOTH THE PEOPLE IN THE ROOM AND ALSO THE PEOPLE WATCHING. >> GOOD MORNING, EVERYONE. I'M AT CDER IN THE OFFICE OF CLINICAL PHARMACOLOGY. I SPEND THE MAJORITY OF MY TIME CONSULTING TO THE DIVISION OF MEDICAL IMAGING PRODUCTS, BUT YOU MAY ALSO ENCOUNTER ME IF YOU'RE DEVELOPING AN OLG LOGIC -- AN ONCOLOLOGICAL THERAPEUTIC BECAUSE I ALSO SPEND SOME TIME THERE. I THOUGHT I WOULD BEGIN BY CASTING THE REST OF WHAT I WAS GOING TO SAY IN ITS CONTEXT OF COURSE EVERYBODY IS INTERESTED IN APPROVAL. IFT THE PRIMARY THRUST OF WHAT WE DO, IT'S ABSOLUTELY OF THE ESSENCE. BUT SOME OF THE THINGS WE DO FROM A CLINICAL PHARMACOLOGY PERSPECTIVE DO NOT ALWAYS DIRECTLY IMPACT APPROVAL PER SE. AT THE END OF THE PROCESS WE WANT TO SEE HIGH QUALITY INSTRUCTIONS FOR USE. SOMETIMES THAT INVOLVES INDIVIDUALIZATION OF DOSE. THE OTHER THING WE HOPE TO HAPPEN OR RATHER HOPE TO AVOID IS POST-MARKETING COMMITMENTS OR REQUIREMENTS. SO SOME OF WHAT I'M GOING TO TALK ABOUT IS WHAT WE WOULD CONSIDER GOOD SOLID DRUG DEVELOPMENT AND IT RELATES TO EFFICACY AND SAFETY FOR THE GENERAL POPULATION BUT IT'S NOT ALWAYS IDENTICAL. I'VE ORGANIZED THE REST OF THE PRESENTATION ACCORDING TO DEVELOPMENTAL MILESTONES. I'VE LISTED THE FIVE THAT I'M GOING TO TALK ABOUT HERE. THESE ARE USUALLY TIMES IN DEVELOPMENT WHERE SPONSORS WILL COME IN AND TALK TO US OR IN THE CASE OF SO MANY PROTOCOLS, WE WILL OFFER COMMENT RECOMMENDATIONS FOR HOW WE THINK THINGS SHOULD GO. NOT SURPRISINGLY, I BEGIN WITH FIRST IN HUMAN TRIAL. A NUMBER OF THE SLIDES THAT I'M GOING TO GO THROUGH ARE GOING TO BE BROKEN INTO SAFETY AND EFFICACY. THERE'S A DISTINCTION THAT'S MADE. IN THE EXTREME, SAFETY ISSUES CAN BE HOLD ISSUES. FDA HOPEFULLY INFREQUENTLY WILL TELL SPONSORS THAT THEY'RE NOT ABLE TO PROCEED WITH THEIR CLINICAL TRIAL BECAUSE THERE ARE SAFETY ISSUES. IN CONTRAST, EFFICACY ISSUES NEARLY ALWAYS ARE NOT ABOUT HOLD ISSUES. RATHER, FDA IS MAKING RECOMMENDATIONS THAT WE THINK WILL ENHANCE YOUR DRUG DEVELOPMENT OR LET YOU BE SUCCESSFUL AT THE END. SO WHEN YOU RECEIVE RECOMMENDATIONS FROM US, YOU'LL WANT TO KEEP THAT IN MIND. SOMETIMES YOU MAY EVEN WANT TO ASK, IS THIS A HOLD ISSUE OR IS THIS SIMPLY WHAT YOU THINK WOULD BE PRUDENT? AT THE TIME OF FIRST TO HUMAN, THERE ARE FEW CLINICAL PHARMACOLOGY ISSUES THAT WILL REALLY RESULT IN A CLINICAL HOLD. MOST OF THEM INVOLVE ANIMAL TOXICITY, NOT CLIN-PH ARM PER SE. HOWEVER, THE FOUR LISTED HERE ARE LOOKED AT. ENTRY CRITERIA IS IMPORTANT. IF YOUR DRUG IS RENALLY EXCRETED, DO YOU HAVE CRITERIA FOR RENAL IMPAIRMENT, ENTRY OF RENAL IMPAIRMENT PATIENTS. MONITORING OF CARDIOVASCULAR SAFETY IS LOOKED AT. -- MONITORING OF CARDIAC SAFETY IS LOOKED AT. WE'RE INTERESTED IN DRUG TO DRUG INTERACTIONS. MOST FREQUENT ISSUE IS WHETHER YOUR DESCRUG A SUBSTRATE, WE'RE ALSO INTERESTED IN YOUR DRUG IS A PERSPECTIVE TRAIL TORE OF DRUG ABOUT HER ACTIONS BUT HERE PRIMARILY WE'LL BE LOOKING TO SEE WHETHER YOU'VE DETERMINED YOUR DRUG IS A SUBSTRATE, THAT IS, A VICTIM OF OTHER DRUGS. FINALLY WE'LL LOOK TO SEE FOR SOME INSTRUMENT, NOT IV'S OR TOPICALS, BUT FOR ARTICLE AGENTS WE WOULD BE INTERESTED IN WHETHER OR NOT YOU'RE GIVING THE DRUG WITH FOOD OR IF THE DRUG'S BIOFARM SUIT IKS PREDICT THERE -- BIOPH ARMACEUTICS, THERE MIGHT BE A FOOD EFFECT. I WON'T TALK ABOUT THIS FOR MOST OF THE PRESENTATION. WHAT WE ARE INTERESTED SOMETIMES FOR ORALS OFTENTIMES IS THAT EARLY INFORMATION ON THE EFFECT OF FOOD BE ACCUMULATED. THE REASON FOR THAT IS WE'RE NOT ONLY INTERESTED IN WHAT HAPPENS AT THE END OF DEVELOPMENT BUT ALSO WE WANT TO SEE OPTIMAL DOSING DURING DEVELOPMENT. I APPRECIATE THIS ISSUE IS NOT LARGE IN DEVELOPING OPTICAL IMAGING AGENTS, MOST OFTEN THEY'RE NOT GIVEN ORALLY AND MOST OFTEN AITS LONG WITH SURGERY WHERE PATIENTS ARE FASTING. THE EFFICACY ISSUES THAT WE THINK ABOUT IN A FIRST TO HUMAN TRIAL, AS I'VE SAID EARLIER, GENERALLY EFFICACY, NONHOLD ISSUES, WE MAKE RECOMMENDATIONS FOR TRIAL DESIGN. SOMETHING THAT IS IMPORTANT AND WE SEE PERHAPS TOO INFREQUENTLY IS THE NOTION OF DETERMINING A NEAR OPTIMAL DOSE. THIS PROCESS WE WOULD LIKE TO SEE IT BE AS COMPLETE AS IT CAN PRIOR TO CONFIRMATORY TRIALS, AND IT'S MOST OFTEN PRUDENT TO BEGIN THIS SORT OF THINKING FROM THE FIRST IN HUMAN TRIAL. MOST SPONSORS ARE THINKING THIS WAY. THEY MAY JUST NOT THINK ABOUT IT AS CAREFULLY AS I HOPE FDA SOMETIMES DOES. WE WOULD DEFINE NEAR OPTIMAL AS A DOSE AND A REGIMEN, IMAGING CONDITIONS, TIMING, THE DEVICE THAT YOU'RE USING, WHICH IS SUPERIOR TO ALTERNATIVES WHICH HAVE BEEN STUDIED. IF YOU THINK ABOUT WHAT WE'RE ASKING HERE, IT WOULD TAKE A MINIMUM OF THREE LOOKS AT ALL THE VARIABLES OF INTEREST. LET'S SAY YOU SUCCEED WITH YOUR INITIAL DOSE, SUCCESS BEING YOU'RE PLEASED, YOU CAN VISUALIZE WHAT YOU HOPED TO VISUALIZE. THE QUESTION WE WOULD HAVE AT THAT POINT IS, WOULD MORE BE BETTER OR WOULD LESS BE JUST AS GOOD? THAT QUESTION WILL ALWAYS LOOM LARGE. THE ONLY EXCEPTION TO THAT WOULD BE IF YOU'RE A TOXICOLOGICAL LIMIT, THEN OF COURSE WEAPON WOULDN'T ASK QUESTIONS ABOUT WHETHER MORE WOULD BE BETTER. THIS INFORMATION IS ACCUMULATED IN AN ITERATIVE PROCESS. WE'RE SUGGESTING HERE THAT IT WOULD BEGIN IN PHASE 1. THE MORE OF IT YOU GET IN PHASE 1, THE BETTER OFF YOU WOULD BE IN PHASE 2, AND THIS IS NOT INTELLECTUAL GENIUS HERE, BUT IT'S GOOD TO THINK ABOUT HOW YOU WILL STAGE IT SO IF THE CONCLUSION IS PHASE 2, YOU WILL BE WHERE YOU HOPE TO BE. THE OTHER THINGS WE LOOK AT IN A PROTOCOL FOR FIRST IN HUMAN TRIAL ARE THE PK SAMPLING IS SUFFICIENT. I ALREADY MENTIONED FOOD AND DRUG INTERACTIONS. THOSE ARE OFTEN THOUGHT OF AS SAFETY ISSUES BUT THEY'RE ALSO EFFICACY ISSUES. BOTH OTHER DRUGS AND FOOD CAN INCREASE AS WELL AS DECREASE CONCENTRATIONS, SO THEY CAN PACK EFFICACY AS WELL AS SAFETY. I'M GOING TO MOVE ASIDE FOR JUST A MOMENT AND TALK ABOUT PHARMACOKINETICS. WE SEE PHARMACOKINETICS AS USEFUL FOR DRUG DEVELOPMENT GOALS AND NOT ONLY PACKAGE INSERT. WHEN WE RECOMMEND PHARMACOKINETICS WE'RE DOING SO NOT ONLY SO THAT AT THE END OF THE PROCESS YOU CAN WRITE A GOOD PACKAGE INSERT BUT SO YOU CAN DEAL WITH ISSUES THAT ARISE IN DRUG DEVELOPMENT. EARLY ON PHARMACOKINETICS CAN IMPROVE THE SELECTION OF IMAGING TIMING, TIMING OF REPEAT DOSING AND AMOUNT OF REPEAT DOSING. THERE CAN BE VARIABILITY IN PK WHICH CAN BE INFORMATIVE AND GIVE INFORMATION TR WHICH IMAGES ALONE WHICH TEND TO BE GOOD ENOUGH OR NOT GOOD ENOUGH, SORT OF A BINARY OUTCOME, DO NOT CONVEY. THE GOAL THAT WE HAVE OR WE HOPE YOU ALSO HAVE IS TO CORRELATE CONCENTRATIONS WITH CLINICAL OUTCOMES. FOR THIS REASON WE RECOMMEND THAT LATE PHASE STUDIES WHERE THE DOSE MAY ALREADY BE LARGELY WORKED OUT FOR THE TYPICAL PATIENTS INCLUDE PHARMACOKINETIC SAMPLE COLLECTION. PART OF DOING GOOD PK IS TO HAVE AN ADEQUATE BIOANALYTICAL METHOD, AND FINALLY FOR TOPICALS, YOU MIGHT SUPPOSE THERE WOULD BE NO NEED TO DO PK. WE DON'T SEE IT QUITE THAT WAY BECAUSE WE'RE LOOKING FOR EVIDENCE THAT THE DRUG INDEED DOES NOT GET ABSORBED. IF IT DOES GET ABSORBED, WE WANT TO KNOW HOW MUCH AND WE WANT TO KNOW IF IT CORRELATES WITH NEGATIVE OUTCOMES. WE ALSO MAY ASK IF YOU DO SMALL NUMBERS OF SUBJECTS OR PATIENTS EARLY ON AND SHOW THAT IT DOESN'T GET ABSORBED, WE MAY FIND THAT INADEQUATE BECAUSE THIS IS A QUESTION OF NUMBERS. IT COULD BE THAT IN AN ODD PATIENT IT HAPPENS AND THEN WE WOULD BE INTERESTED IF THAT CORRELATES WITH TOXICITY. SO WE MIGHT ASK YOU TO CONTINUE THAT PROCESS THROUGH PHASE 3. FOR PHASE 2 TRIAL, AGAIN, SAFETY AND EFFICACY. SIMILAR TO PHASE 1 WITH REGARD TO SAFETY, ONLY INFREQUENTLY THERE WOULD BE HOLD ISSUES RELATIVE TO CLINICAL PHARMACOLOGY. WE OF COURSE, NOT SURPRISINGLY, USE THE PHASE 1 DATA TO TAYLOR OUR -- TAILOR OUR RECOMMENDATIONS THINKING ABOUT SAY PHASE 26789 SIMILAR TO EFFICACY, WE'LL MAKE RECOMMENDATIONS FOR TRIAL DESIGN, SELDOM WOULD THERE BE HOLD ISSUES. AS I INDICATED EARLIER, AT THE END OF THE PHASE 2 TRIAL, WE ARE HOPEFUL THAT WE HAVE THE DISCOVERY OF A NEAR OPTIMAL DOSE AND IMAGING CONDITIONS. WE WOULD ASK FOR PHASE 2 PHARMACOKINETIC SAMPLING FOR THE SAME REASONS I INDICATED ON THE LAST SLIDE, AND ALSO IN PHASE 2 THERE OFTEN MAY BE A BREADTH OF DOSES GIVEN AND THUS A RANGE OF CONCENTRATIONS WHICH ALLOWS US TO GET AT WHETHER OR NOT THERE'S PHARMACOKINETIC LINEARITY. THIS BECOMES IMPORTANT BECAUSE IF LATER IN DEVELOPS YOU LEARN THAT THERE'S SPECIFIC POPULATIONS THAT HAVE ALTERED PK, THE QUESTION BECOMES HOW TO REDUCE DOSE. AND IF YOU UNDERSTAND WHETHER PK IS LINEARITY, YOU CAN USE THE PK INFORMATION YOU ACQUIRE IN THE SPECIFIC POPULATIONS TO ADJUST DOSE. IF WE DON'T KNOW THE LINEARITY, THEN YOU HAVE TO DO AN IT EMPIRICALLY, THIS IS MORE CUMBERSOME AND DIFFICULT. AT THE END OF PHASE 2 MEETING, WE'RE LOOKING FOR THE THINGS THAT I SAID. I'VE ALREADY TALKED ABOUT FOOD EFFECT. I'VE PUT TOGETHER SOME QUESTIONS THAT FREQUENTLY THOSE THAT ARE DEVELOPING DRUGS FOR A SINGLE USE, THEY MAY NOT ALWAYS COME TO MIND. THE FIRST ONE IS AT THE END OF PHASE 2 WE WOULD LIKE TO KNOW WHAT TO MEASURE IN FUTURE STUDIES. THAT IS, WE'RE HOPEFUL BY THIS TIME OF DEVELOPMENT YOU'VE IDENTIFIED MAJOR ACTIVE MET AN LIETSZ. ACTIVE -- METABOLITES. ACTIVE WOULD MEAN IN TERMS OF I AM NAJ OR TOXOCO-LOGIC. IN ORDER TO DO THIS, YOU HAVE TO UNDERSTAND WHETHER YOUR DRUG IS METABOLIZED. OFTENTIMES IN VITRO INFORMATION WILL HELP BUT YOU WOULD HAVE HAD TO THINK ABOUT THAT AND TRY TO MEASURE IT IN HUMANS. ALSO OBVIOUSLY FOR HOPEFULLY OBVIOUSLY FOR DRUGS THAT ARE ADMINISTERED LOCALLY WITHOUT SYSTEMIC ABSORPTION, OUR BASELINE EXPECTATION WOULD BE THAT THERE ARE NOT ACTIVE METABOLITES. QUESTION WE ASK AT THE EFNED OF PHASE 2 MEETING WOULD BE WHAT DATA IN SUBJECTS WITH ORGAN IMPAIRMENTS ARE NEEDED? THIS WOULD DEPEND ON THE ROUTE OF EXCRETION AND ELIMINATION OF YOUR DRUG. AGAIN, THIS IS MOSTLY ORIENTED TO DRUGS WHICH ARE SYSTEMICALLY ABSORBED WHICH MAY BE THE MINORITY IN OPTICAL IMAGING. AT THIS PHASE IN DEVELOPMENT IT'S GOOD TO INQUIRE INPUT FROM US IN HOW SPECIFIC POPULATIONS AND THEIR DOSING WOULD BE ADDRESS IN THE FINAL APPLICATION . WHAT DRUG INTERACTION STUDIES ARE NEEDED AND WHAT DDI STUDIES ARE NEEDED WITH YOUR DRUG AS A PERPETRATOR ARE NEEDED. IN THE CASE OF PERPETRATION, IT'S NOT APPLICABLE TO A MICRODOSE, AND ALSO IF YOU'RE GIVING A SINGLE DOSE, WE WOULD USUALLY DETERMINE IT'S NOT NECESSARILY TO EVALUATE YOUR DRUG AS AN INDUCER, BUT EVEN WITH A SINGLE DOSE, YOUR DRUG COULD PERPETRATE DRUG INTERACTIONS AS AN INHIBITOR, SO THAT IS OF INTEREST. AT THIS POINT OF DEVELOPMENT WE HOPE YOU CAN COME TO US WITH SOME INFORMATION ABOUT WHAT YOUR DRUG DID IN VITRO SO WE CAN HELP DETERMINE WHETHER THIS WILL BE NEEDED PRIOR TO FILING. BY THE TIME OF THE PHASE 3 TRIAL, THE SAFETY ISSUES ARE AS I INDICATED WITH THE OTHERS, BUT INFORMED BY WHAT YOU KNOW. EFFICACY OR NONHOLD ISSUES GENERALLY, AS I SAID, RECOMMENDATIONS FOR TRIAL DESIGN, WE LOOK AGAIN TO SEE IF THE DOSE IS NEAR OPTIMAL. WE REVIEW WHAT WAS DETERMINED AT THE END OF PHASE 2 MEETING. AS I'VE ALREADY HINTED AT, IN PHASE 3 WE WILL OFTEN ASK FOR PHARMACOKINETIC SAMPLING, THE IDEA IS THAT THIS INFORMATION IS USED TO CORRELATE OUTCOMES, IMAGING AS WELL AS SAFETY, WITH CONCENTRATIONS. AND THE WAY THIS INFORMATION WOULD BE USED IS IF YOU HAVE A SPECIFIC POPULATION WITH VARIED PK, WE COULD MAKE DOSE CHANGE RECOMMENDATIONS. ALSO THERE IS POTENTIAL, THIS HAPPENS MOST INFREQUENTLY, USUALLY PHASE 3 IS EMPIRIC AND THE DOSE TO BE APPROVED WILL BE THE ONE THAT WAS STUDIED, BUT IF WE DID HAVE A RANGE OF DOSES IN PHASE 3, THERE IS SOME POTENTIAL FOR US TO AT THE END OF THE PROCESS DETERMINE WHAT THE OPTIMAL DOSE IS AND CHANGE IT FROM WHAT WE THOUGHT IT WAS AT THE END OF PHASE 2. AS I INDICATED, THAT WOULD BE AN EXCEPTION. BY THE TIME YOU COME IN FOR YOUR PRENDA MEETING, HOPEFULLY THINGS ARE ALL TOGETHER. ARE MOST INFREQUENTLY, THIS IS ABOUT FORMATTING DATA TO BE SUBMITTED, NOT ABOUT DO WE HAVE THE RIGHT STUDIES, ARE OUR TRIALS ADEQUATE. SOMETIMES WHEN IT IS NOT -- WHEN DRUG DEVELOPMENT IS NOT ORG NIEPTZED BY BIG FAR -- IS NOT ORGANIZED BY BIG PHARMA, THERE ARE ISSUES LIKE THIS ABILITY TO RELY ON DATA FROM THE LITERATURE, THAT SORT OF THING, BUT THE HOPE IS YOU'VE BEEN TALKING TO US ABOUT BY THIS TIME AND THINGS ARE FAIRLY WELL SORTED OUT. I'VE GIVEN TWO SLIDES WITH GUIDANCE OS THEM. THIS IS THE CLINICAL PHARMACOLOGY GUIDANCE PAGE. THIS LIST IS NOT COMPREHENSIVE, BUT THIS LIST IS SOME OF THE MOST IMPORTANT ONES OR THE ONES THAT MAY BEST APPLY TO YOUR PRODUCTS. NOT THAT THE OTHERS CAN BE NEGLECTED BUT THESE ARE OFTEN THE MEAT AND POTATOES OF WHAT WE'RE INTERESTED IN SEEING. THEN SECONDLY THERE'S ALSO A GUIDANCE PAGE FOR BIOPHARMACEUTICS. AGAIN, NOT COMPREHENSIVEMENT MOST OF THESE ARE RELEVANT TO ORAL PRODUCTS, PROBABLY NOT RELEVANT TO TOPICAL OR ONLY UNUSUALLY RELEVANT TO TOPICAL AND PERHAPS NOT AT ALL TO IV. THE GUIDANCE IS ON THIS PAGE. THANKS TO EVERYBODY WHO HELPED. BRIAN BOOTH IS MY DEPUTY DIRECTOR AND THE CAST OF CHARACTERS IN DMIP ARE ALL HERE TODAY. MOST OF THEM ARE PRESENTERS. SO THANK YOU. [APPLAUSE] >> WE'RE GOING TO HAVE A PANEL AFTERWARDS. HOPEFULLY WE'LL ADDRESS SOME OF THESE QUESTIONS. >> CAN I ASK A QUESTION? >> SORRY. >> WHAT KIND OF METABOLITES DO YOU WANT TO SEE IN HUMANS? ARE YOU GOING ON REQUIRE C14 LABELED DRUG METABOLISM STUDIES OF ALL OF THESE TUMOR-TARGETED DYES? >> SO THE FIRST DISTINCTION WOULD BE MADE OF HOW HAVE THE DRUG IS ADMINISTERED. IF IT'S NOT ADMINISTERED SUCH THAT SYSTEMIC ABSORPTION IS LIKELY, WE PROBABLY WOULD NOT HAVE MUCH CONCERN ABOUT METABOLISM. IF IT IS ADMINISTERED SYSTEMICALLY, THEN THE ANSWER TO THE QUESTION REVOLVES AROUND THE SCIENCE. IF IT'S POSSIBLE THAT YOU HAVE ACTIVE METABOLITES, ACTIVE MEANING THEY'RE TOXICOLOGIC OR THAT THEY CONTRIBUTE TO THE IMAGE OR DETRACT FROM THE IMAGE, WE'RE INTERESTED. THE QUESTION OF WHETHER YOU WOULD HAVE TO USE LABEL DRUG VERSUS COLD DRUG TO SORT IT OUT WOULD BE CASE BY CASE. IF YOUR ANALYTICAL METHODS WERE SUFFICIENT TO DO IT COLD, WE HAVE NO DESIRE TO DOSE C14. >> WELL F YOU'RE DOSING LESS THAN A MILLIGRAM PER PATIENT -- >> THE QUESTION OF ACTIVE MET -- METABOLITES FROM A SAFETY PERSPECTIVE, IF IT'S A MICRODOSE, WE WOULDN'T ASK THE QUESTION ORDINARILY. HOWEVER, IF IT'S FROM THE IMAGING PERSPECTIVE, IT COULD STILL AFFECT IMAGING EVEN THOITS A MICRODOSE. OBVIOUSLY EVEN THOUGH IT'S MICRODOSE, IT'S EFFECTIVE. SIMILARLY IT COULD HAVE AN IMPACT ON IMAGING AND IT WOULD BE OF INTEREST. >> IF YOU LOOK AT THE IMAGE DATA AND YOU LOOK AT THE TOXICITY DATA AND YOU DON'T SEE ANY PROBLEMS WITH EITHER IMAGE CLARITY OR RESOLUTION OR SHARPNESS OR WITH ANY TOXICITY, YOU WOULDN'T REQUIRE A C14 LABELED IN VIVO? >> IT WOULD BE UNUSUAL TO ASK FOR A BALANCE STUDY BUT IT'S NOT AN IMPOSSIBILITY. HOWEVER, THE ABILITY TO SEE AN IMAGE IS NOT INDICATIVE THAT A METABOLITE ISN'T CONTRIBUTING. SO THE QUESTION WOULD THEN BE, LET'S SAY THAT THE METABOLITE RESULTS FROM 2D6 METABOLISM WHERE THERE'S POLYMORPHISM AND THERE COULD BE A SPECIFIC POPULATION THAT WOULD HAVE ALTERED IMAGING AS A RESULT. SO WITH THAT, WE WOULD BE ASKING INFORMATION TO SORT THROUGH WHETHER THAT SOFORT THING IS GOING ON -- WHETHER THAT SORT OF THING IS GOING ON BECAUSE OF INDICATIONS FOR EFFICACY. >> I THINK WE HAVE ONE MORE QUESTION. >> A QUICK QUESTION. GONE ZAL LESS. I'M CURIOUS IF A PK PERSPECTIVE, WHAT ARE SOME OF THE GENERAL THINKING IF A SPONSOR WANTED TO CHANGE THE RATE OF ADMINISTRATION FOR AN IBH, I'M CURIOUS FROM A PK PERSPECTIVE HOW YOU LOOK AT THAT. >> TWO THINGS COME TO MIND. THE FIRST WOULD BE SAFETY, WHICH IS NOT PK, PER SE, BUT THE SECOND QUESTION THAT WILL COME TO MIND IS THE LENGTH OF TIME BETWEEN ADMINISTRATION OF THE DOSE AND THE CAPTURING OF THE IMAGE. SO IF IMAGING IS VERY DISTAL TO ADMINISTRATION, IF YOU IMAGE IT TWO HOURS, GIVING IT OVER FIVE VERSUS TEN MINUTES, AS LONG AS WE HAD EVIDENCE THAT THINGS STAYED LINEAR, IT WOULD PROBABLY BE ACCEPTABLE. >> I WANT TO SAY THESE MICROPHONES ARE NOT WIRED IN, SO IF SOMEBODY IN THE BACK HAS A QUESTION, WE'RE HAPPY TO HAND THE MICROPHONE BACK AS WELL IF THE SEATS ARE TAKEN. PAULA WAS GOING TO GIVE US A TALK ON THE NCI RESOURCES AVAILABLE. >> EBEN ALSO ASKED ME TO GIVE PEOPLE INFORMATION ABOUT LUNCH. THAT WILL COME IN A LITTLE WHILE. YOU HAVE TO STAY FOR A WHILE. THERE'S A CAFETERIA HERE. WE'RE ONLY GOING TO HAVE 45 MINUTES FOR LUNCH. THERE'S A CAFETERIA HERE WHICH HAS A WIDE VARIETY OF THINGS INCLUDING A SALAD BAR AND STUFF LIKE THAT. ACROSS THE STREET THERE'S A BAKERY WHICH HAS VERY GOOD SANDWICHES, THERE'S A SUBWAY, THERE'S A PLACE THAT'S GOT SUSHI OR SOMETHING LIKE THAT. SO THERE ARE THREE OR FOUR PLACES IN AND AROUND HERE THAT ARE AVAILABLE FOR LUNCH. I CONFESS, I HAD TOTALLY FORGOTTEN THAT I WAS GOING TO GIVE THIS TALK, SO YOU'RE GEPG THE RECYCLED ONE THAT I GAVE ON MONDAY. I'LL TALK ABOUT GRANTS, GENERAL FUNDING AND SPECIALIZED IMAGING FUNDING, SBIR, SBIR, STTR. DID I IT WRONG. IT SHOULD BE STTR, NOT STRR. AND THE EXPERIMENTAL THEY ARE PURT IKS PROGRAM WHICH SOME OF -- THERAPEUTICS PROGRAM WHICH SOME OF YOU IN THIS ROOM ARE FAMILIAR WITH BECAUSE YOU'VE USED IT, AND THE NTCN TRIAL NETWORK. AND REGULATORY ADVICE. GRANT FUNDING. THESE SLIDES WILL BE AVAILABLE. FUNDING OPPORTUNITIES ARE AVAILABLE AT THESE LINKS, WITH ANNOUNCEMENTS FOR NIH AND NCI. COMMON TYPES OF GRANTS, UNSOLICITED, RO1'S, RO3'S, R21'S, REQUESTS FOR APPLICATIONS, WE SAY WE WOULD LIKE YOU TO PUT IN GRANT APPLICATIONS ON THIS TYPE OF SUBJECT AND PROGRAM ANNOUNCEMENTS. WE USE PROGRAM ANNOUNCEMENTS FOR IMAGING FAIRLY HEAVILY BECAUSE IT'S HIGHLY SPECIALIZED AND DOESN'T TEND TO BE VERY BUY LOGICALLY ORIENTED. THEY'RE REVIEWED BY SPECIAL PANELS. I'LL ONLY TALK ABOUT SOME OF THE SPECIALIZED ONES WE HAVE FOR IMAGING. THERE'S THE EARLY PHASE CLINICAL TRIALS IN IMAGING AND IMAGE GUIDED INTERVENTION, THERE'S A PAR FOR THAT. YOU HAVE TO BE READY TO SUBMIT OR HAVE YOUR IND BEFORE WE'LL GIVE YOU ANY MONEY. IT CAN'T BE I'M GOING TO DO A FEW ANIMALS AND AT THE END OF THE TWO OR THREE YEARS I MIGHT THINK ABOUT A CLINICAL TRIAL. THIS IS NOT WHAT THIS IS FOR. THIS IS FOR ACTUALLY DOING THE TRIALS. HALF A MILLION DOLLARS, DIRECT COST OVER THREE YEARS, I THINK YOU CAN GET A THIRD YEAR NO COST EXTENSION TO FINISH YOUR TRIAL. SUPPORTS EARLY PHASE TRIALS, NOT LATER. THERE'S ONE FOR IMAGE GUIDED DRUG DELIVERY IN CANCER. AND IN GENERAL, THAT'S NOT AS APPLICABLE TO WHAT YOU'RE DOING HERE. BUT IT'S SOMETHING YOU MIGHT WANT TO LOOK AT. THE STANDARD POLICIES. ENCOURAGES INNOVATIVE TRANSLATIONAL RESEARCH. THERE'S A CO-CLINICAL QUANTITATIVE IMAGING RESEARCH RESOURCES WHICH IS A BRAND-NEW PAR. THAT ONE COULD WELL BE RELEVANT TO THIS WHERE YOU MIGHT WANT TO GO BACK AND FORTH BETWEEN ANIMAL MODELS AND HUMANS TO ESTABLISH HOW YOU QUANTIFY WHAT YOU'RE LOOKING AT. AND THIS ONE I THINK IS OF MORE INTEREST, THE ACADEMIC INDUSTRIAL PARTNERSHIPS FOR TRANSLATION OF SYSTEMS FOR CANCER INVESTIGATIONS. THESE ARE EXPLICITLY FOR ACADEMICS PLUS COMPANIES. THEY CAN BE ANY COMPANY, INTERNATIONAL, LARGE, SMALL. IT IS FOR RESEARCH BUT THERE MUST BE A COMMERCIALIZATION PLAN EMBEDDED. SO AT THE END OF A FIVE-YEAR GRANT PERIOD, YOU WOULD NOT HAVE A PRODUCT TO SELL, BUT YOU SHOULD HAVE CLEARLY A PROTOTYPE THAT'S READY TO DEVELOP. SO THESE ARE VERY EFFECTIVE FOR THE COMBINATIONS THAT WE'RE LOOKING AT HERE WHEN WE'RE TALKING ABOUT DEVICES PLUS DRUGS. SBIR'S AND STTR'S YOU SHOULD BE FAMILIAR WITH. THESE ARE LIMITED TO SMALL COMPANIES. HOWEVER, THEY HAVE A SET-ASIDE WHICH MAY MAKE THEM HIGHLY ADVANTAGEOUS BECAUSE THEY MUST SPEND THIS MONEY. IT DOESN'T GET -- NOBODY GETS TO GO GRAB IT FOR RO1'S OR ANY OTHER PROJECT. CONGRESS HAS SPECIFIED THAT THESE ARE SET-ASIDES. THAT'S ABOUT 700 MILLION ANNUALLY AT NIH, 115 OF THAT IS AT NCI. SO THIS IS NOT INSIGNIFICANT. THIS IS FROM MY ONE ON MONDAY, WHICH WAS ON IMMUNOTHERAPY. IN THIS CASE IT'S HIGHLY RELEVANT TO WHAT PEOPLE ARE DOING HERE AS LONG AS THE COMPANY IS A U.S. SMALL BUSINESS. THERE'S ALSO QUANTITATIVE IMAGING FOR EVALUATION OF RESPONSES. AGAIN, NOT QUITE AS RELEVANT BUT IS APPROPRIATE FOR DEVELOPMENT OF QUANTITATIVE IMAGING METHODS. AND FINALLY THERE ARE A VARIETY OF INFO MAT IKS GRANTS WHICH AGAIN -- INFORMATICS GRANTS, WHICH AGAIN, IF YOU NEED TO PROCESS DATA AND YOU NEED TO DEVELOP SOFTWARE FOR DOING THAT AND THINGS LIKE THAT, THESE ARE APPROPRIATE GRANT OPPORTUNITIES. GRANTS DON'T GET YOU INTO THE CLINIC, WHICH I'M SURE YOU'RE ALL AWARE OF, AND IT'S VERY DIFFICULT TO GET A GRANT, IF YOU PUT IN A GRANT THAT SAYS I'M GOING TO DO A TOXICOLOGY STUDY, THEY'LL LAUGH AT YOU. SO WE NEED TO FIGURE OCCUPANT THE WAYS TO BRIDGE THE VALLEY OF DEATH AND THIS INCLUDES THINGS LIKE STRUCTURE ACTIVITY RELATIONS, TOXICOLOGY STUDIES, PROCESS DEVELOPMENT. WE ARE DREARING THIS WITH THE NCI EXPERIMENTAL THERAPEUTICS PROGRAM, NEXT. IF YOU DOOLG NEXT AT NCI, YOU WILL -- IF YOU GOOGLE NEXT AT NCI, YOU WILL GET THIS PROGRAM. IT'S NOT A GRANT PROGRAM. VERY IMPORTANT TO UNDERSTAND THIS CLEARLY. WE DO NOT GIVE YOU MONEY. IT PROVIDES YOU ACCESS TO NCI RESOURCES AND EXPERTISE. NCI PERFORMS THE PROJECT. SIMPLE APPLICATION PROCESS. THERE IS AN EXTERNAL EXPERT REVIEW. THE SUCCESS RATE IS ACTUALLY NOT TOO DISSIMILAR FROM GRANTS. SO IT'S NOT GREAT. BUT WE DO HAVE A NUMBER OF SUCCESSES. THERE IS AN INTERNAL EXPERT REVIEW WHICH IS LESS ABOUT THE SCIENCE AND MORE ABOUT DOES NCI HAVE THE RESOURCES TO DO WHAT YOU'RE ASKING US TO DO. YOU MAY ASK US TO DO SOMETHING, WE JUST AREN'T ABLE TO DO IT, WE DON'T HAVE THAT. THERE'S FULL TEAM SUPPORT AND THE APPLICANT IS INVOLVED IN THE PROJECT. SOMETIMES WE SPLIT THE WORK AND THE APPLICANT DOES PART OF IT AND WE DO PART OF IT. THE RESOURCES ARE MULTI-AND INTERDISCIPLINARY CLINICAL TRANSLATIONAL TEAMS, EARLY ACCESS TO TRANSLATIONAL TECHNOLOGIES WE DEVELOP OUT AT 23RED RICK, PK -- OUT AT FREDERICK, PK DEVELOPMENT, SAFETY PHARMACOLOGY, FORMULATION IN GNP SCALEUP. WE ACTUAL HAVE A GNP BIOMANUFACTURING FACILITY OUT AT FREDERICK. WE DO IMAGING FOR BIODISTRIBUTION AND IMAGING FOR IMAGING, BUT I ENCOURAGE THEM, IN MANY CASES, PARTICULARLY WITH NEW ANTIBODIES, TO I BELIEVE LA THEM AND USE THAT FOR THE -- TO LAINL THEM AND -- TO LABEL THEM. WE'LL DO DEVELOPMENT AND FORMULATION OF CLINICAL ASSAYS. I WILL POINT OUT HOWEVER WE ARE THE GOVERNMENT, WE'RE NOT FAST. SO IF YOU'RE A SMALL COMPANY AND YOU WANT THIS FOR YOUR NEXT QUARTER OUTPUT, I WOULDN'T BOTHER. IT TAKES A WHILE TO GET THESE THROUGH. WE DO PROOF OF CONCEPT IN FIRST IN HUMAN STUDIES. RESEARCH CURRENTLY SUPPORTS INVESTIGATIONAL DRUGS AND BUY LOGICS, ACADEMIC RS BIOTECH, PHARMA, INTERNATIONAL AND U.S., PHASE 1, 01 AND 2 CLINICAL TRIALS, HIGH THROUGHPUT SCREENING AND OPTIMIZATION. MOST OF THIS GROUP WOULD NOT BE DOING THOSE. IN THAT CASE, AGAIN, WE EMPHASIZE, IT'S NOT BASIC RESEARCH. FOR THE HIGH THROUGHPUT SCREENING, WE'LL NOT IDENTIFY YOUR TARGET FOR YOU BUT IF YOU HAVE THE TARGET WE MAY HELP YOU FIND AGENTS THAT ADDRESS THAT TARGET. PORTFOLIO STRATIFIED HERE BY CLASS. YOU'LL NOTICE WE HAVE A NUMBER OF IMAGING AGENTS. MOST OF THESE ACTUALLY HAVE BEEN COMPLETED EXCEPT FOR DR. CHOYKE'S STUDY OF DCFBC. SO 8% OF THESE ARE IMAGING. IF YOU GO TO THE WIEB, IT'S NOT OBVIOUS THAT WE DO IMAGING, BUT IT CERTAINLY IS THERE. ACCESS IS, AS I SAID, GOOGLE NEXT AT NCI. WE HAVE JUST ADDED SOMETHING WHICH I THINK WILL BE OF INTEREST TO THE PEOPLE IN THIS GROUP. IF YOU GO THERE WHERE IT SAYS RESOURCES, THIS HAS BEEN UPDATED, THERE'S NOW A TAB THAT SAYS RESOURCES, IF YOU LOOK UNDER THAT RESOURCES, THERE WILL BE A PLACE FOR EXPERIMENTAL CONSULTATION. THIS IS SPECIFICALLY FOR BRIDGING UP TO IND BEFORE YOU HAVE PUT IN ANGER APPLICATION. WE HAVE -- BEFORE YOU HAVE PUT IN AN APPLICATION. WE HAVE ENCOUNTERED SEVERAL TIMES WHERE PEOPLE HAVE STARTED THEIR DEVELOPMENT PROGRAM AND THEN PUT IN AN APPLICATION AND HAVE MANAGED TO MESS UP THE MINIMUM THEY COULD HAVE DONE BEFORE GETTING TO THE FIRST IN HUMAN. WE HAVE VERY EXPERIENCED PHARMACOLOGISTS, TOXICOLOGISTS, IMAGING PEOPLE WHO WILL ADVISE YOU PARTICULARLY ON THE REGULATORY ASPECTS AND CRAFTING SCIENTIFICALLY APPROPRIATE PRECLINICAL PROGRAMS RATHER THAN JUST FOLLOWING A GUIDANCE, AND I THINK EBEN CAN TELL YOU ABOUT THIS PROCESS BECAUSE WE WENT THROUGH IT WITH HIM, AND THIS WAS ONE OF THE ONES WHERE IN FACT AFTER MUCH DISCUSSION NO PHARM-TOX STUDIED WERE REQUIRED FOR HIS IND BECAUSE OF THE WAY IT COULD BE PRESENTED THIS A COMPREHENSIVE SCIENTIFIC MANNER. SO THIS HAS JUST BEEN UP LITERALLY IN THE LAST FEW DAYS AND I ENCOURAGE YOU TO TAKE A LOOK AT IT. IF YOU'RE A COMPANY, THERE IS A CONFIDENTIALITY AGREEMENT SO THAT YOU WILL BE PROTECTED. THIS WILL NOT BE PUBLIC. AND THIS CAN LEAD TO YOUR PUTTING IN AN APPLICATION OR NOT. NATIONAL CLINICAL TRIAL NETWORKS TRIAL, JUST TO -- IT'S NOT WORKING VERY WELL. IT'S A HALF CENTURY OLD, CLINICAL TRIAL SYSTEM FOR ONCOLOGY. THEY CONDUCT LARGE SCALE CLINICAL TRIALS. THIS IS A POSSIBLE MECHANISM FOR YOUR PHASE 3 TRIALS OR LATE PHASE 2 TRIALS. THEY ARE DISEASE ORIENTED, WE'VE RESTRUCTURED THEM A COUPLE YEARS AGO INTO HOPEFULLY WHAT IS TRULY A REAL NETWORK. ONE OF THESE GROUPS SPECIFICALLY DOES ADVANCED INVESTIGATIONAL IMAGING. ALL OF THEM USE IMAGING AS PART OF THEIR REGULAR THERAPEUTIC DEVELOPMENT BUT ECOG-ACRIN HAZY THE MANDATE TO ALSO -- HAPPENS THE MANDATE TO ALSO DO SPECIALTY IMAGING. WE WILL PROVIDE REGULATORY ADVICE AND RESOURCES. I DON'T GUARANTEE IT. I'VE BEEN TURNED DOWN BY THE FDA PROBABLY AS MANY TIME AS THE REST OF YOU HAVE BEEN, BUT WE DO FILE IND'S FOR INVESTIGATIONAL TRIALS. IF SPONSORED BY NCI, WE LIKE TO HOALD THE IND. THE WEBSITE HAS WITH IT A I WILL NOTE THAT THE FILINGS FOR ZR-ANTI-POAD ARE POSTED ON OUR WEBSITE, WHICH YOU MIGHT APPROACH WITH OPTICAL IMAGING OF THERAPEUTIC ANTIBODIES WHICH IS WHAT WE DID IN FACT WITH THE EGFR ANTIBODIES. FOMP ANY THAT WE HOLD -- FOR ANY THAT WE HOLD, WE'LL PROVIDE CROSS-FILE LETTERS, 50 TO 60 TO DATE. WE'LL PROVIDE FULL SOP'S. THE VAST MAJORITY HAVE NOTHING TO DO WITH THE EXACT AGENT YOU'RE TALKING ABOUT. TWO ARE SPECIFIC TO THE AGENT, THE REST ARE THINGS LIKE HOW TO DO A STERILITY TEST, HOW TO RECEIVE RAW MATERIALS, THINGS LIKE THAT, THAT YOU MUST HAVE IF YOU ARE MANUFACTURING. YOU CAN TAKE THESE AND USE THEM AS YOU WILL. WE ADVISE IN THE REGULATORY PROCESS. AGAIN, I MAKE NO GUARANTEES, I'M NOT THE FDA. AND WE HAVE FILED NDA'S TO PERMIT ANDA'S. WE DID SO IN FLUORIDE IN 2012 IN 2012. AND WE HAVE BEEN EXPLORING THE ARE POSSIBILITY OF DOING FLUOROMETHYLCHOLINE. THANK YOU VERY MUCH. THAT'S ALL I HAVE TO SAY. [APPLAUSE] QUESTIONS? I THINK I'VE SAVED A LITTLE BIT OF TIME. >> I HAVE A QUICK QUESTION. JIM BASILION, CASE WESTERN. YOU SAID THE CDA PROTECTED THE DISCUSSIONS. BUTTER YOU ALSO MENTIONED PERHAPS DOING A SCREENING AND FINDING A COMPOUND FOR A TARGET. IS THAT AN IP CONSIDERATION THERE AND HOW DOES THE NIH SHARE THAT? >> I'M NOT AS FAMILIAR WITH THAT PART OF IT, BUT THAT'S DONE THROUGH OUR CHEMISTRY BIOLOGY CONSORTIUM AND I'M NOT SURE WHERE THE IP GOES BUT THAT'S PART OF WHAT GETS NEGOTIATED. SO IT'S UNDER DISCUSSION. IN GENERAL, THE ENTIRE NEXT PROCESS ONE OF THE QUESTIONS THAT IS ALWAYS ASKED IS WHAT IS THE IP SITUATION FOR THIS, WHO OWNS IT, HAS IT BEEN LICENSED OR NOT, BECAUSE THAT'S RELEVANT TO THE DEVELOPMENT. >> CAN YOU EXPAND ON THAT COMMENT ABOUT NOT GETTING SAFETY AND TOXICITY FOR ANTI-EGFR? >> RIGHT. OKAY. >> THAT HAD ALREADY BEEN DONE? >> THE BASIC APPROACH WAS, AND THIS WAS ACCEPTED BY MY COLLEAGUES AT THE FDA, THIS WAS PANATUMATAB, IT'S A WELL-KNOWN DRUG, THERE'S MASSIVE AMOUNTS OF SAFETY AND TOXICOLOGY DATA KNOWN ABOUT IT, MOST OF WHICH YOU CAN ACCESS FROM THE BASIS FOR APPROVAL, THE DYE HAD A TOXICOLOGY PACKAGE FOR IT THANKS ON OUR COLLEAGUES AT LICOR, THE INDEPENDENT DYE. THE CHEMISTRY IS KNOWN. AND BASICALLY WE DID SOME PRECLINICAL WORK WITH ANIMAL MODELS. WE ARE MAKING AN EXTREMELY SMALL CHANGE IN THE MOLECULAR WEIGHT. WE DID DO CELLULAR STUDIES TO EVALUATE ANY CHANGE IN BIOLOGICAL ACTIVITY. THAT'S VERY IMPORTANT. THAT'S THE ONE STUDY YOU HAVE TO DO WHEN YOU MODIFY AN ANTIBODY, TO SHOW THAT WE HAD NOT LOST SPECIFICITY FOR EGFR AND THAT WHEN WE DID GRAPHS IN HIGH, MEDIUM AND LOW, THEY CAME OUT HIGH, MEDIUM AND LOW. THAT PLUS A VERY CAREFULLY CRAFTED SAFETY MONITORING IN THE PROTOCOL THAT IS SPECIFICALLY LOOKING FOR PANATUBAMAD SIDE EYE EFFECT. EBEN COULD PROBABLY ADDRESS IT BETTER. >> WE HAD THE TAMEXOFAB DYE AND WE SHOWED IN THE TOXICOLOGY STUDIES IN NON-HUMAN PRIMATES THAT THE ANTIBODY IN THE DYE AND THE ANTIBODY ALONE WERE ESSENTIALLY EQUIVALENT GIVEN THE SMALL MODIFICATION. SO ONCE WE SHOWED THAT THE MODIFICATION WAS THE SAME AS IT WAS IN PAMEXAMAD, WE COULD SHOW THE TWO WERE ROUGHLY EQUIVALENT AND I THINK WE DID HAVE A TOXICOLOGY STUDY, IT WAS JUST ON ANOTHER ANTIBODY AND WE SHOWED THAT IF WE MODIFIED IT IN THE SAME WAY. >> I THINK THIS IS AN EXAMPLE OF WHAT B I O WAS TALKING ABOUT ABOUT TRYING TO MAKE GOOD SCIENCE AND MAKE GOOD SENSE AND COME DISCUSS. >> IT WAS A PRETTY THOROUGH, IT WAS A PRETTY THOROUGH WORK TO SHOW THAT THE TWO ANTIBODIES WERE THE SAME. >> TOM WAYNE FROM MICHIGAN. SO THAT WOULD BE A GREAT WAY TO SAVE A LOT OF TIME AND MONEY IN DEVELOPMENT. THIS WAS FOR PHASE 1, IS THAT CORRECT? WILL THE FDA ACCEPT THIS TYPE OF WORK FOR, SAY, ALL WANT TWIE AN NDA? >> YOU WOULD HAVE TO ASK THE PEOPLE HERE FROM THE FDA, BUT THE LETTER THAT CAME WITH THE IND SEEMED TO INDICATE THAT UNLESS SOMETHING UNUSUAL SHOWED UP, THAT THERE WOULD PROBABLY NOT BE A GREAT DEAL FURTHER WORK NECESSARY. >> LET'S HAVE THE PANEL COME UP MAYBE. >> YES, THIS IS A GOOD PANEL DISCUSSION. >> MAYBE THAT CAN BE THE FIRST QUESTION FOR THE PANEL. I THINK THAT'S AN EXCELLENT QUESTION. >> TO ANOTHER POINT WITH THAT QUESTION, ARE THE STUDIES THAT PAULA ALLUDED TO PUBLISHED FOR OTHER PEOPLE THAT WANT TO GO THE SAME ROUTE WITH ANTIBODIES WITH SAY THE LICOR DYE? THAT WOULD BE VERY VALUABLE TO EVERYBODY TRYING TO DO ANTIBODY STUDIES S THAT DATA WELL-KNOWN TO PEOPLE? >> THE DATA ON THE NON-HUMAN PRIMATE STUDIES IS PUBLISHED THAT WE USE IN THE TOXICOLOGY STUDY, THAT IS CORRECT, SO THAT'S ON TEXAMAB LICOR DYE. >> I GUESS THERE'S A QUESTION THAT PRETTY MUCH EVERYONE HAS WHO WORKS WITH LICOR IS CAN WE JUST REFERENCE THAT STUDY RATHER THAN DO OUR OWN TOXICOLOGY? THAT WOULD BE HUGE, RIGHT? >> WHAT WE'VE SNEEN OUR TOXICOLOGY STUDIES -- WHAT WE'VE SEEN IN OUR TOXICOLOGY STUDIES IS THAT IT'S NOT THE DYE THAT IS AT RISK, THAT IS THE SAFETY ISSUE. THE REASON WHY I THINK IT WAS ACCEPTABLE IS BECAUSE THERE WAS SUCH A LARGE PANEL OF SAFETY INFORMATION ON THE ANTIBODY ITSELF AND THE DYE WAS HAVING A MINIMAL MODIFICATION, SO I DON'T THINK IT'S THE DYE THAT'S NECESSARILY THE PROBLEM, IT'S THE FACT THAT THE ANTIBODY HAD A KNOWN SAFETY PROFILE. >> I'VE HAD A DIFFERENT EXPERIENCE. I JUST GOT AN IND APPROVED FOR SCI5 AND THE FDA WAS CONCERNED MORE ABOUT THE DYE THAN THE TARGETING ENGINE, SO THEY REQUIRED ALL THE FUNNEL PANEL OF TOXICOLOGY. >> ON THE DYE ALONE. >> ON THE DYE ALONE, YEAH. THERE JUST WASN'T ENOUGH HUMAN DATA FOR THE DYE. THERE'S NOT AS MUCH AS LICOR. THAT WAS PROBABLY THE REASON. >> BECAUSE IT'S A PARADIGM SHIFT. WE'RE ALWAYS TAUGHT ONCE YOU TWEAK THE MOLECULE IT'S A NEW CHEMICAL ENTITY AND YOU HAVE TO START OVER FROM PHASE 1, FROM STAGE ZERO. IT'S GREAT THAT YOU'VE BEEN ABLE TO DO THIS. I'M WONDERING HOW EXTRAPOLATABLE IT IS TO OTHER COMPOUNDS. >> HOPEFULLY THE FDA WILL NOT REALIZE THAT THEY DID THAT NOW. [LAUGHTER] >> IF I CAN MAKE SOME COMMENTS ON THAT. >> GOOD SCIENTIFIC DISCUSSION. >> LET'S INTRODUCE THE PANEL AND THEN WE CAN GO INTO THE QUESTIONS. I DO WANT TO SAY ONE THING, I THINK WHAT YOU'RE HEARING HERE IS THAT THE FDA IS INDIVIDUALIZED FOR EVERY SUBMISSION AND TO QUOTE OR PUT IT INTO SORT OF A DONALD TRUMP SCENARIO, IT'S SORT OF LIKE PORNOGRAPHY, THEY'RE GOING TO KNOW IT WHEN THEY SEE IT. SO YOU'LL PUT YOUR PACKAGE TOGETHER AND THEY'LL TELL YOU IF IT'S RIGHT OR NOT. CAN WE START HERE AND INTRODUCE THE PANEL. >> ADD BEE LANIYONU. -- I'M ADEBAYO LANIYONU. >> MY NAME IS PHILLIP LOW, I'M AT PURDUE UNIVERSITY AND PROFESSOR FOR DRUG DISCOVER AND FOCUS A -- AND STARTED A COMPANY FOR FLUORESCENT GUIDED SURGERY DYES. >> GENE WILLIAMS. I'VE BEEN DOING THIS FOR A WHILE. I LEARNED NOT QUITE AS LONG AS NEIL THAT I'VE BEEN DOING T BUT I'VE BEEN CONSULTING TO MEDICAL IMAGING FOR ABOUT FIVE YEARS AND MY ONCOLOGY EXPERIENCE GOES BACK MORE THAN TEN YEARS PRIOR TO THAT. >> JOSH PFEFER, LABORATORY LEADER FOR OPTICAL DIAGNOSTIC DEVICES AND FDA CENTER FOR DEVICES AND RADIOLOGICAL HEALTH. >> PETE CHOYKE, RADIOLOGIST AT MOLECULAR IMAGING PROGRAM AT NCI. >> MIKE TWEEDLE, CHEMIST, BIOLOGIST BY TRAINING BUT MANY YEARS IN DRUG DISCOVERY AND DEVELOPMENT COMMERCIALLY, NOW I'M A PROFESSOR MT MEDICAL SCHOOL AT OHIO STATE UNIVERSITY. >> JAMEY WIEK -- JAMEY WEICHERT, UNIVERSITY OF WISCONSIN, FOUNDER OF SELECTAR WHICH IS DEVELOPING A NEARLY UNIVERSAL OPTICAL AGENT AND WE'VE LEARNED A LOT ABOUT THE REGULATORY PATHWAYS HERE SO FAR. >> TW GONZALES. I'M SITTING IN FOR STEVE CHEN. I'M NOT STEVE. WE HAVE INVESTIGATIONAL AGENT IN THE SPACE THAT'S ENZYME ACTIVATED. >> I'M JIM BASILION, CASE RESERVE UNIVERSITY, I'M MODERATING TODAY. I STAND HERE AS A LITTLE DISAPPOINTED THIS MORNING AS I'M COMING FROM THE MIDWEST WHERE NOTHING REALLY EXCITING SEEMS TURNOVER HAPPEN, WHICH IS GOOD AND BAD, BUT THEY JUST TOOK AWAY OUR CONTESTED CONVENTION LAST NIGHT AND IT WAS QUITE A CHANGE THAT NO ONE ANTICIPATED. SO WE MAY HAVE A VERY MILD SUMMER. IN ANY EVENT, I HAVE A COUPLE THOUGHTS HERE, MOST OF WHICH HAVE BEEN ANSWERED, BUT I'LL TAKE YOU THROUGH THEM REALLY QUICKLY AND OPEN UP TO THE ROBUST DISCUSSION THAT WE ALREADY HAD. I THINK AS WE THINK ABOUT CLASSES OF AGENTS, ONE THING THAT WE DIDN'T REALLY COVER IS DO THEY I AM PART DIFFERENT QUALITIES OF -- IMPART DIFFERENT QUALITIES OF DETECTION RGS IN OTHER WORDS, DIFFERENT ROUTES OF ADMINISTRATION, DIFFERENT TYPE OF PARTICLES, DO THEY CHANGE WHAT YOU'RE DETECTING. ONE BIG THING THAT PEOPLE NEED TO THINK ABOUT IS CAN TOPICAL APPLICATIONS SEE CELLS THAT ARE NOT YET VASCULARIZED. SO THE PLUMBING LIMITS AN IV AGENT, THE TOPICAL DOES NOT. THAT MAY BE SOMETHING THAT'S IMPORTANT IN THINGS LIKE BRAIN TUMORS WHERE THE CELLS MIGRATE AWAY FROM THE TUMOR. IN TERMS OF SAFETY AND TOXICITY, ONE THING THAT'S COME UP HERE THAT JUST MAKES ME SQUIRM IN MY SEAT A LITTLE BIT IS EVERYBODY HAS BEEN TALKING ABOUT THESE AGENTS AS DRUGS AND I THINK OF THEM AS IMAGING PROBES. DRUGS ARE DESIGNED AND DOSED TO MODIFY BIOLOGY AND IMAGING AGENT ARE NOT. SO PERHAPS THE TERM ISN'T COMPLETELY CORRECT ALTHOUGH I UNDERSTAND WHY THE FDA WOULD FALL TO THEIR KNOWN APPROACH. SO OUR REGULATORY REQUIREMENTS THAT ARE NOW USED BY DEFAULT FOR DRUGS ARE THESE REQUIREMENTS BEING APPLIED TO THE IMAGING AGENTS AND WILL THERE BE AN EVOLUTION OF THE REGULATORY REQUIREMENTS FOR THESE POTENTIALLY SAFER OPTICAL AGENTS THAT ARE NOT DRUGS AS THERE HAVE BEEN FOR NUCLEAR AGENTS PERHAPS MODIFIED EI ENDING. THEN FINALLY THERE ARE SOME QUESTIONS ABOUT IF YOU APPLY IT TOPICALLY TO THE SKIN, IS THAT SYSTEMIC AND THESE WERE ANSWERED EARLIER. IF YOU SPRAY IT INTO A CAVITY IN VIVO, IS THAT SYSTEMIC? THESE ARE THE SORTS OF THINGS THAT I WAS THINKING ABOUT, SOME OF WHICH HAVE BEEN ANSWERED, BUT I'LL OPEN IT UP TO THE QUESTION. I CUT SOMEBODY OFF TO START THIS. WHO WAS THAT PERSON THAT WAS CHATTING? >> TOM. >> DO YOU WANT TO FINISH, TOM, WITH YOUR QUESTION TO THE PANEL? >> I CAN'T EVEN REMEMBER WHAT THE QUESTION WAS NOW. >> IT WAS REALLY GOOD. >> OH, OKAY. IN THAT CASE. WE WERE TALKING ABOUT THE -- >> BASICALLY IF YOU TWEAK -- IT'S A LITTLE BIT RELATED TO YOUR PREVIOUS QUESTION EARLIER IN THE DAY WHERE IF YOU HAVE A MOLECULE AND YOU MODIFY T LET'S SAY YOU HAVE ONE THING AND YOU ADD A DIFFERENT KIND OF PROBE. >> SO THIS IS RELEVANT TO BIOSIMILARS, OR YOU REQUIRE THE SAME LEVEL OF RIGOROUS BIOTOX AS THE ANCH AGENT. >> IT'S LIKE ACTUALLY IT'S NEW, WE HAVE, THE OFFICE OF NEW DRUGS, THE DIRECTOR FOR BIOSIMILARS, AND THIS QUESTION IS BEST ADDRESSED BY THEM. BUT THE DISCUSSION STARTED WITH YOUR COMPOUNDS, PUBLICLY ACKNOWLEDGE IT, I CAN ADDRESS THAT. SOME OF THE ISSUES HAVE ALREADY BEEN DISCUSSED, FOR EXAMPLE, THE PHARMACOLOGY, THIS HAS BEEN USED AS A MUCH LARGER DOSE, IF IT WERE TO BE USED AS A THERAPEUTIC AND HERE ALSO I ALLUDED TO THE FACT THAT UNLIKE THE I'D SEEN GREEN -- THE INDOCYANINE GREEN, I CANNOT REMEMBER THE DETAILS, BUT THE FOAK AL THEN WAS TO PLACE A GREATER EMPHASIS ON WHAT WE DO NOT KNOW. WHAT WE FELT WOULD BE THE INITIAL AND TO APPROACH IT FROM THAT PERSPECTIVE. IT FOINTS WHAT WE'VE BEEN TRYING ARTICULATE THAT BECAUSE OF THE DIVERSE NATURE OF THIS COMPOUND, WE ARE FLEXIBLE, WE NEED TO BE SCIENCE DRIVEN AND WE NEED TO TAILOR REQUIREMENTS TO THE NEED AT THE TABLE. SO THAT'S PART OF WHAT IS DRIVING THAT. THE OTHER GOAL, RECALL THAT, THE SPONSOR AND NCI, THERE ARE BRIDGE STUDIES TO UNDERSTAND THAT THE DYE HAS NOT CHANGED, THE PK CAN STILL BE REASONABLY, SO DEPENDING ON THE COMPLEXITY, THERE MAY BE SOME STUDIES. AND FOR BUY LOGICS, ANOTHER IMPORTANT THING THAT COMES INTO THE DISCUSSION, THE BULK OF EVIDENCE THAT MAY BE NEEDED, THEY MAY HAVE REQUIRED DOSE EVIDENCE AND THEN PHARMACOLOGY WE WOULD THEN BE RELYING ON THE EVIDENCE THAT THEY'VE ASKED THE SPONSOR TO PROVIDE. SO THOSE ARE SOME OF THE THINGS THAT I WORK ON BECAUSE WE ASK FOR FIVE OR MORE STUDIES. WE WORK FROM THE ASSUMPTION THAT YOU SIMPLY GIVE US THE EVIDENCE TO CONVINCE US AND ACCORDING TO THE REGULATION. >> TO EXTEND ON THAT. WE HAVE SOME GUIDANCE THAT WE'RE DOING GUIDANCE FOR MICRODOSING AND WE HAVE SOME GUIDANCE FROM FDA THAT MICRODOSING DOESN'T ALWAYS MEAN THE THRESHOLD FOR MICRODOSING THAT YOU COULD DO FOUR OR FIVE TIMES A MICRODOSE LEVEL AND IT'S STILL SAFE BECAUSE IT'S ORDERS OF MAGNITUDE BELOW A PHARMACOLOGIC DOSE S THAT VIEWED AS IN CONVENTIONAL THOUGHT AT FDA? >> NO. RECALL THAT, I'M ASSUMING THAT YOU ARE VERY FAMILIAR WITH THE MICRODOSE GUIDANCE. YOU SHALL AUTOLY -- USUALLY WHAT YOU'RE GOING TO DO, IT'S UP TO 400 MICRODAMPER DOSE, THE REQUIREMENTS FOR THAT, IF YOU ARE GIVEN REPEATED DOSES. SO ASSUMING FOR THE SAKE OF THIS DISCUSSION THAT THE TOTAL DOSE IS JUST 5 MICROGRAMS. SO THERE'S ROOM ALREADY. AND PROBABLY PARTICIPATE IN ABOUT 3 TO 4 HOURS. SO IF YOU WANT TO DO -- IF YOU DO A TOX STUDY THAT'S ALREADY USED THE MICROGRAM TIMES THAT, THEN ALREADY THE RANGE OF DOSES THAT YOU'RE ANTICIPATING HAS ALREADY BEEN COVERED BY YOUR TOX STUDIES BECAUSE OF THE SAFETY MARGIN OF THE PRODUCTS. SO HOW WE GO ABOUT MAKING DOSE DETERMINATION AND IF IT IS NOT CLEAR, PLEASE ASK US, PLEASE ASK US BECAUSE WE HAVE ALSO A VESTED INTEREST IN OPTIMIZING PRODUCT DEVELOPMENT. >> I MEAN, JUST EXTENDING THIS IDEA THAT THERE ARE SO MANY BIOLOGICS THAT WE COULD TAG FLUORESCENT AGENTS TO AND IF WE'RE USING THEM AT TRACER DOSES THAT ARE 100 TIMES OR MORE BELOW THE THERAPEUTIC DOSE, IT OPENS UP A HUGE WINDOW IN SURGICAL GUIDANCE FOR ALL THE BIOLOGIC AGENTS, THE FAD'S, MONOCLONAL ANTIBODIES AND EVERYTHING, REALLY IT CAN EXPLODE THIS FIELD POTENTIALLY IF IT REDUCES THE TOXICITY PACKAGE THAT NEEDS TO BE DONE. >> WE WILL HAVE A DIALOGUE AND WE ALSO EXACTED AND TBAWKD A LOT OF POSSIBILITIES OF WHAT CAN BE DONE. >> DO YOU WANT TO COMMENT? >> I WAS JUST GOING TO RAISE A RELATED QUESTION. CAN I DO THAT? >> SURE THIS QUESTION WILL BE RELEVANT TO ALL THE PROBE MAKERS , VIRTUALLY EVERYONE WHO IS MAKING A PROBE DESIGNS IT TO BE LAY RECEPTOR OR BE A SUBSTRATE OF A SPECIFIC ENZYME THAT IS OVEREXPRESSIONED OR INDUCED IN MALIGNANT TISSUE OR OTHER DISEASED TISH EWE RELATIVE TO -- TISSUE RELATIVE TO NORMAL TISSUE. IF YOU DEMONSTRATE THAT PROBE IN SAY YOUR FIRST CANCER THAT OVEREXPRESSES YOUR ENZYME OR RECEPTOR AND THEN IN A SECOND AND THEN IN A THIRD, IS IT POSSIBLE TO GET A GENERIC APPROVAL FOR ALL CANCERS THAT EXPRESS THIS ENZYME OR THIS RECEPTOR AND WHAT HAS TO BE DONE TO OBTAIN THIS GENERIC APPROVAL? THIS WILL SAVE A LOT OF MONEY, INSTEAD OF HAVING TO GO ONE BY ONE THROUGH MAYBE 20 DIFFERENT CANCERS, IF YOU ESTABLISH EFFICACY, IN OUR CASE WE'VE SEEN IT IN FOUR DIFFERENT CANCERS, THERE DOESN'T SEEM TO BE ANY EXCEPTION, SO HOW MANY MORE HAVE TO BE DONE IN ORDER TO GET A GENERIC APPROVAL? >> I THINK IN THIS PARTICULAR CASE, A STUDY COULD BE CONDUCTED WHERE YOU WOULD BE ABLE TO GENERALIZE ACROSS A NUMBER OF CANCERS DEPENDING ON THE ETLE TO PACKAGE OF THE DATA -- DEPENDING ON THE TOTAL PACKAGE OF THE DATA THAT YOU HAVE. LET'S SAY YOUR PROBE IS TARGETING JUST FOR THE SAKE OF SOMETHING THAT'S VERY POPULAR THESE DAYS, STATIN RECEPTORS AND SOME RECEPTORS ARE EXPRESSED IN NORMAL TISSUES, IN DIFFERENT CANCER TYPES, YOU COULD POTENTIALLY, YOU KNOW, HAVE A BROAD INDICATION THAT WOULD ALLOW YOU TO HAVE THE INDICATION BE APPLICABLE ACROSS DIFFERENT PATIENTS. WE ALREADY DO THIS IN THE CONTEXT, SO BASICALLY WITH EXTRAPOLATION OF DATA. SO IF YOU HAVE A MIXED PATIENT POPULATION, WHAT CONFIDENCE DO YOU HAVE THAT THE RESULTS IN ONE SUBGROUP APPLY ACROSS ALL THE OTHER GROUPS FOR WHICH THIS IS APPLICABLE? SO DEPENDING ON THE EVIDENCE THAT YOU HAVE, WE MIGHT ALLOW A STUDY TO PROCEED WHERE YOU HAVE A BROAD PATIENT POPULATION SO THE PRIMARY END POINT WOULD BE IFN DR. BY THE -- WOULD BE DRIVEN BY THE BROAD POPULATION THEN YOU WOULD BE ABLE TO DO SUBGROUP ANALYSIS WHICH WOULDN'T BE POWDER TO SHOW EFFICACY IN EACH SUBGROUP BUT WOULD GIVE SOME QUALITATIVE INFORMATION ABOUT WHETHER THE PRODUCT SEEMS TO WORK SO YOU COULD COMBINE EVIDENCE OF BINDING SPECIFICITY, A MIXED PATIENT POPULATION. WE WILL DO THAT, WE EXTRAPOLATE FOR INSTANCE ACROSS AGE GROUPS, ACROSS AND WE DO THAT NOT ON THE BASIS OF DATA BUT ON THE BASIS OF PHARMACOLOGY, SO THE APPROACH BASICALLY IS POSSIBLE. IT'S NOT SOMETHING THAT WOULD APPLY TO A THERAPEUTIC INDICATION, BUT FOR IMAGING, I MEAN, BASICALLY THINK ABOUT CONTRAST INDICATIONS. WE STARTED OUT WITH CONTRAST INDICATION THINKING THAT IT WOULD HAVE TO BE ORGAN SPECIFIC, SO THE GA LIDIUM CONTRAST AGENTS GOT APPROVED FOR CNS INDICATIONS THEN WENT TO TOTAL BODY INDICATION AND WE SAID OH BUT IT DOESN'T INCLUDE THE HEART BECAUSE AT THAT TIME YOU COULDN'T IMAGE THE HEART. BUT NOW WE'VE GOT TONE THE POINT WHERE WE KNOW THAT YOU GIVE THE CONTRAST, IT DISTRIBUTES EVERYWHERE AND YOU CAN BASICALLY IMAGE EVERYWHERE SO WE'RE GOING MORE TOWARDS A DIFFERENT APPROACH WHERE THE IMAGING INDICATION CAN BE GENERIC. >> CAN I ASK YOU TO BE JUST A BIT MORE SPECIFIC? ALMOST EVERYONE WHO INTRODUCES A NEW PROBE IS GOING TO START WITH A VERY SPECIFIC INDICATION, A SPECIFIC CANCER. THEY JUST SPREAD IT OUT AMONG A LOT, THEY'LL NEVER GET IT APPROVED. SO LET'S SAY THEY'RE GOING TO START IN LUNG CANCER, THEN THEY GO TO BREAST CANCER AND OVARIAN CANCER AND YOU DEMONSTRATE THE UTILITY IN EACH OF THESE. THE QUESTION THEN MORE SPECIFICALLY IS HOW DO YOU GET THE GENERIC, FOLLOWING THAT, THAT PROGRAM OF DRUG DEVELOPMENT, HOW DO YOU GET THE GENERIC INDICATION? HOW MANY TIMES DO YOU HAVE TO REPEAT THIS ON ADDITIONAL TUMORS? >> WE COULDCYTE -- WE COULD CITE THE EXAMPLE OF LYMPHOSEEK WHERE THE INITIAL STUDIES WERE DONE IN A MIXED PATIENT POPULATION. IT WAS, IF I REMEMBER CORRECTLY, MELANOMA AND BREAST CANCER AND THEY WERE ABLE TO GET THE LYMPHATIC MAPPING AND THEN FOR THE PURPOSE OF SENTINEL NODE BIOPSY ALL THEY DID WAS THEY DID A STUDY IN HEAD AND NECK CANCER AND WE EXTRAPOLATE THAT HAD ACROSS THE OTHERS. SO THAT'S ONE EXAMPLE WHERE WE LOOKED AT THE TOTALITY OF THE DATA AND SO CURRENTLY THEY HAVE AN INDICATION, A BROAD INDICATION FOR SENTINEL NODE BIOPSY AND THE OTHER THING THAT WE'RE TRYING TO DO IS WE'RE ALSO TRYING ON GIVE MORE GENERAL INDICATIONS, AND SO, YOU KNOW, UNLESS WE HAVE SPECIFIC DATA IN A SPECIFIC PATIENT POPULATION THE PRODUCT WOULD BE PROBLEMATIC, WE WOULD STRIVE TO GO FOR A BROADER. >> IN CONTEMPLATING HOW BROAD IT COULD BE, ONE OF THE THINGS THAT WOULD COME UP IS WHAT IS THE WORST CASE. SO IF YOU KNEW VARIED TISSUES HAD VARIED ABILITY TO SEE THE IMAGE, VARIED RECEPTOR DENSITIES, BEFORE WE BROADEN, WE WOULD ASK THE QUESTION WHERE IS THIS IN CONTINUUM AND HOW MUCH DATA DO WE HAVE ALONG THAT CONTINUUM. SO A REGULATORY STRATEGY, IF THERE WAS SUCH A CONTINUUM, COULD BE TO TAKE WHAT IS ARGUABLY THE WORST CASE, PROPOSE TO STUDY IT THERE, AND THEN COME TO TALK TO US. ACTUALLY THE WORST CASES COULD BE BOTH ON THE LOW END AND ON THE HIGH END BECAUSE OFF THE BAYS ON THE HIGH END, IN BOTH CASES IT WOULD BE ABOUT SIGNAL TO NOISE. IF YOU WANTED TO BROADEN, THAT WOULD BE A WAY TO APPROACH IT THAT WOULD BE A RATIONAL DRUG STRATEGY. >> WE'LL GO TO JAMEY, BUT I WANT TO BRING ONE COMMENT UP HERE THAT HASN'T COME OUT. I THINK WITH AGENTS THAT ARE SORT OF LOOKING AT VASCULARITY OR LEAKINESS THAT'S ONE ISSUE AND HOW YOU WOULD EXPAND THAT IS DIFFERENT THAN A TARGETED AGENT SO IF YOU TOOK A TARGETED AGENT, FOR EXAMPLE, TARGETING TRANSFER ON WHICH IS OVEREXPRESSED IN 70% OF CANCERS, 30% AREN'T GOING TO WORK, SO PERHAPS YOU COULD PROVE THAT IT WORKS BY THE MECHANISM AT WHICH YOU PROPOSE, THAT IS, INTERNALIZATION THROUGH THE TRANSFER ON RECEPTOR AND THEN YOU COULD ADD A COROLLARY WHERE YOU TOOK 100 PATIENTS OR SOME STATISTICALLY SIGNIFICANT NUMBER OF PATIENTS AND DID IMMUNOHIS CHEMISTRY AND SAY IT WOULD BE APPLICABLE TO THIS CANCER BECAUSE THE TARGET IS UPREGULATED SO YOU COULD COMBINE BIOLOGY AS WELL AND I DON'T KNOW IF THE FDA HAS THOUGHT ALONG THOSE LINES BUT IT MAY HELP SOLVE A PROBLEM. >> IN FACT, FOR INSTANCE, FOR CONTRAST AGENTS, THE TUMORS CAUSE LEAKINESS. ARE THE BLOOD-BRAIN BARRIER, PROBABLY FOR CNS TO VISUALIZE AREAS OF PATHOLOGY, IT MAY ACTUALLY SAY, YOU KNOW, TUMORS. SO FOR THAT PARTICULAR CASE, IF THE MECHANISM OF VISUALIZATION OF THE DYE IN THE BRAIN IS DEPENDENT ON THE BREAKDOWN OF THE BLOOD-BRAIN BARRIER AND CANCER DOES THAT, THEN YOU DON'T HAVE TO SHOW THAT YOU CAN IMAGE GLIAL BLASTOMA THAT CAUSES BREAKDOWN WILL RESULT IN THE ABILITY TO -- >> I'M SUGGESTING A SIMILAR ROUTE FOR TARGETED THERAPIES LOOKING AT A CHANGE IN THE MARKER. I ALSO THINK YOU HAVE TO BE CONSIDERED IN INFORMING THE POSITIONS THAT THIS IS NOT 100%, THAT THERE COULD BE A CANCER THAT DOESN'T HAVE IT, AND YOU HAVE TO UNDERSTAND THAT HAS YOU USE THESE AGENTS. THEY AGE. THEY'RE NOT DEFINITIVE. >> EBEN DID THAT WITH A BETA. >> I WOULD JUST SAY, JIM, REGARDING THAT, WE'VE HAD A GOOD EXPERIENCE BECAUSE WE STARTED WITH IMAGING, PET IMAGING, WE'VE DONE SIX OR SEVEN CLINICAL TRIALS, PHASE 1, PHASE 2, NOW IN PET, IN MULTIPLE TUMOR TYPES, AND I KNOW THE AGENCY ALLOWED US THE FLEXIBILITY TO DO IMAGING. OF COURSE, IT'S SUBPHARMACOLOGIC DOSE, TRACER DOSE LEVEL, BUT WE'VE ALSO DONE THE SAME THING WITH TARGET RADIOTHERAPY IN MULTIPLE DIFFERENT TUMOR TYPES EARLY ON, AND I GUESS THE WAY WE LOOK AT IT IS IS WE USE IT AS A SURVEY OF CANCERS. I MEAN, OBVIOUSLY WE ALSO WANT TO KNOW IF THERE'S ANY DIFFERENCES BETWEEN THE DIFFERENT CANCER TYPE PATIENTS IN THE BIODISTRIBUTION AND PHARMACOKINETICS AND CLEARANCE, BUT THAT'S ALL EASILY ACCESSIBLE GLOBALLY BY PET IMAGING. WE CAN SEE THIS SO EASILY, WE CAN QUANTIFY, IT'S EXTREMELY POWERFUL, AND NOW WE'RE ACTUALLY FOCUSING THE PHASE 2'S AND SUBSEQUENT TRIALS NOW IN OUR STRATEGY TOWARDS SPECIFIC CANCERS NOW THAT WE HAVE SOME DATA IN SOME OF THESE THINGS. SO I THINK THE BROADNESS I THINK IS THERE IF YOU APPROACH IT CORRECTLY AND IT'S BEEN A BIG PLUS FOR US SO FAR. >> ONE APPROACH WOULD BE TO LOOK AT A WELL DEFINED PATIENT POPULATION AND THEN ONCE THE PRODUCT IS APPROVED, THEN ONE COULD RELY ON PUBLICATIONS AND COME BACK FOR SUPPLEMENTAL APPLICATIONS TO EXTEND THE INDICATION BASED ON LITERATURE DATA. BUT THE EXAMPLE YOU CITED IS VERY IMPORTANT. F18 FAG IS NOT SPECIFIC TO ANY CANCER. IT'S LOOKING AT UPTAKE OF GLUCOSE AND WE KNOW THAT THE UPTAKE IS IT UPREGULATED IN CANCERS AND THAT'S THE WHOLE BASIS FOR THE IMAGING. SO IT'S NOT SPECIFIC TO A TUMOR TYPE, IT'S SPECIFIC TO ANY KIND OF TUMOR AND YOU CAN USE IT TO VISUALIZE TUMORS, YOU CAN TRY TO EVALUATE TUMOR RESPONSE, THERE'S A NUMBER OF THINGS. >> AND THERE ARE EXAMPLES WHERE IT DOESN'T WORK WELL AND WE UNDERSTOOD THOSE FROM APPLYING IT BROADLY. >> I WANTED TO ASK GENE, SO WHEN COMPANIES ARE CONSIDERING THEIR PHASE 1 SAFETY TRIAL, DOES IT MAKE SENSE FOR THEM TO DO AN ALL-COMERS PHASE 1 SO THAT YOU TAKE ALL CANCER TYPES, AS JAMEY IS INGT POB OUT, OR IF YOU HAVE A GENERAL PROBE -- AS JAMEY IS POINTING OUT, OR IF YOU HAVE A GENERAL PROBE, OR IS IT BESES TO START WITH ONE SPECIFIC CANCER AND TRY TO EXTRAPOLATE? IT SEEMS TO ME LIKE THE ALL-COMER PHASE 1 MAKES MORE SENSE BECAUSE YOU'RE LOOKING AT A VARIETY OF DIFFERENT TUMORS AND YOU'RE LOOKING AT SAFETY ANYWAY. >> YEAH, I THINK IT WOULD DEPEND ON A PARTICULAR CASE, BUT I AGREE WITH YOUR MIND SET THAT THERE COULD BE UTILITY IN LOOK BEING AT ALL OF THEM. IN THE THERAPEUTIC SIDE OF ONCOLOGY OFTENTIMES THEY TAKE ALL-COMERS IN PHASE 1 IT'S PROBABLY OFTEN PRAGMATIC BECAUSE THEY'RE TRYING TO GET PATIENTS, CAN'T GIVE THE DRUG TO HEALTHY SUBJECTS, SAFETY END POINTS. IN IMAGING I THINK MORE FREQUENTLY IF YOU'RE NOT USING HEALTHY SUBJECTS, IT'S BECAUSE YOU MAY BE TRYING TO GET INFORMATION ON THE IMAGE, IN WHICH CASE PATIENTS THAT ARE CLOSEST TO WHAT YOU HOPE TO DEVELOP LATER ON HAVE THE GREATEST UTILITY. BUT IF YOU'RE STILL SORTING THROUGH THAT AND YOU DON'T KNOW, THEN, SURE, YOU MIGHT BE ABLE TO GET INFORMATION THAT WOULD BE INFORMATIVE IN PHASE 1 AND HELP YOU MAKE YOUR PHASE 2 DECISION. DOES THAT MAKE SENSE? >> I DON'T HAVE THE DATA, BUT JUST FROM ANECDOTAL EXPERIENCE, IT TURNS OUT THAT A MORE PARSIMONIOUS APPROACH WORKS OUT BETTER BOTH FOR SAFETY AND EFFICACY TO HAVE A VARIED PATIENT POPULATION, IT HELPS YOU DETECT A SIGNAL IF IT'S THERE AND IT ALSO HELPS YOU MINIMIZE VARIABILITY AND RESULTS, INCREASING YOUR CHANCE OF SUCCESS. SO THE TYPICAL PATH IS TO BE VERY WELL DEFINED AND THEN TO TRY TO EXTRAPOLATE LATER AND EXPAND THE PATIENT POPULATION. SO YOU CAN GO EITHER WAY, BUT THERE'S A TRADE-OFF IN TERMS OF THE RISKS AND BENEFITS. >> YEAH, NATURALLY I WOULDN'T DISAGREE WITH THAT. IT DEPENDS ON WHAT YOU KNOW ABOUT THE AGENT AND WHAT YOU'RE STRIVING TO ACCOMPLISH. OTOTOXICITY SIDE, IT BECOMES ESPECIALLY PROMINENT BECAUSE YOU DON'T WANT TO HAVE SITUATIONS WHERE YOU DON'T KNOW IS IT THE DRUG OR THE DISEASE. SO BEING HOMOGENOUS IN THAT REGARD CAN BE A BIG HELP. >> I WANT TO BRING UP ONE POINT ABOUT THE METABOLISM OF THESE AGENT AS YOU'VE MENTIONED. MOST OF US HAVE LIMITED OUR DISCUSSION AND THOUGHT TODAY TO TARGETED AGENTS, PARTICULAR RECEPTOR, SMALL MOLECULES LABELED WITH A FLUOROCHROME, BUT WHAT ABOUT NANOPARTICLES AND WHAT DOES THAT ELICIT DIFFERENTLY FROM THE REGULATORY PERSPECTIVE OF METABOLISM? YOU HAVE A NANOPARTICLE THAT WILL BE SYNTHESIZED IN A DIFFICULT WAY BUT ONCE YOU DO YOU'VE GOT TEN COMPONENTS IN THERE. ARE WE GOING TO LOOK AT METABOLISM OF EACH OF THOSE COMPONENTS AS PART OF OUR -- >> SO FIRST THING I WOULD REITERATE FROM MY PRESENTATION IS WE THINK IT CAN HELP IN DRUG DEVELOPMENT AND NOT JUST REGULATORY BOX CHECKING. SO THE QUESTION, IF YOU HAVE A MIXTURE THAT IS OF GREAT ENOUGH COMPLEXITY THAT IT BECOMES IMPRACTICAL OR WITH OUR TECHNOLOGY IMPOSSIBLE TO GET ALL OF IT, THEN THE QUESTION IS HOW FAR YOU COULD GO AND HOW MUCH UTILITY YOU WOULD HAVE. YOU COULD DO THINGS LIKE SIZE EXCLUSION, DEPENDING ON WHAT THE SPECIFIC PRODUCT IS AND HOW IT WORKS. SO WE'RE NOT INTERESTED IN JUST DOING THIS TO DESCRIBE THINGS OR CHASING THINGS AT THE END OF THE DAY WOULD BE OF LIMITED UTILITY. THE HOPE WOULD BE THAT IF YOU BETTER UNDERSTAND HOW THE DRUG GOES, THAT YOU CAN MAKE RATIONAL DECISIONS ABOUT WHAT TO MEASURE AND THAT IT MIGHT CHANGE HOW YOU DOSE OR HOW YOU DOSE SELECTED PATIENTS. >> I HAVE A FOLLOW-UP QUESTION. GO AHEAD. >> ACTUALLY I JUST WANTED TO ADDRESS ONE ASPECT OF THIS RELATING TO LASER SAFETY, OPTICAL SAFETY FROM THE DEVICE PERSPECTIVE RELATING TO NANOPARTICLES AND OTHER EXOGENOUS AGENTS. BEFORE DR. MARCU RAISED THE ISSUE OF STANDARDS AND PARTICULARLY LASER SAFETY STANDARDS THAT ADDRESS THE SKIN AND THE EYE AND THE FACT THAT THEY DON'T ADDRESS A LOT OF THE OTHER INTERNAL TISSUES LIKE WE TYPICALLY USE IC60825 FOR LASER SAFETY AND IC62471 FOR NONCOHERENT LIGHT SOURCES, BUT THESE DON'T ADDRESS INTERNAL TISSUES. WE'VE DONE SOME WORK IN THE LAB LOOKING AT UV SAFETY AND DNA DAMAGE INDUPSED MANY INTERNAL TISSUES VERSUS SKIN AND WE SEE A REAL SIGNIFICANT DIFFERENCE. SO THAT I THINK IS ONE ASPECT OF SAFETY THAT HAS TO BE PAID ATTENTION TO AND IS NOT EASY IN THAT IT'S PRESCRIBED IN THE STANDARDS. IN TERMS OF EXOGENOUS AGENTS LIKE NANOPARTICLES, THERE ARE ISSUES THAT ARE RAISED LIKE PHOTOTHERMAL AND PHOTOMECHANICAL DAMAGE BECAUSE BASICALLY YOU HAVE ABSORBERS IN THERE THAT ARE NOT TYPICALLY IN TISSUE AND WERE NOT ACCOUNTED FOR IN THE STUDIES THAT WERE PERFORMED TO DEVELOP THE LASER SAFETY STANDARDS. SO YOU HAVE THESE CHROMOFORS ABSORBS HEAT, ALSO CAN GENERATE PRESSURE WAVES PARTICULARLY TALKING ABOUT NEW TECHNOLOGIES LIKE PHOTOACOUSTICS WHERE YOU'RE DELIVERING VERY SHORT HIGHER RADIANCE LASER PULSES, YOU CAN GENERATE CAVITATION EFFECTS AND GET ABLATION, THERE'S ALSO PHOTOCHEMICAL ISSUES WITH THESE FLUORESCENT AGENTS CHRKS ARE VERY WELL KNOWN FOR GENERATING REACTIVE OXYGEN SPECIES, USED FOR PDT AND PHOTOIMMUNOTHERAPY NOW AND, SO THERE'S THE ISSUE OF GENERATION OF INDIRECT PHOTO TOXICITY DUE TO PHOTOPRODUCT GENERATION. SO THERE'S A NEED FOR MORE UNDERSTANDING OF THESE DIFFERENT SAFETY ISSUES AND DEVELOPMENT OF STANDARDS TO ACCOUNT FOR THESE NEW MECHANISMS. SO THERE ARE TESTS LIKE CELL VIABILITY STUDIES, DNA DAMAGE ASSAYS THAT CAN BE DONE, ROS ASSAYS THAT CAN BE PERFORMED, BUT I THINK THERE'S A FAIR AMOUNT OF VARIABILITY IF YOU TALK TO NEIL VERSUS IF YOU GO AND HAVE A DEVICE THAT, FOR EXAMPLE, UROLOGY DIVISION OR AN OB-GYN OR ORAL CANCER DETECTION OR IF YOU'RE GOING ON OIR WITH A MAMMOGRAPHY TYPE DEVICE, YOU MIGHT GET DIFFERENT ANSWERS PARTICULARLY BECAUSE THERE ARE NO STANDARDS. SO I THINK WORK IN THIS AREA TOWARDS DEVELOPING STANDARDIZED TEST METHODS AND APPROACHES FOR ASSESSING SAFETY WOULD REALLY BENEFIT INDUSTRY AND THE WHOLE REGULATORY PROCESS. >> JIM? >> AFTER EBEN, I CAN. >> TRADITIONALLY CONTRAST AGENTS HAVE BEEN APPROVED FOR A SINGLE DOSE AND A SINGLE PERSON ONCE, AND YET IT'S NOT REALLY HOW THEY WERE USED OVER TIME. AND OVER TIME THERE WERE SOME PROBLEMS WITH METABOLISM AND VERY LONG LIVED METABOLITES. IS THAT POSSIBLE IN OPTICAL AND IS IT GOING TO BE A CONSIDERATION WHEN WE FILE IND'S, NDA'S, AND GET NEW PACKAGE INSERTS? >> SOMETIMES THE PRACTICE OF MEDICINE IS UNPREDICTABLE AND IT IS NOT OUR PLACE TO ACTUALLY DETERMINE HOW THESE PRODUCTS MIGHT BE USED. AND IN ESSENCE, THAT THEN BOILS DOWN TO WHY SOMETIMES CERTAIN REQUIREMENTS THAT AT FIRST BLUSH YOU SAY YOU WANT TO SMOKE WHAT THEY ARE SMOKING, IF YOU ASK, YOU TAKE A STEP BACK, YOU DON'T SEE HOW THIS PROCESS WILL BE ON A DAY TO DAY USE, THEN SOME OF THE STUDIES ARE REPEATED SO IT MAKES SENSE. IN REALITY, THE EXAMPLE THAT YOU BROUGHT UP IS VERY PERTINENT BECAUSE SOMETIMES YOU DO NOT WANT TO PRESS SCRIBE, YOU DO NOT WANT TO MAKE RECOGNITIONS THAT THERE ARE CERTAIN OUTLIERS BECAUSE IF WE DIDN'T DO THAT, THE COST WOULD THEN BE PROHIBITIVE. TO A LARGE EXTENT, YOU TAKE A MEASURED APPROACH AND YOU ASK THOSE QUESTIONS THAT YOU NEED TO ASK AND AS WE UNDERSTAND THE PRODUCT BETTER, ADDITIONAL QUESTIONS MIGHT ARISE THAT HOPEFULLY YOU'VE GOTTEN MORE BUT YOU CANNOT SAY CONCLUSIVELY YOU'VE GOT EVERYTHING RIGHT, KIND OF A THING. >> THAT'S AN EXCELLENT QUESTION AND I AGREE WITH THE RESPONSE. AGENTS WHERE NEPHROGENICS CNE PH ROFIBROSIS POPPED UP AND I THINK THE COMMUNITY AND THE REGULATORS WORKED TOGETHER TO IDENTIFY THE RISK FACTORS SO ONCE THERE WERE CHANGED MADE TO THE LABELING TO EXCLUDE SUSCEPTIBLE PATIENTS, THAT WENT AWAY. NOW WE'RE NOW FACING ANOTHER SITUATION WHERE THERE'S EVIDENCE OF LONG-TERM DEPOSITION OF GADOLINIUM AND WE DON'T KNOW WHAT THE IMPLICATIONS ARE. SO THE POINT IS WHEN A PRODUCT GETS APPROVED, YOU KNOW, WE HAVE LIMITED AMOUNT OF SAFETY DATABASE BUT THEN I THINK THE INDUSTRY AND THE FDA THEN LOOK OVER THE LIFETIME OF THE DRUG, AT THE SAFETY PROFILE. WE HAVE SAFETY EVALUATORS AND THEIR JOB IS TO GO THROUGH SPONTANEOUS REPORTS, THROUGH THE LITERATURE TO SEE IF THERE'S ANY SIGNALS THAT ARE EMERGING. AND WE NOW HAVE LARGE DATABASES WHERE WE CAN ACTUALLY DO EXPLORATORY SEARCHES TO SEE IF SPECIFIC ADVERSE EVENTS ARE CRERS EGG THE SIZE AND LOOKING FOR ASSOCIATION -- ARE INCREASING THE SIZE AND LOOKING FOR ASSOCIATIONS. SO IT'S AN IMPORTANT QUESTION. WE BASE RISK BENEFIT ON A LIMITED EXPERIENCE BUT THEN FOR THE LIFETIME OF THE DRUG OR THE DEVICE WE TON RELY ON SPONTANEOUS REPORTS TO SEE WHETHER ANY OTHER SIGNAL EMERGE AND IF ANYTHING NEEDS TO BE DONE. >> SO I'LL COMMENT FROM THE PERSPECTIVE OF THE SPECIFIC EXAMPLE OF GADOLINIUM CONTRAST AGENTS AND THIS MAY NOT BE APPLICABLE TO OTHERS, BUT FROM THE METABOLISM PERSPECTIVE, THE AMOUNTS THAT WE'RE TALKING ABOUT ARE VERY SMALL. SMALLER THAN YOU WOULD USUALLY EXPECT TO BE ABLE TO ACCOUNT FOR IN, SAY, A MASS BALANCE STUDY. IN OTHER WORDS, THE RESIDUAL AMOUNT. SO IF YOU'RE ASKING IS IT LIKELY THAT WE WOULD BEGIN TO ASK FOR MASS BALANCE STUDIES WHERE YOU ASSURE THAT YOU HAVE GOTTEN GREATER THAN 99% OF ADMINISTERED MATERIAL, THE ANSWER IS MOST CERTAINLY WE WOULD DO IT FOR REGULAR DRUGS THAT ARE NON-- THAT ARE ORGANIC THAT DON'T HAVE INORGANIC IONS BECAUSE IT SIMPLY WOULDN'T BE ACCOMPLISHABLE. RECENTLY I ATTENDED A SEMINAR WHEN SOMEONE CLAIMED THAT THE AVERAGE AMOUNT YOU GET BACK IN MASS BALANCE STUDY FOR AN ORDINARY DRUG OBVIOUSLY NONOF THE AGENTS WE'RE TALKING ABOUT ARE NOT ALTOGETHER ORDINARY, IS 87%. SO INORGANIC IONS MAY BE A LITTLE DIFFERENT. DO WE FACTOR WHAT WE LEARN INTO OUR RECOMMENDATIONS, YES, BUT WE DO GO OUT OF OUR WAY TO ATTEMPT TO NONGENERALIZE HOPEFULLY THAT HELPS A LITTLE. >> EBEN, THEN TITO, THAT WILL TAKE UPS A FEW MINUTES INTO LUNCH -- TAKE URS A FEW MINUTES INTO LUNCH. >> FOR THINGS THAT ARE KNOWN PROBABLY TO ACCUMULATE, PERHAPS NANOPARTICLES, METAL NANOPARTICLES THAT ARE KNOWN TO ACCUMULATE, IS HOW DOES THE FDA CONSIDER THOSE IN TERMS OF KNOW THAT GO A LARGE PART OF THEM ARE PROBABLY NOT GOING TO BE EXCRETED? >> SO I LOOK FORWARD TO AID FROM MY COLLEAGUES, BUT MY BASELINE THINKING ABOUT THIS SORT OF THING IS I GUESS LIKE I ORGANIZED MY PRESENTATION, YOU DIVIDE IT INTO SAFETY AND EFFICACY. FROM THAT PERSPECTIVE WOULD IT AFFECT SUBSEQUENT IMAGING, YOU WOULD HAVE TO THINK ABOUT THAT IF YOU'RE GOING ON REPEAT IMAGE. USUALLY THE MAJOR CONCERN IS SAFETY. THERE'S A CONCERN BUT WE OF COURSE DO NOT WANT TO PREVENT VALUABLE DRUGS, IMAGING AGENTS, FROM GETTING TO MARKET. SO WE'RE PUT IN A POSITION WHERE WE HAVE TO GO WITH WHAT WE CAN LEARN FROM NONCLINICAL STUDIES AND SOMETIMES WE CAN UNDERSTAND WHAT TO MONITOR IN CLINICAL STUDIES, BUT IT'S SIMPLY DIFFICULT. IT DOESN'T PRECLUDE OUR ACTING WHEN WE CONCEDE THAT SOMETHING WOULD BE A VALUABLE CONTRIBUTION. MAYBE MY COLLEAGUES WANT TO CHIME IN. >> IT'S PARTICULARLY CHALLENGING IN MEDICAL IMAGING DRUGS WHERE THE PHYSICIAN THAT ADMINISTERS THE DRUG IS TYPICALLY NOT THE DOCTOR THAT FOLLOWS THE PATIENT. SO IT'S VERY DIFFICULT TO PICK UP SIGNALS. HAVING SAID THAT, I THINK THAT WE WOULD RELY ON PRECLINICAL DATA AND IF WE HAD A CONCERN, WE WOULD DO CHRONIC TOXICOLOGY STUDIES, BUT AT THIS POINT I DON'T THINK THAT WE HAVE SEEN ANY SPECIFIC REASON TO CONDUCT THOSE KINDS OF STUDIES. >> I DON'T THINK SO. SOMETIMES THERE MIGHT BE LITTLE SPECIFICITY ANYWAY THAT USING THIS PRODUCT, I MEAN, STILL THE POSSIBILITY, YOU MIGHT HAVE FORGOTTEN THAT BECAUSE OF THE LACK OF A RELATIONSHIP, CAUSE AL RELATIONSHIP, IT MAY NOT BE THAT OBVIOUS. SO AGAIN, IT'S AT THE BACK OF ONE'S MIND, TO ACKNOWLEDGE. FOR THE NANOPARTICLES WE ACTUALLY RELY A LOT ON THE CDRH COUNTERPARTS IN DESIGNING TOXICOLOGY STUDIES THAT MAY ADDRESS SOME OF THE ISSUES THAT HAVE COMMONALITY WITH WHAT WE ALSO SEE. >> TAKE US HOME. >> SO I THOUGHT THE QUESTION ABOUT ARE THEY DRUGS IS A REALLY INTERESTING THOUGHT, AND IT JUST OCCURRED TO ME THAT THERE'S SO MUCH DIVERSITY FROM SPECIFICALLY MOLECULARLY TARGETED AGENTS ALL THE WAY TO ESSENTIALLY METAL PARTICLES THAT, YOU KNOW, THAT SPAN THE RANGE FROM CHEMICAL ACTION ALL THE WAY TO PHYSICAL ACTION. SO I'M CURIOUS GIVEN ALL THE RECENT SPERNTION WITH THE NEW INVESTIGATIVE AGENTS -- EXPERIENCE WITH THE NEW INVESTIGATIVE AGENTS WITH THE THINKING OF DEVICE VERSUS DRUG AND WITH THE THINKING OF DEVICE-DEVICE COMBINATIONS. >> PERHAPS WE SHOULD DEFER THAT QUESTION TO THIS AFTERNOON. THERE WILL BE A LONG DISCUSSION. THERE'S A PORTION OF THE FDA WHICH IS DEDICATED TO MAKING THESE DETERMINATIONS, AND I AGREE WITH YOU, YOU MAKE AN EXCELLENT POINT. THERE'S A WIDE RANGE OF PRODUCTS AND SOME LOOK MORE LIKE DRUGS, SOME LOOK MORE LIKE DEVICES AND SOME ARE LIKE IN BETWEEN. SO WE RELY A LOT ON PRECEDENT BECAUSE WE HAVE TO HAVE A LEVEL PLAYING FIELD, SO WE HAVE A PROCESS BY WHICH WE DO THIS. INTERESTINGLY, HISTORICALLY, A LOT OF THESE PRODUCT WERE REGULATED AS DEVICES, BARIUM SULFATE AND THEN AS THEY EVOLVED AND AS THEY BECAME ADMINISTERED SYSTEMICALLY, YOU KNOW, THERE WAS INCONSISTENCY ACTUALLY AND THERE WAS A LEGAL SUIT AND THERE WAS A LEGAL DECISION THAT DETERMINED THAT THESE PRODUCTS SHALL BE DRUGS AND THEN WE HAVE FOLLOWED THAT PARADIGM EVER SINCE. BUT THERE ARE STILL VERY DIFFICULT DECISIONS THAT NEED TO BE MADE, BUT WE HAVE A PROCESS BY WHICH YOU CAN PROVIDE SCIENTIFIC EVIDENCE THAT SAYS OKAY, I BELIEVE I SHOULD BE CLASSIFIED AS A DEVICE OR NO, I BELIEVE I SHOULD BE CLASSIFIED AS A DRUG. >> OKAY. I JUST WANT TO THANK THE FDA FOR BEING HERE IN SUCH NUMBERS AND REALLY BEING VERY INFORMATIVE TO US. LET'S GIVE THEM A HAND. [APPLAUSE] >> AND I THINK WE'LL BREAK FOR LUNCH. TITO IS GOING TO HOLD HIS QUESTION. OKAY. >> HI, EVERYONE. MY NAME IS CARLA, I AM THE POLICY ANALYST FOR THE EARLY FEASIBILITY PROGRAM IN CDRH. TODAY I'M GOING TO TALK TO YOU ABOUT THE EARLY FEASIBILITY STUDY FOR THE IDEs, WHICH IS REALLY ANOTHER TERM FOR [INAUDIBLE]. SO INFORMAL DESIGNATION WE ALL EARLY FEASIBILITY STUDIES SIMILAR TO PHASE 1 STAGE FOR DRUGS. AN INTENT STO ACKNOWLEDG TO ACKNOWLEDGE TH E UNIQUE PURPOSE OF THIS EARLY STAGE CLINICAL STUDY. CDER WILL PROVIDE CONSULTATION FOR THE DRUG COMPONENT WHEN IT COMES INTO OUR CENTER. OF COURSE IDE STANDS FOR INVESTIGATIONAL DEVICE EXEMPTION, WHICH IS A CLINICAL STUDY OF AN INVESTIGATIONAL DEVICE, AND IT'S REALLY JUST A STANDARD I.D. EXCEPT FOR THERE ARE SIGNIFICANT UNKNOWNS ABOUT HOW THE DEVICE WILL PERFORM BECAUSE IT'S EARLY IN DEVELOPMENT OR HAS A NEW INTENDED USE, THEREFORE A SMALL NUMBER OF SUBJECTS ARE INCORPORATED INTO THE CLINICAL INVESTIGATION. SO WHY THE FOCUS? HISTORICALLY, CLINICAL STUDIES OF NOVEL TECHNOLOGY HAVE BEEN CONDUCTED OUTSIDE OF THE UNITED STATES. THE PROBLEM WITH THIS IS THAT DEVICES THEN MAY BE APPROVED OUTSIDE THE UNITED STATES ONLY, OR THERE MAY AB SIGNIFICANT DELAY BETWEEN WHEN THEY'RE APPROVED IN THE U.S. VERSUS THE UNITED STATES. ALSO DEVICE INNOVATION MAY PROVE OUTSIDE THE UNITED STATES FIRST. SO THE GOAL IS TO IMPROVE PATIENT ACCESS TO BENEFICIAL TECHNOLOGY, AS WELL AS SUPPORTING INNOVATION IN THE UNITED STATES. SOME OF THE PROGRAM BENEFITS, WE BELIEVE THIS ENCOURAGES THE DEVELOPMENT OF HIGH QUALITY PRODUCTS AND ALLOWS FOR DEVICE AND PROCEDURE CHANGES EARLY IN THE PRODUCT DEVELOPMENT PROCESS. HIGH QUALITY CLINICAL DATA CAN DEMONSTRATE A PROOF OF CONCEPT WHICH MAY BE VALUABLE TO INVESTORS, ALLOW FASTER U.S. MARKET APPROVAL BY BUILDING ON EARLY FEASIBILITY KNOWLEDGE, AND USED IN COMPASSIONATE USE OR EMERGENCY USE CASES WHICH WILL HELP EXPANDING DEVICE INDICATIONS OR POTENTIALLY LAUNCHING MARKET APPLICATIONS. SO THIS IS TERMINOLOGY IN CDRH FOR THE DIFFERENT STAGES OF CLINICAL INVESTIGATION. THE FIRST IS THE EARLY FEASIBILITY STAGE, TYPICALLY THERE'S LESS THAN 15 PATIENTS, A SMALL STUDY. THERE ARE FUNDAMENTAL QUESTIONS ABOUT DEVICE PERFORMANCE AND SAFETY. THE A DEVICE DESIGN MAY CHANGE AND WE ENCOURAGE THAT. THERE MAY BE LIMITED NON-CLINICAL DATA AVAILABLE AT THIS POINT IN TIME, AND THE PURPOSE OF THE STUDY CAN BE TO DEMONSTRATE A PROOF OF CONCEPT, TO GET A VERY EARLY LOOK AT SAFETY AND EFFICACY, TO EXAMINE HUMAN FACTORS TO DETERMINE WHAT DESIGN OR PROCEDURE CHANGES COULD OPTIMIZE THE THERAPY, AND DETERMINE PATIENT CHARACTERISTICS THAT MAY IMPACT THE DEVICE PERFORMANCE. ON THE FEASIBILITY STUDY OR TRADITIONAL FEASIBILITY STUDY IT'S SOMETIMES CALLED, TET VICE DESIGN IS TYPICALLY MORE FINAL. THERE WILL BE THE NUMBER OF PATIENTS CAN VARY WIDELY AND THE PURPOSE OF THE STUDY IS TYPICALLY TO CAPTURE PRELIMINARY SAFETY AND EFFECTIVENESS INFORMATION THAT WILL BE USED TO PLAN AN APPROPRIATE PIVOTAL STUDY. OF COURSE THE PIVOTAL STUDY, THE NUMBER OF PATIENTS IS DETERMINED STATISTICALLY AND ULTIMATELY FOR MARKET APPLICATION. OF NOTE NOT ALL THE STAGES ARE NECESSARILY REQUIRED FOR MARKET APPROVAL BUT THEY MAY BE. SO A COUPLE YEARS AGO, WE DRAFTED AN EARLY FEASIBILITY GUIDANCE DOCUMENT AND I WANT TO TALK ABOUT SOME KEY ELEMENTS OF THIS GUIDANCE DOCUMENT. THE FIRST SR. WE WANT T IS WE WANT TO MAKE SURE THE RIGHT TESTING AT THE RIGHT TIME IS COMPLETED. FDA RECOGNIZES THAT COMPREHENSIVE TESTING DURING EARLY PHASES OF DEVICE DEVELOPMENT MAY ADD COST WITHOUT SIGNIFICANT RETURN, AND THEREFORE SOME TESTING MAY BE DEFERRED TO A LATER STAGE IN CLINICAL DEVELOPMENT. THE GUIDANCE ALSO ACKNOWLEDGES THAT UNKNOWNS IN RISK MAY BE ADDRESSED BY THE USE OF CLINICAL MITIGATIONS TO PROVIDE PATIENTS WITH EXTRA PROTECTION. THE USE OF MORE FREQUENT AND DETAILED REPORTING AND ALSO OUTLINES RECOMMENDATIONS FOR WHAT SHOULD BE AN INFORMED CONSENT. THE GUIDANCE DOCUMENT ALSO ALLOWS FOR TIMELY DEVICE AND CLINICAL PROTOCOL CHANGES. MORE CHANGES CAN BE MADE THROUGH A FIVE-DAY NOTIFICATION RATHER THAN FDA APPROVAL. IT ALSO ALLOWS FOR CONTINGENT APPROVAL IF THERE ARE ANTICIPATED PROPOSED DEVICE CHANGES. IT ALSO PROVIDES RECOMMENDATIONS FOR WHAT SHOULD BE INCORPORATED INTO A PRE-SUBMISSION. HIGH QUALITY SUBMISSIONS ARE REALLY IMPORTANT AND THEY CAN MAKE THE PROCESS MORE EFFICIENT. SO I'D LIKE TO TALK ABOUT THIS A LITTLE FURTHER, IN PARTICULAR BECAUSE THE TYPE OF SPONSOR THAT SUBMITS EARLY FEASIBILITY STUDIES ARE FREQUENTLY NOT VERY KNOWLEDGEABLE ABOUT THE FDA REGULATORY PROCESSES. WE FOUND IN ORDER TO BE SUCCESSFUL IT HELPS IF THEY USE RESOURCES SO THEY ACCESS THE FDA GUIDANCE DOCUMENTS, THEY'RE COMMUNICATING WITH FDA STAFF, AND THEY ALSO ARE SEEKING ASSISTANCE WITH REGULATORY NON-CLINICAL TESTING AND CLINICAL TRIAL ISSUES IF NEEDED. AGAIN, IT'S IMPORTANT THAT SUBMISSIONS ARE HIGH QUALITY, SO IN ADDITION TO BEING WELL ORGANIZED, IT'S IMPORTANT THAT HIGH QUALITY SCIENTIFIC EVIDENCE IS PROVIDED, AND FOR EARLY FEASIBILITY STUDY, IT'S VERY IMPORTANT THAT THE SPONSOR IS ABLE TO LINK TOGETHER THE INFORMATION AND TELL A STORY OF WHY AN EARLY FEASIBILITY STUDY IS THE NEXT RIGHT STEP. AND WHAT THAT MEANS IS WHY ADDITIONAL NON-CLINICAL TESTING WILL NOT BE INFORMATIVE AND HUMAN CLINICAL TRIAL IS APPROPRIATE. IT'S ALSO IMPORTANT THAT THE SUBMISSIONS ARE WELL PLANNED. WE RECOMMEND FOLKS REACH OUT TO THEIR FDA TEAM INFORMALLY EVEN AND TALK ABOUT WHAT SUBMISSION PROCESS MAKES THE MOST SENSE FOR THEM DEPENDING ON WHERE THEY ARE IN THE DEVICE DEVELOPMENT PROCESS, AND WE ALSO RECOMMEND THAT IN THE INITIAL PRESUBMISSION THAT THEY INCLUDE THEIR FULL DESIGN CONCEPT. THE CLINICAL CONTEXT AND RATIONALE FOR THE EARLY FEASIBILITY STUDY. IN ADDITION, A DESCRIPTION OF THE RISKS AND EXACTLY HOW THEY WILL BE ADDRESSED IS VERY HELPFUL. I WANTED TO TALK A LITTLE ABOUT PRESUBMISSIONS. THIS IS A VERY HELPFUL TOOL, AGAIN ESPECIALLY FOR INFREQUENT SUBMITTERS. IT CAN BE VERY USEFUL WITH NON-CLINICAL TESTING NEEDED IS UNCLEAR. SUCH THAT THE FDA AND THE SPONSOR CAN AGREE UPON THE TEST PLAN THAT'S REQUIRED. IT MAY AVOID THE NEED TO RE-DO EXPENSIVE AND TIME-CONSUMING TESTING, AND ALSO MAY HELP TO DETERMINE APPROPRIATE CLINICAL MITIGATIONS, REPORTING REQUIREMENTS, AND THE PATIENT POPULATION FOR WHOM THE AGAIN BEN FIT-RISK PROFILE SUPPORTS INCLUSION INTO THE EARLY FEASIBILITY STUDY. LASTLY, THE DECISION TO START HUMAN CLINICAL WORK IS WELL SUPPORTED AND EXPLAINED IN A HIGH QUALITY SUBMISSION. THERE'S A CLEAR IDENTIFICATION OF THE POTENTIAL RISKS AND HOW THEY WILL BE ADDRESSED, EITHER WITH NON-CLINICAL TESTING OR IN SITUATIONS WHERE THE NON-CLINICAL TESTING IS NOT VERY INFORMATIVE, WHAT CLINICAL MITIGATION STRATEGIES AND REPORTING WILL BE INCORPORATED TO PROTECT PATIENTS. LASTLY, RATIONALE IS PROVIDED WHY THE PLAN IS SUFFICIENT, EXPLAINING WHAT CAN AND CANNOT BE LEARNED FROM BENCH TESTS AND ANIMAL MODEL, AND WHY ANY INFORMATION TO BE LEVERAGED IS DIRECTLY APPLICABLE TO THE STUDY. I JUST WANT TO INCLUDE MY CONTACT INFORMATION. I'M HAPPY TO ANSWER ANY QUESTIONS AT ANY TIME OR IF YOU'VE ALREADY GONE THROUGH THE EARLY FEASIBILITY PROGRAM, I'D LOVE TO HEAR ABOUT YOUR EXPERIENCE. HERE ARE MORE HELPFUL LINKS, YOU RECEIVED A BUNCH ALREADY TODAY. MOST IMPORTANTLY IS THE FIRST WURNTION THE EARLY FEASIBILITY STUDY GUIDANCE, WHICH IS VERY INFORMATIVE. LASTLY, THIS IS OUR TEAM, IT'S JUST A NOTE THAT THESE ARE EARLY FEASIBILITY REPRESENTATIVES ARE IN EVERY DIVISION THAT KNOW AND UNDERSTAND THE GUIDANCE DOCUMENTS THOROUGHLY THAT CAN HELP AND ADVISE NOT OHM THE SPONSORS BUT THE FDA STAFF. THANK YOU. >> QUESTIONS? >> HOW MANY HAVE BEEN INITIATED? CAN YOU TELL US THAT? >> FOR THE FISCAL YEAR OF 2015, I THINK WE HAD ABOUT 46 EARLY FEASIBILITY STUDY PROPOSALS, AND ABOUT 38 WERE APPROVED. IT VARIES SOMEWHAT FROM -- SOME DIVISIONS HAVE A LOT, SOME DIVISIONS HAVE LESS. >> THIS IS DIRECTED AT SIGNIFICANT RISK DEVICES? >> OR -- CASES THAT REQUIRE I.D. >> HI, THIS IS JORGE. I HAVE A QUESTION. RIGHT NOW WE ARE CONDUCTING AN IDE FEASIBILITY STUDY IN BREAST CANCER INDICATION. WHAT IF WE WANT TO GO INTO AN INDICATION AND DO AN EARLY FEASIBILITY STUDY, DO WE SUBMIT A SUPPLEMENT TO THE CURRENT I.D. OR DO WE GO TO A NEW I.D. PROCESS? >> IT WOULD LIKELY BE -- CORRECT ME IF I'M WRONG BUT IT WOULD LIKELY BE A NEW I.D., DEPENDING ON HOW MUCH INFORMATION CAN BE LEVERAGED IN THE REPORTING REQUIREMENTS, SO YOU'D HAVE TO ASK THE REVIEW TEAM SPECIFICALLY. SOME OF THE LOGISTICS BECOME COMPLICATED. >> ALL RIGHT, THANK YOU VERY MUCH. >> GOOD AFTERNOON, PHILIP DAVIS, I'VE BEEN WITH THE AGENCY SINCE 2008. TODAY I'M GOING TO SPEAK TO YOU A LITTLE BIT ABOUT PHASE 1 AND 2 STUDIES FROM HIGH ALTITUDE PERSPECTIVE AND SOME OF THE SAFETY ISSUES THAT ARE ASSOCIATED WITH THEM AND THOUGHTS WE SHOULD BE EXPLORING TODAY. SO TO PROVIDE SOME CONTEXT, I'LL START OUT WITH JUST SHARING WITH YOU THE FDA MISSION, HOW WE'RE INVOLVED BASICALLY IN NEW DRUG DEVELOPMENT WF WDEVELOPMENT BEFORE WE MOVE INTO LOOKING AT PHASE 1 AND 2 STUDIES WITH A SLIGHT EMPHASIS ON SAFETY. SO WHAT DO WE DO? THE FDA ARE MANDATED TO PROTECT THE PUBLIC HEALTH BY SHARING THE SAFETY AND EFFICACY OF DRUGS AND VETERINARY PRODUCTS, BIOLOGICAL PRODUCTS AND MEDICAL AT TH DEVICES. WE'RE ALSO INVOLVED IN ADVANCING THE PUBLIC HEALTH AND ADVANCING ADVANCING -- IN CONTRAST TO HOW PATIENTS AND CLINICIANS MAY MAKE DECISIONS, WE AT THE FDA ON A DAILY BASIS LOOK AT HOW OUR DECISIONS ARE GOING TO AFFECT THE POPULATION AT LARGE. SO NOT A FEW PEOPLE, HUNDREDS OF PEOPLE, BUT ULTIMATELY THOUSANDS AND HUNDREDS OF THOUSANDS OF PEOPLE. SO OUR ROLE IN NEW DRUG DEVELOPMENT, AGAIN, WE ARE TASKED WITH ASSURING THAT NEW DRUGS ARE SAFE AND EFFECTIVE, WE ALSO MAKE SURE STUDY PARTICIPANTS ARE PROTECTED. THIS TIES INTO INFORMED CONSENT, GOOD CLINICAL PRACTICES AND APPROPRIATE SAFETY MONITORING IN ALL PHASES OF NEW DRUG DEVELOPMENT. WE'RE ALSO INVOLVED IN SPEEDING INNOVATION. SO HELPING IN THE DEVELOPMENT OF MORE EFFECTIVE, SAFER AND MORE I A FORDABLE DRUGMOREAFFORDABLE DRUGS AND PR OMOTING GOOD SCIENCE. I THINK A KEY MESSAGE HERE IS THAT EFFECTIVE COMMUNICATION IS PARAMOUNT, AND WE DO LIKE TO BECOME INVOLVED IN YOUR PLANS EARLY ON, AS EARLY AS POSSIBLE. I THINK THAT MAKES FOR A MORE EFFICIENT PATHWAY AND A MORE EFFICIENT DIALOGUE AND ULTIMATELY BETTER RESULT IF WE'RE INVOLVED EARLIER RATHER THAN LATER. I'LL FORWARD THROUGH THE ANIMATION QUICKLY HERE. MAINLY I JUST WANT TO HIGHLIGHT, AGAIN, WE'RE INVOLVED IN ALL PHASES OF NEW DRUG DEVELOPMENT BUT HERE I WANT TO SHOW SOME OF THE MORE IMPORTANT MEETINGS THROUGHOUT THE CLINICAL DEVELOPMENT PROGRAM. SO THREE OF THE MOST IMPORTANT MEETINGS WE HAVE WITH SPONSORS, AND WHERE WE LOOK AT THE SAFETY OF DATA GATHERED IN THE INITIAL PHASE 1 AND 2 TRIALS, WHERE WE REVIEW PHASE 3 STUDY PLANS AND IDENTIFY ANY KEY MISSING INFORMATION THAT NEEDS TO BE EXPLORED IN PHASE III. SO A FEW GENERAL THOUGHTS ON PHASE 1 AND 2 STUDIES. IT'S IMPORTANT TO HIGHLIGHT FROM A REGULATORY -- OFFER NO THERAPEUTIC ADVANTAGE, SO THEY MUST HAVE AN ACCEPTABLE SAFETY THRESHOLD AND THIS SAFETY THRESHOLD IS OFTEN HIGHER THAN THAT SEEN WITH THERAPEUTIC DRUGS, SO THERE SHOULD BE NO SIGNIFICANT ADVERSE EVENTS ASSOCIATED WITH THE DRUG. KEY IS THAT EARLY ON, SPONSORS THINK CRITICALLY ABOUT THE PROPOSED CLINICAL USE, HOW THE DRUG IS GOING TO ULTIMATELY BE USED SO THAT PHASE 1, 2 AND 3 STUDIES ARE DESIGNED IN A WAY THAT ALLOWS YOU TO MOVE FROM ONE STEP TO THE NEXT. I MEAN, THAT'S WHAT THIS PATHWAY IS ALL ABOUT, GETTING TO THE NEXT STEP, RIGHT? SO WE WANT TO EP COURAG ENCOURAGE YOU TO THINK EARLY ABOUT DESIGNING PHASE 1 AND 2 STUDIES SO THAT YOU CAN GET TO THE NEXT STEP, AND THAT, AGAIN, INVOLVES THINKING ABOUT THE INDICATION STATEMENT, THE ULTIMATE CLINICAL USE OF THE DRUG. >> I APOLOGIZE FOR INTERRUPTING. I DID WANT TO JUST GO TO THAT SLIDE THAT YOU JUST HAD WHERE -- I'M SORRY, THE OTHER ONE. THE ONE WHERE YOU SHOWED THE SAFETY, IF IT'S A DIAGNOSTIC AGENT, THAT THE SAFETY REQUIREMENTS ARE MUCH HIGHER, AND I RECOGNIZE THAT AT THE SAME TIME THE AGENTS THAT WE'RE PROPOSING HERE IN SOME WAYS ARE FOR THERAPY, IN OTHER WORDS, WE'RE PUTTING THE PATIENT USUALLY UNDER GENERAL ANESTHESIA, PERHAPS, AND THE PATIENT HAS A LIFE-THREATENING DISEASE. WHERE DOES THIS FALL AS A DYING DIAGNOSTIC VERSUS A THERAPEUTIC AGENT IN TERMS OF HOW YOU VIEW THE TOXICITY -- THE ACCEPTABLE TOXICITY? >> I THINK PART OF IT LIES IN TS --EVERY CASE IS UNIQUE, RIGHT? A LOT OF WHAT I SEE ARE AGENTS THAT ARE USED TO BETTER IDENTIFY, SAY, TUMOR, TUMOR MARGINS, METASTATIC LYMPH NODES AND SUCH. SO WITH THOSE TYPE AGENTS, THOSE TYPE OPTICAL IMAGING AGENTS, YOU WOULD NOT EXPECT TO HAVE SIGNIFICANT ADVERSE EVENT. I THINK YOU'RE TOUCHING ON AN AGENT WHERE THE ULTIMATE USE OR ULTIMATE INDICATION MAY BE TO AFFECT THERAPY, AND SO EACH CASE IS UNIQUE AND IF YOU HAVE SUCH A DRUG OR COMBINATION DRUG/DEVICE WHERE YOU KNOW FROM PRE-CLINICAL AND YOUR EARLY STUDIES THAT THERE LIKELY WILL BE AN EFFECT ON THERAPY, THEN WE CAN ADJUST WHAT WE ACCEPT FOR SAFETY THRESHOLD. I THINK A GENERAL STATEMENT IS OUR REGULATIONS ALLOW US A GOOD BIT OF JUDGMENT, A GOOD BIT OF CLINICAL JUDGMENT ON EACH STUDY WE REVIEW. SO EACH CASE IS UNIQUE. THESE ARE WRITTEN FROM MY PERSPECTIVE, MY EXPERIENCE, AND A LOT OF WHAT I SEE ARE DRUGS WITH RESPECT TO OUR CONVERSATION, DRUGS THAT ARE USED WITH DEVICES OR COMBINATION PRODUCTS THAT ARE MORE DIAGNOSTIC IN THEIR SCENARIO, AND IN THEIR PROPOSED ULTIMATE USE AND INDICATION STATEMENT OFTEN IS NOT TO AFFECT THERAPEUTIC OUTCOMES. BUT IN THE CASE YOU'RE DESCRIBING, IF YOU'RE DEVELOPING A PRODUCT WHERE YOU HAVE DATA, YOU HAVE EARLY DATA THAT THIS THR IS GOING TTHEREIS GOING TO BE AN EFFEC T ON THERAPY, THEN THE SAFETY THRESHOLD WE WOULD ALLOW WOULD BE CLOSE INVENTORY A THERAPEUTIC DRUG. WE HAVE A LOT OFLY WAY BUT IN GENERAL WE SEE A LOT OF DIAGNOSTIC AGENTS WHERE YOU'RE NOT GOING TO ALLOW THOSE TYPE OF ADVERSE EVENTS, SO IT'S A JUDGMENT CALL. >> SO SOME GENERAL THOUGHTS, AGAIN, FROM OUR PERSPECTIVE, MOST OF THE AGENTS WE LOOK AT OFFER NO THERAPEUTIC ADVANTAGE, SO THE SAFETY THRESHOLD TYPICALLY IS HIGHER HIGHER. I THINK IT'S IMPORTANT TO BEGIN THINKING EARLY ON ABOUT THE PROPOSED CLINICAL USE. THE INDICATION STATEMENT, THE SPECIFIC WORDS YOU WANT IN YOUR INDICATION STATEMENT SO THAT YOU DESIGN YOUR PHASE 1, 2 AND 3 STUDIES TO GATHER THE DATA TO SUPPORT THOSE WORDS BASICALLY IN THE INDICATION STATEMENT. WE SEE A LOT OF PHASE 1 AND 2 STUDIES THAT ARE NOT DESIGNED IN A WAY THAT WILL ALLOW YOU TO TAKE A STEP FORD AN FORWARD AND ULTIMATELY PROVE YOUR PROPOSED CLINICAL USE OR EARLY WORKING INDICATION STATEMENT, SO I THINK IT'S VERY IMPORTANT TO THINK ABOUT THAT CRITICALLY, EARLY ON. SO PHASE 1, THIS IS THE INITIAL INTRODUCTION OF AN INVESTIGATIONAL DRUG INTO HUMANS, SHOULD BE USED TO COLLECT SAFETY DATA, DISTRIBUTION, PK AND EARLY DOSING INFORMATION, CLOSELY MONITORED STUDIES, GENERALLY SMALL NUMBER OF SUBJECTS WHERE YOU HAVE SMALLER DOSING. RATHER THAN TESTING THREE OR FOUR DIFFERENT DOSES ALL AT THE SAME TIME. YOU HAVE TO HAVE ADVERSE EVENT COLLECTION DURING IMAGING AND FOLLOW-UP AND IT'S IMPORTANT TO HAVE BASELINE AND MULTIPLE TIME POINTS WHERE YOU LOOK AT VITAL SIGNS, EKG, PREGNANCY TESTING FOR WOMEN OF CHILD BEARING AGE. SO AGAIN IMPORTANT TO DESIGN YOUR STUDY TO MOVE FROM PHASE 1 TO PHASE 1. EARLY SAFETY AND TOLERANCE DATA, IMAGING UP TAKE CHARACTERISTICS, BEST IMAGING TIME POINTS, AND ALTHOUGH DOSING AS WE'VE TALKED ABOUT TODAY IS TYPICALLY NOD WE ENCOURAGE TO YOU THINK ABOUT THE OPTIMAL DOSE EARLY ON. THESE ARE THE STUDIES TO COLLECT EARLY EFFECTIVENESS DATA AND TO GENERATE HYPOTHESES FOR TESTING IN PHASE 3. THIS IS FURTHER REFINED BASED ON EARLY DATA FROM PHASE 1, THIS IS WHERE WE REFINE OUR IMAGING TIME POINTS, IMAGING PROCEDURE, AND WE ENCOURAGE YOU TO THINK EARLY ALSO ABOUT INTERPRETATION STANDARDS AND REFERENCE STANDARDS FOR YOUR HYPOTHESIS TESTING IN PHASE 3 DURING PHASE 1 AND 2 DEVELOPMENT. PHASE 2 STUDIES ALSO AIDS IN OUR EARLY UNDERSTANDING IN THE ADVERSE EVENT PROFILE OF THESE DRUGS, WELL CONTROLLED, CLOSELY MONITORED, SMALL NUMBERS OF SUBJECTS AND APPROPRIATE CLINICAL LABORATORY AT MULTIPLE TIME POINTS. AN EXAMPLE WE SEE OFTEN WITH OPTICAL IMAGING AGENTS IS WHERE YOU HAVE A DRUG THAT'S GIVEN BY I.V. INJECTION PRIOR TO A SURGICAL PROCEDURE IN ONCOLOGY PATIENTS, IGNORE THE STAGE IV, THAT'S NOT IMPORTANT. PATIENTS WHO ARE SCHEDULED TO UNDERGO SURGERY FOR A GIVEN TYPE OF CANCER WHERE THE STANDARD OF CARE SURGICAL PROCEDURE IS CARRIED OUT AND THEN THE IMAGING AGENT IS USED TO SEE IF YOU IDENTIFY THE TUMOR, THE TUMOR BORDERS, THE LYMPH NODES BET WE ARE THE IMAGING AGENT. ONE POINT I WANTED TO MAKE WAS AT THIS POINT, YOU'RE GENERATING HYPOTHESES, YOU'RE NOT PROVING THEM, SO IT'S IMPORTANT TO MAKE SURE IN YOUR STUDY PROTOCOLS AND WHAT YOU SAY TO US, YOU ENSURE STANDARD OF CARE FOR THE SUBJECTS AND OFTEN WE SEE THE END POINTS IN THESE STUDIES BEING -- TYING THE IMAGING CHARACTERISTICS TO A REFERENCE STANDARD LIKE HISTOLOGY. BUT WHAT MIGHT EVEN BE MORE VALUABLE BUT ALSO MORE CHALLENGING WOULD BE -- DISCUSSING A SCENARIO LIKE THIS IS WHERE YOU ACTUALLY TIE THE USE OF THE IMAGING AGENT TO THERAPEUTIC OUTCOME. A LITTLE MORE COMPLEX AND MORE CHALLENGING INITIATIVE, BUT ONE THAT MAY YIELD HIGHER VALUE. AGAIN, APPROPRIATE SAFETY MONITORING BASELINE AND FOLLOW-UP. THEY'RE IMAGING AGENTS, TYPICALLY MOST OFTEN THERE'S NO KNOWN THERAPEUTIC ADVANTAGE, THE EARLY STUDY SHOULD ENSURE STANDARD OF CARE TREATMENT. WE NEED APPROPRIATE MONITORING AND LABORATORY ASSESSMENTS AND COLLECTION OF DATA THAT ALLOWS US TO MAKE REFINEMENTS THAT ALLOWS US TO MOVE FROM PHASE 1 TO PHASE 2 AND PHASE 3. EACH STUDY SHOULD COLLECT SUFFICIENT INFORMATION IN TERMS OF EARLY EFFICACY DATA AND BIODISTRIBUTION SO THAT YOU CAN REFINE AND MOVE FROM PHASE 1 AND ENHANCE YOUR STUDY DESIGN IN YOUR PHASE TWO STUDIES BASED ON EARLY COLLECTED DATA SO THAT YOU CAN MOVE TO A PHASE 3 STUDY WHERE YOU'RE TESTING A ROBUST HYPOTHESIS. OUR GOI DANCES HERE, FDA.GOV, GUIDANCE FOR DRUGS. THANK YOU VERY MUCH. QUESTIONS? [APPLAUSE] >> FOLLOWING UP ON THAT DISCUSSION ON THE THERAPEUTIC BENEFIT DIAGNOSTICS, IDEALLY YOU WOULD WANT TO SHOW THAT. WHAT WOULD YOU -- HOW WOULD YOU VIEW THINGS LIKE THE OPERATION RATES? -- PRODUCTION BECAUSE OF BENEFITED -- [INAUDIBLE] >> I THINK IF YOU COULD PROVE THAT YOU HAD A LOWER INCIDENCE OF -- SO THE QUESTION WAS, HOW WOULD WE VIEW A DECREASE IN RE-OPERATION RATE WITH REGARDS TO THERAPEUTIC OUTCOMES? AND I THINK OUR NEXT SPEAKER, DR. BALLARD, IS GOING TO TOUCH ON THAT, AND MAYBE DR. MARZELA CAN ALSO -- SO IT'S BOUNCING HERE TO HERE, AND -- >> DR. MARZELA IS THE ULTIMATE DECIDER. >> DID YOU HAVE ANOTHER QUESTION QUESTION? >> ON A VERY RELATED QUESTION, THAT IS, MANY OF US THAT ARE BRINGING FORWARD TUMOR TARGETED IMAGING AGENTS DON'T HAVE A LOT OF MONEY, AND SO WE WOULD LIKE TO GENERATE A REVENUE STREAM BEFORE WE HAVE TO REALLY CONDUCT EX-PENTIVEXPENSIVE STUDIES. IS IT POSSIBLE TO OBTAIN A PHASE 3 -- BEING ABLE TO IMAGE AND RESECT MORE DISEASE TISSUE AND THEN FOLLOW THESE PATIENTS IN A PHASE 4 TO SEE IF WE ALSO SIMULTANEOUSLY IMPACT OUTCOME, LIKE OVERALL SURVIVAL? >> I THINK WHAT YOU'RE DESCRIBING WOULD BE LIKE AN EFFICACY SUPPLEMENT, BUT THE FIRST PART OF YOUR QUESTION, TO GAIN APPROVAL IN PHASE 3 FOR WHAT? >> TO CONDUCT THE PHASE 3 SO THAT YOU CAN BEGIN TO SELL THE IMAGING AGENT SO THAT SURGEONS CAN USE IT UNDER THE LABEL THAT IT ALLOWS THEM TO SEE AND RESECT MORE DISEASE, WHATEVER, I MEAN, THERE'S A LOT OF DIFFERENT SCENARIOS, EVERYBODY HAS A DIFFERENT ONE FOR THEIR PARTICULAR APPLICATION, AND THEN SUBSEQUENTLY, FOLLOW THE OUTCOME OF THESE PATIENTS TO SEE IF YOU HAVE IMPROVED THEIR OVERALL SURVIVAL. >> SURE, YOU CAN DO THAT. >> AND THEN CHANGE THE LABEL. >> SURE. SO WHAT YOU'RE TOUCHING ON IS WHAT THE REGULATIONS REQUIRE US TO REVIEW IN YOUR DATA AND BE CONFIDENT, AND THAT'S ONE THAT THE DIAGNOSTIC AGENT CAN CONFIDENTLY EITHER IDENTIFY, YOU KNOW, A PROCESS, A PHYSIOLOGICAL PROCESS OR ANATOMICAL STRUCTURE, AND THAT THAT'S USEFUL. SO FOR YOUR INITIAL APPROVAL, IF YOU CAN SHOW THAT YOUR IMAGING AGENT IDENTIFIES SOMETHING AND THAT'S CLINICALLY USEFUL, YOU CAN ABSOLUTELY GET APPROVAL WITH THAT AND THEN PURSUE AN ADDITIONAL INDICATION. BUT THE TWO MAIN THINGS ARE SHOWING THAT YOU CAN IDENTIFY SOMETHING AND IT'S USEFUL. AND IF IT'S NOT ALREADY GIVEN THAT IT'S USEFUL, YOU WOULD HAVE TO SHOW THAT IN YOUR STUDIES. >> FOR THOSE WHO DON'T KNOW ME, MY NAME IS BETSY BALLARD AND I'M RECENTLY JOINED THE DIVISION OF MEDICAL IMAGING PRODUCTS AS A MEDICAL OFFICER/REVIEWER. HOWEVER, I STARTED MY CAREER AT FDA IN CDRH AS A MEDICAL OFFICER/REVIEWER IN THE GENERAL SURGERY DEVICE BRANCH SO I HAVE THE UNIQUE PERSPECTIVE BEING INVOLVED IN MANY OF THESE CLB RANGE OF MOTION TYPE REVIEWS FOR THESE COMBINATION PRODUCTS. SO I'VE BEEN GIVEN THE DUBIOUS TASK ABOUT TALKING ABOUT THE SELECTION OF EFFICACY END POINT -- END POINTS ARE IMPORTANT BECAUSE THEY ALLOW US TO CLEARLY DEFINE EVENTS AND RECOGNIZE THEM WITH OBJECTIVE CRITERIA SO THEY CAN BE REPORTED UNIFORMLY. IF THEY'RE UNIFORMLY DEFINED, IT ALLOWS US TO IDENTIFY TRENDS AND SAFETY SIGNALS SO WE CAN MAKE CHANGES AS WE GO ALONG. THE FIRST PART OF MY TALK IS GOING TO BE REGULATORY CONSIDERATIONS FOR EFFICACY STUDIES APPLICABLE TO THE MEDICAL IMAGING SECTION AND I'M GOING TO TRY AND TOUCH ON SOME OF THE END POINTS -- SOME OF THE THINGS THAT WERE BEING TALKED ABOUT IN TERMS OF WHAT THE CLINICAL NEEDS ARE AND HOW THEY MIGHT BE DIFFERENT WHEN WE'RE LOOKING AT THOSE THINGS. ONE OF THE THINGS THAT I'VE SEEN IN MY EXPERIENCE CERTAINLY IN CDRH IS A DISCONNECT BETWEEN WHAT THE REGULATORY SCIENCE REQUIRES AND WHAT IS GOOD CLINICAL PRACTICE. JUST AS AN EXAMPLE, IDE WHERE THE SPONSOR WAS TOLD THEY HAD TO COME IN TO THE FDA BY THEIR IRB FOR A SIGNIFICANT RISK DETERMINATION. A DI SIGNIFICANT RIS SK IMPORTANT BECAUSE THAT DEFINES WHETHER YOU NEED AN IDE OR NOT. THIS SURGEON IS DOING A PROCEDURE HE'S DONE A MILLION TIMES, YES, THERE ARE INHERENT RISKS TO THE PROCEDURE, HE HAD IDENTIFIED WHERE HE WAS GOING TO USE HIS DEVICE, WHICH WAS AN APPROVED DEVICE, BUT IN A NEW AND NOVEL WAY. AND HE IDENTIFIED WHERE THAT MIGHT AFFECT PATIENT MANAGEMENT OR PROLONG ANESTHESIA TIME OR THESE TYPES OF THINGS, AND HE HAD INCORPORATED THOSE ISSUES INTO HIS PROTOCOL TO MITIGATE ANY KIND OF ADDITIONAL RISK TO THE PATIENT. BUT THE WHOLE PURPOSE OF HIS DOING THE STUDY WAS BECAUSE HE WANTED TO SEE IF HE COULD IMPROVE THE PATIENT STAGING AT THE TIME OF SURGERY. SO HE CAME IN TO US AND, YOU KNOW, BASICALLY I LOOKED AT WHAT HE HAD DONE, I AGREE WITH HIM COMPLETELY. HE HAD DONE ALL THE RIGHT MITIGATION, HE HAD PUT THE STRATEGIES IN PLACE AND REDUCED THE PATIENT RISK. HOWEVER, WHEN YOU LOOK FROM A REGULATORY STANDPOINT, WHEN I HAVE TO PUT ON MY REGULATORY CAP, WE DEFINE SIGNIFICANT RISK A LITTLE DIFFERENTLY, SO BECAUSE HE WAS LOOKING AT CHANGING THE DIAGNOSIS AND AFFECTING THE DISEASE AND SUBSEQUENT TREATMENT, BY DEFINITION, IT'S A SIGNIFICANT RISK. SO THIS IS SORT OF WHERE I THINK A LOT OF THE PROBLEMS AND SOME OF THE MISCOMMUNICATIONS COME INTO PLAY, WHEN INDUSTRY OR ACADEMICS SORT OF INTERACT WITH THE FDA. SO WHAT DO THE REGS SAY FOR A NEW DRUG APPLICATION? YOU NEED TO HAVE ADEQUATE WELL CONTROLLED STUDIES AND THE PROTOCOL NEEDS TO HAVE CLEAR STATEMENT OF OBJECTIVES, THE STUDY DESIGN NEEDS TO HAVE A VALID -- SO WE CAN HAVE A QUANTITATIVE ASSISTMENT AND PATIENTS NEED TO BE ASSIGNED IN A WAY THAT MINIMIZES BIAS. THE TYPE OF STUDY DESIGN CONTROL KROALS WE CAN SEE CAN BE PLACEBO, IT CAN BE DOSE COMPARISON, IT CAN BE NO TREATMENT OR IT CAN BE AN ACTIVE TREATMENT WHERE A NO TREATMENT OR PLACEBO WOULD BE ETHICALLY UNACCEPTABLE. YOU HAVE TO HAVE A WELL-DEFINED METHOD FOR ASSESSING RESPONSE AND AFFECTING THE DRUG ON THE PROCESS. THE FDA SAYS WE REQUIRE TWO ADEQUATE AND WELL CONTROLLED STUDIES TO ESTABLISH EFFECTIVENESS AND AS YOU GO THROUGH THE DRUG DEVELOPMENT PROCESS, YOU NEED TO FIND APPROPRIATE DOSE, YOU'RE GOING TO BE STUDYING PATIENTS WITH GREATER AND LESSER DEGREES OF COMPLEXITY AND SEVERITY OF DISEASE PROCESS, YOU'RE TYPICALLY PROBABLY GOING TO GET THIS TYPE OF DATA SO IT'S NOT A PARTICULARLY ONEROUS BURDEN IT WOULD PLACE ON INDUSTRY. FDA CANNOT APPROVE A DRUG WITHOUT EVIDENCE THAT THERE'S A BENEFIT TO THE PATIENT. SO JUST BECAUSE YOU CAN IDENTIFY SOMETHING, YOU HAVE TO SHOW US THAT THERE'S A CLINICAL BENEFIT OR A CLINICAL UTILITY TO HAVING DONE THAT. AND BECAUSE THAT INFORMATION IS HELPFUL IN ONE OF TWO WAYS, IT CAN HELP FACILITATE CLINICAL MANAGEMENT BY MAKING A MORE ACCURATE DIAGNOSIS, IT CAN CONTRIBUTE TO THE BENEFICIAL CLINICAL OUTCOME, ALLOWING YOU TO CHOOSE THE RIGHT CLINICAL OUT COME OR PROCEDURE, AND IT CAN ALSO BE USED TO PROVIDE ACCURATE PROGNOSTIC INFORMATION. YOU NEED TO DEMONSTRATE THE RESULTS ARE VALID AND RELIABLE, THAT THE TESTS OBTAINED WITH THE AGENT IS EVALUATED WITHOUT KNOWLEDGE OF THE TRUE STANDARD AND THE KNOWLEDGE OF THE OUTCOME, SO THEY HAVE TO BE INDEPENDENT, AND THE TRUE STATE OF THE SUBJECTS CAN BE DETERMINED BY THE TRUE STANDARD, AGAIN, WITHOUT THE KNOWLEDGE OF THE AGENT OBTAINED UNDER REVIEW. SO TYPICALLY WHERE THIS COMES INTO -- TYPICALLY THIS IS WHERE WE'LL SEE THE BLINDING, THE PATHOLOGIST WILL BE BLINDED, THE SURGEON MIGHT NOT BE BLINDED BUT YOU BLIND THE PATHOLOGIST SO THE PATHOLOGIST DOES NOT KNOW WHAT THE OUTCOME OF THE DEVICE WAS, AND IS LOOKING AT IT IN THAT REGARD. END POINTS -- I CAN'T TELL YOU WHAT SPECIFIC END POINTS YOU NEED. THE REASON I CAN'T TELL YOU THAT IS BECAUSE THE END POINTS THAT YOU'RE GOING TO NEED TO PICK FOR YOUR TRIAL ARE GOING TO DEPEND ON WHAT INDICATION YOU'RE SEEKING, AN THEY'RE GOING TO CHANGE FROM PRODUCT TO PRODUCT AND FROM DISEASE TO DISEASE, SO YOU WANT TO MAKE SURE THAT YOU'RE IN LINE WITH WHAT TYPE OF INDICATION YOU'RE SEEKING WHEN YOU'RE TRYING TO LOOK AT HOW YOU WOULD DETERMINE THE END POINTS. CLEARLY THE MOST COMMON THING WE SEE IN IMAGING IS THE DELINEATION OF ANATOMY, OR STRUCTURE DELINEATION. CAN YOU DEFINE NORMAL ANATOMY, CAN YOU DEFINE ABNORMAL ANATOMY. FOR THE PURPOSES OF WHAT WE'RE TALKING ABOUT HERE, IT'S PRETTY MUCH DO YOU SEE THE LIGHT, YOU DON'T SEE THE LIGHT. BUT YOU DO NEED TO BE ABLE TO SHOW THAT IF YOU'RE DOING AN IMAGING AGENT, WHAT ARE THE CHARACTERISTICS FOR WHAT AN ABNORMAL RESPONSE WOULD LOOK LIKE VERSUS WHAT A NORMAL RESPONSE WOULD LOOK LIKE. SO THESE ARE THE TYPES OF THINGS THAT YOU NEED TO CHARACTERIZE IN THE EARLY PHASES OF THE STUDY. WE RECOMMEND WHEN THE TRIALS DEMONSTRATE THE DIAGNOSTIC OR THERAPEUTIC MANAGEMENT IS IMPROVED, THAT YOU COMPARE IT TO MANAGEMENT WITHOUT THE USE OF A DEVICE OR THE IMAGING AGENT. YOU NEED TO ESTABLISH ALSO WHETHER THIS CHANGES FOR THE BETTER OR FOR THE WORSE. AND IF YOU USE THE AGENT, YOU NEED TO SHOW THAT IT RESULTS IN WETTER PATIENT THERAPYBETTER PATIENT THERA PY THAN WE HAVE WITH CURRENT EXISTING METHODS. CURRENTLY YOU HAVE TO ESTABLISH THE ACCURACY OF THE TESTS AND THE CLINICAL VALUE OF THE TESTS. BOTH OF THOSE REQUIREMENTS NEED TO BE FULFILLED FOR APPROVAL OF THE AGENT. WE RECOMMEND THAT THE -- TO ESTABLISH THE VALIDITY, WHAT WE'RE LOOKING AT HERE IS SENSITIVITY AND SPECIFICITY OF THE PRODUCT. WE'RE LOOKING AT THE FALSE NEGATIVE RATE AND THE FALSE POSITIVE RATE. GOING TO THE QUESTION ABOUT THE TOXICITY, IT'S NOT SO MUCH ABOUT TOXICITY FROM THE DRUG, BUT YOU WANT TO MAKE SURE THAT WE'RE NOT MISSING FALSE NEGATIVES F YOU'RE TALKING ABOUT TEAIN ABOUT DEALING WITH CANCER PATIENTS -- SO LOOKING AT END POINTS WE WANT TO SEE HOW DOES THIS COMPARE, WHAT IS THE FALSE NEGATIVE RATE FOR THIS PRODUCT, SO YOU WANT TO USE PROT DUCT IN CONTEXT WITH SORT OF A BIGGER PICTURE TYPE OF A THING. IN TERMS OF SPECIFIC THINGS THAT COME UP TODAY, LYMPHATIC MAPPING VERSUS SENTINEL NODE. WE DEFINE LYMPHATIC MAPPING AS A STRUCTURE OF THE LIN YAITION CLAIM AND THE PRODUCT IS USED TO LOCATE NODES DURING THE PRIMARY DRAINING TUMOR. THE END POINT THERE IS GOING TO BE CONFIRMATION THAT WHAT YOU'VE ACTUALLY IDENTIFIED IS LYMPH NODE DETECTED BY THE TRACER AND USUALLY FOR THE PURPOSES OF THIS WORKSHOP, THE TRUE STANDARD IS GOING TO BE THE HISTOPATHOLOGY. THE DIFFERENCE OF SENTINEL NODE IS THAT YOU'RE TALKING ABOUT A DIAGNOSTIC CLAIM BASICALLY BECAUSE THE STATUS OF YOUR SENTINEL NODE IS GOING TO IMPACT THE PATIENT MANAGEMENT AND PROGNOSIS OF THE PATIENT. SO THOSE REQUIRE A DIFFERENT TYPE OF END POINT, AND AS I SAID PREVIOUSLY, YOU NEED TO BE ABLE TO SHOW US WHAT THE FALSE NEGATIVE RATE, WHAT THE FALSE POSITIVE RATES -- FALSE POSITIVE, WHAT THE SENSITIVITY AND WHAT THE SPECIFICITY ARE, BECAUSE OF THE IMPLICATIONS OF IT ARISE IF YOU MISS A POSITIVE NODE. WHEN WE TALK ABOUT LESION DETECTION, WHEN YOU'RE LOOKING AT PRIMARY TUMORS, THERE'S THE HETEROGENEITY OF THE DISEASE, AND I THINK IN THIS DAY WHERE WE'RE HEADING TOWARDS MOLECULAR SUBTYPING AND GENETIC SUBTIGHTING, THIS IS PARTICULARLY IMPORTANT BECAUSE WHEN WE LOOK AT THESE STUDIES, IS IT BROAD SPECTRUM OF THE DISEASE OR ONLY TO A SMALL SELECT PART OF THE POPULATION. GENETICS, THE HETEROGENEITY OF THE POPULATION, WE'D LIKE TO KNOW DO THESE PRODUCTS WORK DEFINITELY IN A PATIENT WHO'S GENETICALLY PREDISPOSED FOR ANOTHER TYPE OF CANCER OR DO THEY FUNCTION THE SAME WAY? SO YOU NEED TO CONSIDER ALL OF THESE TYPES OF THINGS THAT YOU -- AS YOU GO FORWARD IN THE DEVELOPMENT OF YOUR PRODUCT. YOU NEED TO -- SINCE THESE ARE GOING TO BE TYPICALLY CLINICAL OUTCOME CLAIMS, YOU NEED TO HAVE CLINICAL FOLLOW-UP AND YOU NEED TO HAVE HISTOLOGY, YOU NEED TO SHOW US WHAT WAS THE HISTOLOGY AND WHAT WAS -- SO AGAIN I CAN'T EMPHASIZE ENOUGH THE FACT THAT FOR THE TYPE OF PRODUCTS HERE, WE'RE TALKING ABOUT TUMOR, WE REALLY NEED TO LOOK AT THE FALSE NEGATIVE RATE. THEN YOU WANT A MINIMIZATION OF BIAS. THAT CAN SOMETIMES BE CHALLENGING WITH THESE PRODUCTS. BECAUSE YOU'RE DOING THEM IN REALTIME DURING SURGERY. SO THE SURGEON IS NOT WHRIEPPEDDEDBLINDED,THE SURGEON KNOWS WHET HER THE PATIENT GOT THE DRUG OR NOT. THAT'S DIFFERENT FROM PREOPERATIVE IMAGING, YOU'RE IDENTIFYING THINGS BUT YOU DON'T REALLY KNOW IF IT'S DISEASE OR NOT DISEASE. SO AGAIN, IF YOU'RE GOING TO USE THE IMAGING TECHNOLOGY TO DO YOUR -- DIRECT YOUR BIOPSY, YOU NEED TO AGAIN CONFIRM IT WITH THE HISTOPATHOLOGY. AND AS I SAID BEFORE, TYPICALLY WE SEE SINCE THE SURGEON CAN'T BE BLINDED, THE NEXT BEST OPTION IS TO BLIND THE PATHOLOGY TO THE RESULTS OF WHAT YOU'VE USED. TUMOR MORNING DETECTION, NEIL SORT OF ALLUDED TO THIS EARLIER. THERE IS A SINGLE DEVICE THAT'S BEEN APPROVED THROUGH THE PMA PROCESS, FOR EX VIVO MARGIN DETECTION IN PATIENTS UNDERGOING RESECTION OF PRIMARY BREAST CANCER. SOME ISSUES THAT CAME UP DURING THAT TRIAL, A LOT HAD TO DO WITH BIAS. THIS WAS BECAUSE THE USE OF THE PRODUCT BASICALLY GAVE THE SURGEON AN ADDITIONAL OPPORTUNITY TO GET IT RIGHT. THAT HE WOULDN'T HAVE HAD, WITH THE STANDARD OF CARE PROCEDURE, AND SO THAT'S SOMETHING THAT YOU'RE GOING TO HAVE TO TAKE INTO ACCOUNT AS YOU LOOK AT YOUR END POINTS. BECAUSE THE SURGEON IS NOT TYPICALLY BLINDED TO THE PATIENT ASSIGNMENT FROM A STATISTICAL STANDPOINT T PUTS YOU INTO THE SORT OF -- YOU'RE NO LONGER RANDOMIZING THE RESULTS. SO -- BUT BASED ON -- THIS WENT TO PANEL, SO BASED ON THE PANEL RECOMMENDATIONS, I CAN GIVE YOU SOMETHING IN TERMS OF TUMOR DETECTION THAT MAY BE HELPFUL FOR END POINTS. THOUGTHEY DID SAY THAT YOU NEED TO RE-EVALUATE THE EXCISION RATE. BECAUSE THIS IS A BREAST CANCER PRODUCT, THEY WANTED COSMESIS AT 6 AND 12 MONTHS. SO YOU WANTED TO SHOW THAT THERE WAS A CLINICAL BENEFIT OR PATIENT-CENTERED OUTCOME THAT WAS APPROPRIATE. IT'S IMPORTANT THAT YOU -- THEY ALSO SUGGESTED THAT -- THEY ALSO RECOMMENDED YOU PRESPECIFY THE DIAGNOSTIC PERFORMANCE CHARACTERISTICS, SO YOU WANT TO PRESPECIFY THE SENSITIVITY AND SPECIFICITY, AND MOST IMPORTANTLY, YOU WANT TO DEFINE WHAT IS A MEANINGFUL IMPROVEMENT? IF WE KNOW PRODUCT X IS 90% ACCURATE, YOU WANT TO DEFINE HOW MUCH BETTER YOUR PRODUCT IS OR WHAT WOULD BE A CLINICALLY ACCEPTABLE IMPROVEMENT USING YOUR PRODUCT? SO CLEARLY FOR THE OPTICAL IMAGING PROCEDURES WE'RE TALKING ABOUT NOW, WE'RE GOING TO NEED CLINICAL OUTCOMES. KAWPT DO IT ANY OTHER WAY. BECAUSE THESE PRODUCTS ARE GOING TO BE USED IN SUCH A WAY THAT ARE GOING TO AFFECT PATIENT MANAGEMENT AND PATIENT DECISION MAKING IN REALTIME. WE DO NEED CLINICAL OUTCOMES AND FOR FINAL APPROVAL, YOU'RE GOING TO HAVE TO PROBABLY DO STUDYS THAT HAVE A LONGER FOLLOW-UP PERIOD THAN YOU MIGHT TYPICALLY SEE BECAUSE YOU WANT TO SHOW THAT YOUR PRODUCT HAS HAD AN IMPACT ON OUTCOME OF THE PATIENT. ONE OF THE THINGS IS, YOU KNOW, FOR DETECTION OF GASTROINTESTINAL LEAGUES, MY COLLEAGUES TELL ME ALL THE TIME, WE DON'T NEED HELP KNOWING WHAT A CANCER IS, WE KNOW WHAT A CANCER LOOKS LIKE. WE WANT HELP IDENTIFYING THE PREMALIGNANT LESIONS OR ATYPICAL LESIONS AND WE WANT COMBINATIONS THAT WILL HELP US GET THERE, WE DON'T NEED HELP WITH IDENTIFYING CANCER. SO AS YOU'RE DEVELOPING PRODUCTS, YOU WANT TO KEEP IN MIND WHAT REALLY IS THE CLINICAL NEED. DO WE NEED ANOTHER PRODUCT THAT TELLS US IT'S CANCER? PROBABLY NOT. ASSESSMENT OF REVASCULARIZATION, VISUALIZATION OF ANATOMICAL STRUCTURES AT RISK SO YOU CAN AVOID INADVERTENT RESECTION. TYPICALLY IN THE BRAIN THIS IS ALWAYS AN ISSUE, HOW DO YOU TAKE OUT ENOUGH BUT NOT TOO MUCH, AND THEN FOR THINGS LIKE OVARIAN CANCER, WHERE YOU WANT TO DEBULK WIDELY INFILTRATED TUMORS, YOU CAN ALSO LOOK AT WHETHER YOU DECREASE THE RE-OPERATION RATE BECAUSE YOU'VE DONE A MUCH BETTER DEBULKING PROCEDURE THAN YOU WOULD HAVE, AND THEN THE SENTINEL NODE DETECTION, AGAIN, WE TYPICALLY LIKE TO SEE THE SENTAL NODE DETECTION DONE IN THE CONTEXT OF A REGIONAL LYMPH NODE DIE SESSION BECAUSE THEN WE HAVE THE COMPARATOR OF THE REMAINDER OF THE NODAL BASIN TO COMPARE WITH THE IDENTIFICATION WITH THE PRODUCT, UNDERSTANDING THERE ARE SOME CASES SUCH AS BREAST AND ME MELANOMA WHERE THE STANDARD OF CARE -- IT WOULD BE UNETHICAL TO SEED AND DO AT TRIAL ONE THAT LOOKED LIKE THAT. HOWEVER THERE ARE A LOT OF OTHER TUMOR TYPES WHERE SENTINEL NODE IS NOT YET THE STANDARD OF CARE SO IT'S CERTAINLY REASONABLE TO PICK ONE OF THOSE TYPES OF CANCERS AS WAS SAID EARLIER TODAY TO LOOK A -- SPECIFICALLY AT THE SENTINEL NODE IDENTIFICATION BECAUSE YOU WILL THEN HAVE THE CONTEXT OF WHAT THE REMAIPPEDDER OF THREMAINDER OFWHAT THE REGIONAL NODE BA SIN LOOKS LIKE. YOU'VE SEEN THESE EARLIER, THESE ARE THE CDER GUIDANCES FOR THE DEVELOPMENT OF NEW DRUGS, AND THEN THESE ARE SOME OF THE PERTINENT GUIDANCES FROM THE CDR8 SIDE. THAT I DON'T THINK HAVE BEEN PRETTED BEFORE. ON THE CDRH SIDE, WE REALLY LOOK AT THE -- BOTH SIDES LOOK AT THE BENEFIT RISK DETERMINATIONS AND AGAIN, YOU WANT TO MAKE SURE THAT YOU CAN -- CLINICAL BENEFIT FOR USING THE DRUG OVER THE INSTANCE WHERE YOU DON'T HAVE ACCESS TO IT OR DON'T USE IT. WITH THAT, I'M DONE. >> HI. YOU SAID SOMETHING IN PASSING, I JUST NEED CLARIFICATION ON BECAUSE I THINK -- [INAUDIBLE] TUMOR TEE TEXT DETECTION -- MY UNDERSTANDING IS IT HAS LEGAL AUTHORITY [INAUDIBLE] BUT YOU SEEM TO IMPLY THAT THE AGENCY'S POSITION IS THAT WHENEVER ONE IS LOOKING AT A TUMOR RESECTION, IT WOULD AUTOMATICALLY FALL INTO A SIGNIFICANT RISK CATEGORY. IS THAT THE -- >> IF YOU LOOK AT HOW THE REGULATION DEFINES SIGNIFICANT RISK FOR US, ANY TIME THAT YOU'RE GOING TO TAKE INTO ACCOUNT DIAGNOSIS, PROGNOSIS, MITIGATION OR TREATING A DISEASE, BY DEFINITION, IT'S GOING TO BE SIGNIFICANT RISK. NOW DOES THAT MEEP THE PATIENT IS GOING TO BE -- EVEN IF YOU'VE DONE EVERYTHING TO MINIMIZE THE RISK IN THE PROCEDURE OR ANYTHING LIKE THAT, BY DEFINITION, BECAUSE YOU'RE GOING TO AFFECT THE DIAGNOSIS OF THE PATIENT IT WOULD BE CONSIDERED SIGNIFICANT RISK. >> BUT THAT'S REALLY IMPORTANT FOR EVERYONE IN THIS ROOM, BECAUSE IT MEANS EVERYONE DEVELOPING A DRUG, EVEN IF THEY PROPOSE TO USE A DEVICE THAT'S ALREADY APPROVED FOR ANOTHER INDICATION, IS GOING TO HAVE TO SUBMIT AN IDE ON THE DEVICE AS PART OF THE IDE BECAUSE EVEN IF THE IRB DETERMINES IT WOULD BE NON-SIGNIFICANT RISK, THE AGENCY CAN BLOCK THAT AT THE LEVEL OF THE IND, WHERE THE DEVICE IS SPECIFIED. SO I THINK WE'VE CREATED -- >> WE DON'T TYPICALLY -- MY UNDERSTANDING IS YOU EITHER HAVE AN IND OR YOU HAVE AN IDE. WE DON'T SEE BOTH. SO DEPENDING ON WHICH CENTER IS GOING TO BE LEAD FOR THE PRODUCT, YOU'RE NOT GOING TO HAVE TO DO AN IDE AND AN IDE, SO IT'S GOING TO BE ONE OR THE OTHER. REGARDLESS OF WHICH CENTER IS REVIEWING IT, IT'S GOING TO HAVE TO MEET THE REQUIREMENTS FOR BOTH SIDES. THEY'RE NOT THAT DISSIMILAR, TO BE HONEST WITH YOU. >> I GUESS THAT CONFUSES SOME OF US BECAUSE IF THE IRB HAS THE LEGAL AUTHORITY TO MAKE THE DETERMINATION BUT YOU'VE EE STENGS SENGSLY MAKE THE DETERMINATION -- >> IF YOU DON'T COME TO US, WE WON'T KNOW. IF YOUR IRB IS COMFORTABLE AND DOESN'T TELL YOU YOU HAVE TO COME TO CDRH FOR SIGNIFICANT RISK DETERMINATION, IT'S NON-AN ISSUE. >> I KNOW, BUT FOR THOSE OF US WHO DON'T LIKE TO BREAK THE RULES KNOWINGLY, I THINK YOU'VE JUST MADE AN AGENCY POSITION. SO I JUST WANT TO CLARIFY IF THAT'S THE AGENCY'S POSITION, BECAUSE IT MEANS THAT ANYONE IN THE ROOM WHO GOES TO THEIR IRB AND GETS THE NSR DETERMINATION IS AGAINST THE POSITION OF THE AGENCY SO IF SOMETHING HAPPENED, I THINK IT WOULD BE KIND OF UGLY UGLY. >> I JUST WANTED TO COMMENT AND MAKE SURE THAT, IN FACT, YOU DO HAVE THE RESPONSIBILITY AS AN VIGHT VEGHINVESTIGATOR, YOU ARE THE FIRST LINE IN TERMS OF -- AS AN INVESTIGATOR, YOU HAVE RESPONSIBILITIES TO YOUR PATIENTS, AND YOU GET -- DO YOU GET TO MAKE THE DETERMINATION. HOWEVER, WE ARE HOPING THAT YOU DON'T MAKE THE WRONG DETERMINATION, SO WE'RE NOT -- YOU KNOW, WE'RE NOT SAYING WE DON'T CARE, THERE ARE REAL LEGAL RESPONSIBILITIES THAT YOU HAVE, AND FOR DRUGS THE SAME THING APPLIES, YOU DO GET TO MAKE A DETERMINATION OF WHETHER OR NOT YOU CAN BE EXEMPTED FROM AN IND. WE DON'T REQUIRE THAT YOU COME TO THE FDA, BUT CLEARLY, IF IT'S AN UNAPPROVED DRUG, IT NEEDS AN IND. >> [INAUDIBLE] CLEAR BY VIRTUE OF THE FACT THAT YOU'RE USING A NEW AGENT UNDER AN IMD FOR AN APPLICATION THAT IS RELATED TO TUMOR RESECTION, WHETHER THE DEVICE IS CONSIDERED A SIGNIFICANT RISK DEVICE BY THE AGENCY JUST BY DEFINITION, BEFORE EVEN KNOWING WHAT THE DEVICE IS. THAT'S WHAT I'M HEARING. I THINK WE ALL NEED CLARIFICATION ON THAT BECAUSE NOBODY QANTS WANT WANTS TO GO AGAINST WHATEVER THE RULES ARE. >> AGAIN, IF IT'S A COMBINATION PRODUCT, WHAT YOU HEARD IS THAT YOU'D HAVE TO MEET THE REQUIREMENTS FOR BOTH DRUGS AND DEVICES, SO IF IT'S UNDER -- YOU DON'T HAVE TO SUBMIT AN IDE. BOTH COMPONENTS OF THE PRODUCT WOULD BE REVIEWED BY THE FDA. DOES THAT MAKE IT CLEARER? >> WELL, I GUESS IT DOESN'T MATTER FOR THOSE OF US WHO HAVE CONTROL OF THE DEVICE AND THE DRUG SO IT REALLY DOESN'T AFFECT ME BUT I THINK IT AFFECTS A LOT OF PEOPLE IN THE ROOM WHO DON'T HAVE THE CONTROL OF THE DEVICE AND THE DRUG AND I THINK IT'S IMPORTANT FOR THE FIELD TO HAVE CLARITY ABOUT PEOPLE WHO HAVE EXCITING DRUGS MOVE THEM FORWARD FOUGHT WITHOUT GETTING INTO PROBLEMS. I SEE GRAY THAT I DIDN'T SEE THIS MORNING. >> THE SCENARIO THAT YOU'RE DESCRIBING DOES NOT APPLY, BECAUSE WE CONSIDER -- IN REVIEWING THE SAFETY OF A DRUG, WE CONSIDER NOT ONLY THE DRUG ITSELF BUT THE INVESTIGATIONAL PROCEDURE ITSELF. YOU DON'T HAVE ADEQUATELY TRAINED STAFF TO DO THE PROCEDURE OR APPROPRIATE MONITORING OR IF YOU'RE USING AN APPROVED DRUG, WE DO THIS ALL THE TIME. IT'S PART OF THE VEGGAL PROCEDURE TO DO PET OR MRI, YOU WANT TO GIVE THIS ANTIPSYCHOTIC AGENT FOR HEALTHY VOLUNTEERS OR GIVE AN ANESTHETIC, THOSE ARE INVESTIGATIONAL RISKS WE DO CARE ABOUT AND DO WANT TO SEE, SO THE SAME APPLIED TO A DEVICE. IT COMES UNDER OUR SCRUTINY WHETHER OR NOT IT'S CLEAR, IT'S UNCLEAR, WE WOULD ALWAYS AUTOMATICALLY CONSULT. >> I THINK WHAT LOU IS SAYING IS IF YOU PUT IN AN IMD FOR A DRUG WITH AN APPROVED DEVICE, THE DRUG -- WILL TELL YOU IF YOU NEED MORE INFORMATION ABOUT THE DEVICE, YOU HAVE GIVEN IT TO THE FDA, THEY WILL GO TO THE DEVICE SIDE AND SEE IF THERE'S ANY ISSUES, RIGHT? >> YES. >> SO YOU'RE NOT AT RISK AT THAT POINT OF DISOBEYING THE RULES BECAUSE YOU HAVE GONE TO THE FDA, AND TRUST ME, THEY WILL COME BACK AND SAY WE DON'T LIKE YOUR DEVICE IF THEY DON'T LIKE YOUR DEVICE. >> THIS INVESTIGATIONAL DRUG -- AGENT WAS BEING USED WITH A SEDATIVE WHICH WAS NOT BEING GIVEN IN A SAFE MANNER AND WE PUT THE IND ON HOLD. >> MORE QUESTIONS? >> A FEW OF US ARE INTERESTED IN IMAGING NERVES, YOU CLEARLY HAVE -- IN THE GUIDANCE, IT STATES LIGHTING UP STRUCTURES MIGHT BE OBVIOUS ENOUGH, ALTHOUGH A FEW OF US HAVE BEEN TOLD IN PREIND MEETINGS THAT YOU NEED TO SHOW A REDUCTION IN YOUR CUTTING RATE. THESE ARE VASTLY DIFFERENT POWERED TRIALS. CAN YOU TALK ABOUT THAT A LITTLE BIT? >> I THINK THE FACT GOES TO THAT'S WHERE THE EXAMPLE FOR LYMPH NODE MAPPING VERSUS SENTAL NODE IS APPLICABLE. IF IT'S -- DELINEATION, THE BAR IS ONE THING, BUT IF YOU'RE SAYING WE CAN REDUCE THE INJURY RATE OR WHATEVER, THAT'S A DIFFERENT BAR. IT GOES BACK TO WHAT ARE YOU ACTUALLY TRYING TO DO WITH YOUR PRODUCT, WHAT IS THE INDICATION THAT YOU'RE SEEKING, AND DEPENDING ON THAT, THAT IS WHAT YOUR CLINICAL TRIAL, WHAT YOUR END POINTS AND WHAT EVERYTHING IS GOING TO HAVE TO BE GEARED TOWARDS. SO THE REAL GOAL IS REDUCING NERVE DAMAGE DURING A PROCEDURE, THAT'S WHAT YOU'RE GOING TO HAVE TO SHOW. PICK END POINTS THAT REFLECT THAT, WE HAVE REDUCED -- FASTER RECOVERY TIME OF THE NERVE. THOSE ARE THE TYPES OF THINGS WOULD YOU HAVE TO CONSIDER WHEN YOU'RE SELECTING END POINTS FOR YOUR TRIAL. >> VISUALIZATION MAY NOT BE GOOD ENOUGH? >> IT MAY BE IN SOME CIRCUMSTANCES. YOU'RE DEVELOPING THE PRODUCT SO YOU HAVE TO DECIDE WHAT IT IS YOU WANT, AND THEN BASE YOUR IND POINTS ON WHAT IT IS YOU WANT. AS WAS SAID THIS MORNING, IT'S MUCH EASIER TO GET THE NOW I KNOW THIS IS A NERVE, I CAN AVOID IT TYPE OF A PICTURE, AND IT MAY BE EASIER TO GO TO THAT. THERE'S NO REASON WHY YOU COULDN'T GET THAT FIRST AND THEN CONTINUE -- IF YOU CONTINUE TO STUDY THE DRUG AND GET MORE SPEERPSED, THEEXPERIENCED, LOOK AT EXPANDI NG THAT TO SAY NOT ONLY ARE WE IDENTIFYING THE NERVE AND REDUCED THE RISK OF INJURY. SO IT'S A SPECTRUM. JUST BECAUSE YOU'VE DONE THIS AND YOU'VE FINISHED DOESN'T MEAN YOU'RE NECESSARILY DONE WITH WHERE YOU WANT TO GO WITH YOUR PRODUCT. >> IS IT FAIR THAT INHERENT CLINICAL VALUE, YOU CAN GET AN IMPROVEMENT ON SIMPLE STRUCTURE IDENTIFICATION, MAKE IT ADDITIONAL FOR -- [INAUDIBLE] >> IT DEPENDS, LET ME TRY TO PUT THIS IN CONCRETE TERMS, I THINK WE CAN ALL UNDERSTAND. THE COMPLICATION RATES YOU'RE TALKING ABOUT, EITHER -- OR RESECTION OF A URETER OR NERVE IS SO LOW THAT IT WOULD TAKE A THOUSAND PATIENTS TO DO. WELL, IF THAT'S UNFEASIBLE, THEN IT WOULD DEPEND ON HOW WELL ESTABLISHED THE CLINICAL CAN BE IS, SO WE HAVE, LET'S SAY, A RATE OF COMPLICATION, THAT'S WELL UNDERSTOOD, AND THAT'S INDEPENDENT OF YOU DO IT TO NORTH AMERICA, SOUTH AMERICA, THIS EXPERIENCE, IT'S VERY STABLE, VERY PREDICTABLE, IT'S NOT BEEN ON THE RISE, IT'S BEEN 2% FOR THE PAST 20 YEARS, SO NOW YOU HAVE A WAY THAT YOU CAN ACTUALLY OUTLINE AN ANATOMIC STRUCTURE THAT OBJECTIVELY YOU COULD NOT SEE BEFORE. SO IF YOU PRESENTED A PICTURE, IT WOULDN'T BE A SUBJECTIVE DETERMINATION, YOU COULD HAVE A SCALE THAT SAYS OKAY, ON A SCALE OF 1 TO 4, I GAVE THE DRUG TO 100 OF THESE PATIENTS AND IT'S NEVER 100%. ANY TIME YOU GIVE ME DATA THAT'S 100%, IT'S FISHY. SO IN 10% OF THE PATIENTS, ACTUALLY I GET MORE CONFUSED AND I CANNOT SEE IT AS MUCH. BUT IN 90%, I CAN SEE IT CLEARLY, AND I'M CONFIDENT THAT IN THIS PARTICULAR SETTING, IT WOULD HAVE NO PRACTICALITY IN OPEN PROCEDURE WHERE YOU HAVE WIDE EXPOSURE AND YOU CAN SEE WHAT YOU'RE DOING SO IT COULD BE A LIMITED PATIENT POPULATION, YOU HAVE A VERY LIMITED SURGICAL APPROACH. YOU HAVE OBJECTIVE EVIDENCE THAT YOU CAN VISUALIZE THE STRUCTURE. WELL, WE MIGHT BE PERSUADED THAT THE ABILITY TO VISUALIZE IT IS MEANINGFUL, TO SAY WITHOUT THE CONTRAST, CAN I NOT SE I CANNOT SEE ANYTHI NG AND WITH THE CONTRAST, I CAN SEE IT. BUT WE MIGHT STILL ASK YOU TO AT LEAST POWER THE TRIAL TO EXCLUDE A NON-INFERIORITY MARGIN, YOU WANT TO AT LEAST BE PERSUADED THAT YOU'RE NOT DOING HARM TO THE PATIENT SO YOU COULD SAY, OKAY, I COULD POWER IT TO EXCLUDE THAT THIS PROCEDURE IS NOT LIKELY TO WORSEN THE ACTUAL RATE OF COMPLICATIONS TO MAYBE 3% OR 4%. THAT'S WHAT I MEAN BY A CASE-BY-CASE BASIS. IN SOME OTHER CONDITIONS, IT WOULD NOT WOUL WOULD NOT WORK. THE EXAMPLE DR. BULLARD WAS TALKING ABOUT, I'M DOING AN INTESTINAL RESECTION BECAUSE THERE WAS ARTERY THROM POE CYST ANTHROMBOSIS ANDI CAN REALLY TELL YOU WHAT VIABLE MARGIN; I CAN SEE IT, AND WE'RE NOT GOING TO BE PERSUADED. YOU CAN SCREAM ALL YOU WANT, BUT WE WILL WANT CLINICAL DATA, BECAUSE ALSO THE QUESTION WERE YOU ASKING BEFORE, THE RISK BENEFIT IS VERY DIFFERENT, SO HERE THE PATIENT WILL DIE IF THEY HAVE A BREAKDOWN, SO IT'S COMPLICATED, BUT AS WE'RE SAYING THIS MORNING, IT'S SCIENCE-BASED SCIENCE-BASED. >> I REALLY ENJOYED THAT LAST POINT YOU MADE ABOUT THE NATURE OF THE CLAIM. I WAS JUST HOPING MAYBE YOU COULD ELABORATE A LITTLE BIT MORE. IN TALKING ABOUT THE NATURE OF CLAIM, FOR EXAMPLE, BEING ABLE TO SEE THAT URETER BETTER, SO THAT'S ONE CLAIM. I CAN SEE A DIAGNOSTIC KIND OF A FLAME BUT I'M ALSO STRUCK BY HOW THE FIELD OF OPTICAL IMAGING IS GOING TOWARDS THE THERAPEUTIC TYPE CLAIM, MEANING BETTER BLADDER CONTROL VERSUS THAT SORT OF THING OR EVEN SURVIVAL, REEXCISION RATES, THAT SORT OF THING. SO IN THESE HIGHER THRESHOLD-TYPE CLAIMS OF ACTUALLY IMPROVING PEOPLE'S LIVES TANGIBLY, IS THERE NECESSARY ALWAYS GOING TO BE A REQUIREMENT TO HAVE SENSITIVITY AND SPECIFICITY WHICH IS ONE WOULD HAVE FOR AN TO ANATOMICAL DIAGNOSTIC-TYPE CLAIM OR DO THESE BENEFITS IN TERMS OF BLADDER CONTROL, IMPROVED FUNCTION/SURVIVAL, EVEN, IS THAT ENOUGH BENEFIT IN IT SELF. THERE MAY BE SITUATIONS WHERE IT'S JUST SO CHALLENGING TO GET A TRUTH STANDARD, WHERE YOU'RE IN A QUANDARY TO COME UP WITH SENSITIVITY AND SPECIFICITY, YET THE CLAIM IS TOWARDS IMPROVED SURVIVAL OR IMPROVED BLAH KER CONTROL. BLADDER CONTROL, REALLY STRONG CLIP CAL CLAIMS. CAN YOU ELABORATE A LITTLE? >> FOR THOSE THAT DON'T KNOW, DUANE USED TO BE MY BOSS, SO HE'S ASKING A QUESTION THAT HE KNOWS THE ANSWER TO. BUT I'LL TRY. AND YOU CAN TELL ME IF I'M CLOSE. SO CLEARLY, YOU KNOW, WE LOVE TO SEE CLINICAL OUTCOME DATA. WE LOVE TO SEE RANDOMIZED CLINICAL TRIALS AND CLEARLY A SURVIVAL BENEFIT TRUMPS ANYTHING AND WE'RE WILLING TO ACCEPT ALL SORTS OF TOXICITY BECAUSE IT'S A RISK-BENEFIT SITUATION. BUT AGAIN, YOU KNOW, WE ARE LOOKING FROM THE STANDPOINT OF HOPING THAT YOU HIT A HOME RUN BUT GOING FOR THAT SIN SIN GEL, AND IF YOU MAKE THAT SINGLE, YOU'RE ON BASE, USING A SPORT ANALOGY NOW TO TALK ABOUT SUPPLEMENTAL NDA, THEN YOU GO TO SECOND BASE. SO FOR EFFICIENCY SAKE, I THINK THAT IT'S VERY VALUABLE TO START WITH UNDERSTANDING WHAT THE PRECISION AND ACCURACY OF YOUR MEASUREMENT IS. SO MIGHT AS WELL GIVE MY LECTURE RIGHT HERE. >> YOU MIGHT AS WELL. >> FOR THE SAKE OF TIME, MAYBE WE WANT TO HAVE YOU GO UP AND START -- WE'LL GET YOU OFF -- >> BUT THE ANSWER IS I DIDN'T WANT DUANE TO FEEL SHORTCHANGED, YES, WE WILL ACCEPT SURVIVAL. >> BUT I THINK THERE WERE A COUPLE OTHER QUESTIONS SO AS YOU'RE TRANSITIONING, MAYBE YOU CAN TRANSITION TO GIVE YOUR TALK AND WE COULD HEAR ONE OF THE OTHER QUESTIONS FLEURCHLT >> I'M A SURGEON AT PENN. I HAVE A QUICK QUESTION. WHERE IS THE BAR FOR AN END POINT? SO AT WHAT POINT DO YOU SAY LET'S PRETEND OUT OF 40 PATIENTS, YOU HELP STAGE 1 PATIENT FROM -- YOU GO INTO -- STAGE 1, YOU COME BACK WITH A STAGE 2. IS THAT ENOUGH? NO MATTER -- RIGHT NOW YOU'RE ONLY ADDING TO THE STANDARD OF CARE SO IS THAT SUFFICIENT? IS THAT ENOUGH OF A BAR? WHERE IS THE BAR? >> IT'S AN EXCELLENT QUESTION. IT'S A RISK-BENEFIT CALCULATION. THE LAW DOESN'T DEFINE WHAT SAFE AND EFFECTIVE IS. SO WE DON'T HAVE AN ARBITRARY STANDARD. IN PRINCIPLE, IF THE RISK WAS SUFFICIENTLY LOW, YOU KNOW, BETTER THAN CHANCE, AN OUT COME THAT MIGHT BE BETTER IN CHANCE MIGHT BE -- IT HAS TO BE JUSTIFIED. SO LET'S SAY THAT YOU HAD AN ADJUNCTIVE IMAGING TEST THAT ADDED TO STANDARD OF CARE PROVIDED IMPROVED THE SENSITIVITY, ALLOWED YOU TO PICK UP, I DON'T KNOW, 10 MORE PATIENTS, YOUR SENSITIVITY WEPT FROM 60% TO 70%. YOU COULD MAKE AN ARGUMENT THAT THAT'S A BENEFIT. IF IT WAS ADJUNCTIVE, IF IT ADDED ADDITIONAL INFORMATION THAT ULTIMATELY HELPED IN MANAGING A PATIENT. ON THE OTHER HAND, IF YOU WERE TRYING TO USE, AGAIN, AN IMAGING TEST, AND LET'S SAY WERE YOU TRYING TO USE IT TO DETERMINE WHETHER YOU'RE TAKING OFF -- WHETHER A CANCER SPACE HAS RESPONDED OR NOT, SO YOU HAVE A CANCER RATE WITH SURVIVAL RATE OF 100% BUT IT'S ALSO VERY TOXIC AND IT KILLS EVERYBODY UNLESS -- SO IT'S A RISK-BENEFIT CALCULATION. IT WOULD BE -- WE WOULD BE VERY HARD PUT TO SEMI TAKING OFF A PATIENT FROM LIFE SAVING THERAPY IF THE PERFORMANCE OF THE TEST WAS ONLY SLIGHTLY BETTER THAN CHANCE, SO AGAIN, TO ANSWER YOUR QUESTION, THERE'S NO LEGAL STANDARD FOR WHAT'S SAFE AND EFFECTIVE. IT'S A RISK-BENEFIT. THE MORE THE RISK, THE MORE THE BENEFIT. DOES THAT ANSWER YOUR QUESTION? SO I JUST WANTED TO THANK AGAIN PAULA AND ALL THE OTHER ORGANIZERS FOR THE HARD WORK, I WOULD LIKE TO ACKNOWLEDGE NOSHIN TODD FOR THE ROLE SHE PLAYED IN GETTING THIS GOING AS WELL AS BETSY, SO THANK YOU ALL. THANK YOU TO EVERYBODY FOR THIS OPPORTUNITY TO HAVE THIS DISCUSSION. WE FIND IT EXTREMELY HELPFUL. SO I WANTED TO 50 ABOUT REGULATORY CONSIDERATION FOR EFFICACY STUDIES THAT ARE APPLICABLE FIRST OF ALL TO IMAGING DRUGS IN GENERAL. ONE POINT THAT I WANT TO MAKE IS THAT IN GENERAL, STUDY DESIGN CONSIDERATIONS ARE REALLY APPLICABLE TO THERAPEUTIC AS WELL AS DIAGNOSTIC AGENTS, THAT THERE'S NO REAL DISTINCTION. THE OTHER THING THAT I WANT TO EMPHASIZE IN THIS TALK IS THAT TO BE SUCCESSFUL, YOU KNOW, YOU NEED TO HAVE A STRATEGIC PLAN. YOU HAVE TO HAVE AN APPROACH TO DEFINE HOW YOU'LL DEVELOP YOUR DRUG. AND WE, AGAIN THE MESSAGE YOU HEARD, YOU NEED TO INTERACT EARLY WITH THE FDA BECAUSE THIS WILL MAXIMIZE THE LIKELIHOOD OF YOUR SUCCESS. THE OTHER POINT WE WERE MAKING TODAY WAS DESIGNING A STUDY THAT MAXIMIZED THE EFFICIENCY OF THE WORK THAT YOU'RE DOING AND THE VALUE OF THE DATA. A CRITICAL, MINIMIZING BIAS IS A CRITICAL, CRITICAL ASPECT OF WHAT YOU NEED TO DO. THERE ARE A NUMBER OF CREATIVE WAYS BY WHICH WE CAN ACHIEVE THIS. THE GOLD STANDARD, RANDOMIZED TRIALS, PARALLEL ARM, CLINICAL OUTCOMES. BUT I WANT TO BE A LITTLE HEDGIER AND TALK ABOUT MAYBE WAYS BY WHICH YOU CAN ACTUALLY DO INTERPATIENT CONTROL STUDIES. IN SITUATIONS WHERE YOU DON'T ACTUALLY NEED TO WORK AT CHANGES IN PATIENT MANAGEMENT, AND SO HOPEFULLY SOME OF THE EXAMPLES THAT I WILL PRESENT WILL HIGHLIGHT THIS TYPE OF STRATEGY. SO IT'S IMPORTANT THAT YOU HAVE AN OVERALL STRATEGY FOR CLINICAL STUDY AT THE VERY EARLY STAGES OF DRUG DEVELOPMENT. SO YOU NEED TO BEGIN WITH THE PROPOSED INDICATION FOR USE. YOU SHOULD HAVE IT AS AN EXERCISE TO SAY DRUG X IS GOING TO BE AN ADJUNCT TO DRUG B AND IT WILL RESULT IN THIS. THE INDICATION STATEMENT SHOULD DEFINE THE PATIENT POPULATION IN WHOM YOU THINK THIS DRUG IS GOING TO PROVIDE A BENEFIT, AND THEN YOU WANT TO LOCK AT OUTCOMES THAT DEMONSTRATE CLINICAL UTILITY. THE TITLE OF MY TALK, AND THIS WILL SHOW YOU THE LEFT LEVEL OF INVOLVEMENT I HAD IN THE PLANNING, HOW DO THE END POINTS CHANGE THE FACE OF CLINICAL DEVELOPMENT? SO I THOUGHT OH, IT DOESN'T CHANGE, AND DECIDE -- I HAVE TO TALK ABOUT SOMETHING ELSE. SO BASICALLY YOU SHOULD BE, FROM THE GET-GO, YOU SHOULD BE THINKING WHAT IS THE INDICATION STATEMENT, THEN USE MULTIPLE END POINTS. THIS IS SOMETHING THAT I BECOME REMINDED ALL THE TIME THAT THE FDA NOW IS NO LONGER THE ONLY DETERMINANT OF WHAT THE COMMERCIAL SUCCESS OF A DRUG WILL BE, BECAUSE IN ADDITION TO APPROVAL, THERE'S OTHER -- I'M THINKING OF TERMS IN THIRD PARTY PAYORS THAT BECOME INVOLVED IN MAKING THE DECISIONS OF WHETHER TO REIMBURSE OR NOT. AS YOU KNOW, THIRD PARTY PAYORS TEND TO VALUE CLINICAL OUTCOMES. SO THE ADVICE THAT YOU WILL HEAR FROM US IS THAT IT PAYS TO BE EFFICIENT AGAIN, SO FOCUS ON DETERMINING WHAT THE ACCURACY OF THE TEST IS, NEN TR THEN TRY TO PRODUCE OUTCOMES THAT COULD POTENTIALLY PRODUCE CLAIMS FOR PATIENT MANAGEMENT. SO I THINK THIS POINT CAME UP EARLIER THIS MORNING, THAT IT'S A GOOD STRATEGY, IT'S A SMART STRATEGY TO BEGIN WITH THE FOCUS OF MINIMIZING HETEROGENEITY, REDUCE VARIABILITY, SO YOU WANT TO SORT OF BE VERY PARSIMONIOUS IN TERMS OF THE PATIENT POPULATION THAT YOU WORK WITH TO TRY TO GET A GOOD OUTCOME FROM THE STUDY, THEN IN PHASE 3, YOU CAN THINK ABOUT EXPANDING PATIENT POPULATION, YOU CAN GENERALIZE, OR YOU CAN BE EVEN MORE CONSERVATIVE AND SAY OKAY, I'M GOING TO GET ON THE MARKET WITH THIS SPECIFIC INDICATION, IT'S A WELL DEFINED OBLIGATION INDICATION AND WE'LL COME BACK WITH A SUPPLEMENTAL APPLICATION TO PROVIDE ADDITIONAL INDICATIONS FOR USE. THE SELECTION OF END POINTS, I THINK IT'S ALWAYS CRITICAL TO THINK IN TERMS OF ESTABLISHING THE PRECISION AND THE ACCURACY OF YOUR TEST, AND IT HAS TO BE DIAGNOSTIC PERFORMANCE RELEVANT TO SOME -- IT CAN BE A COMPOSITE, IT CAN BE CLINICAL FOLLOW-UP, PATHOLOGY,ICALLY, COMBINATION OF BOTH, IT CAN BE A TENTATIVE DIAGNOSIS WHERE YOU THINK YOU'VE IDENTIFIED SOME RECURRENT MALIGNANCY AND YOU EE EE EE RADIATE IT AND THE TUMOR MARKER DROPS, SO YOU CAN BE CREATIVE BUT IT'S CRITICAL THAT YOU HAVE A REFERENCE STANDARD AGAINST WHICH TO COMPARE THE PERFORMANCE OF YOUR TEST. IF YOU LIKE, CAN YOU HAVE AN ACTIVE COMPARATOR AND THEN YOU CAN HAVE A COMPARISON THAT LOOKS AT WHAT IS THE PERFORMANCE OF THE IMPROVED COMPARATOR, THE ACTIVE COMPARATOR TO YOUR DRUG. I CERTAINLY DO NOT ADVISE THIS BECAUSE OUR EXPERIENCE HAS BEEN THAT CURRENT TECHNOLOGY ALWAYS TENDS TO BE BETTER THAN THE OLDER TECHNOLOGY, SO LOOKING AT A COMPARISON WITH AN ACTIVE COMPARATOR TENDS TO ACTUALLY BIAS THE STUDY IN FAVOR OF A GUILD COMPARATOR. THE OTHER IMPORTANT POINTS IS THAT YOU ALWAYS HAVE TO HAVE PRESPECIFIED I POZS AND WHAT DETERMINES THE NUMBER OF PATIENTS, 300, 200 IS DRIVEN BY IS THAT TIS TICS AND IT THBYSTATISTICS. THE CRITERIA FOR EFFICACY END POINTS, THE BENEFIT NEEDS TO BE IMPLIED OR SHOWN THROUGH CLINICAL OUT KS COMES. WE'V OUTCOMES. WE'VE DISCUSSED EXAMPLES OF OF HOW THAT COULD BE DONE. AGAIN, HISTORICALLY, CONTRAST AGENTS, WE HAVE CONSIDERED -- FOR CONTRAST AGENTS, WE'VE CONSIDERED THE ABILITY TO IMAGE TO BE IN AND OF ITSELF A BENEFIT. HOWEVER, FOR NEW TARGETED AGENTS, WHERE WE DON'T UNDERSTAND WHAT THE ACTUAL CLINICAL USE IS, THEY MAY REQUIRE ACTUAL PERFORMANCE OUTCOMES RELATIVE TO A TRUE STANDARD. IN TERMS OF TRIAL PHASE AGAIN, I THINK THAT IT WILL BE IMPORTANT TO TERM THE SINGLE PRIMARY END POINT FOR YOUR PHASE 3 STUDIES, BUT EARLY ON, YOU SHOULD BE USE USING ANY END POINTS YOU CAN TO LEARN AS MUCH ABOUT THE TREATMENT EFFICACY AS YOU CAN. YOU USE THEM TO DEVELOP HIGH POTASSIUM CIRCLES PRIMARY, YOU USE THEM TO DETERMINE EFFICACY, SECONDARY, THEY'RE SUPPORTED FOR EFFICACY, PROVIDE INFORMATION IN SUBGROUPS FOR SAFETY AND EFFICACY. WE TALKED ABOUT THE LIKELIHOOD THAT IF THERE'S STRONG PRESUMPTIVE INFORMATION, THAT THE BENEFIT OF THE DRUG IS LIKELY TO BE GENERALIZABLE, THAT WE WILL LOOK AT A BROAD PATIENT POPULATION AND LOOK FOR SIGNALS IN SUBGROUPS TO DETERMINE WHETHER THE EFFECT IS REALLY EXTRAPOLATABLE. THE OTHER THING I ALSO WANT TO EMPHASIZE IS THAT EVEN IN EFFICACY TRIALS, YOU CAN USE MULTIPLE OUTCOMES AND MULTIPLE ANALYSIS AND THERE'S SIMPLE TECHNIQUES, THE STEP-DOWN APPROACH, THAT YOU CAN USE TO PRESERVE THE A ALPHA. TALK TO YOUR FRIENDLY STATISTICIANS AND THAT IS SOMETHING THAT IS VERY, VERY IMPORTANT TO MAXIMIZE THE EFFICIENCY OF WHAT YOU DO. SO SOME EXAMPLES OF EFFICACY OUTCOMES OF PHASE 3 TRIALS, ANATOMIC OR FUNCTIONAL OUTCOMES IN TRIALS OF THERAPEUTIC DRUGS. RADIOLOGIC JOINT SPACE NARROWING AND EROSIONS WITH DMARDS FOR RA, IN CASES OF DIAGNOSTIC DRUGS, AGAIN, WE DON'T REQUIRE ACTUAL OUTCOME, ABILITY TO DETECT, ABILITY TO VISUALIZE CAN BE JUST AS GOOD. THIS IS A POINT THAT WE ALWAYS EMPHASIZE, THE CONSIDERATION FOR THERAPEUTIC AND DRUG AND DIAGNOSTIC DRUG APPROVAL IS BASICALLY SIMILAR STANDARDS, SIMILAR PROCEDURES, EXCEPT THAT AS I WAS MENTIONING, THE EXAMPLE WE TAUGHT TO GREAT EXTENT, VISUALIZATION OF THE URETER, OF THE BILE DUCT IN SURGICAL PROCEDURE, THAT WE COULD BE PERSUADED THAT, YOU KNOW, PARTICULARLY IF A STUDY POWERED TO LOOK FOR COMPLICATION RATES IS NOT ACCEPTABLE, THAT WE WOULD BE WILLING TO ACCEPT OBJECTIVE MEASURES OF IMPROVEMENT IN VISUALIZATION AND LOOK AT THE COMPLICATION RATES AS A SAFETY ENDPOINT. HERE I'VE ADDED AGAIN SOME EXAMPLES, THE INCREASED -- OF POORLY VISUALIZED STRUCTURES AND PRETOURS OPROCEDURES COULD BE USEFUL IF AS I MENTIONED WE HAVE A STABLE HISTORICAL CONTROL RATE AND YOU CAN GO TO 15 CLINICAL CENTERS -- WELL, MAYBE YOU DON'T HAVE TO COULD THAT MANY 16 POR -- IF IT'S STABLE, WE WOULD BE WILLING TO ACCEPT SOME HISTORICAL CONTROL SO WE CAN BE CREATIVE. THE PRIMARY END POINT AS I MENTIONED COULD BE AN OBJECTIVE MEASURE OF MEANINGFUL IMPROVEMENT IN VISUALIZATION, SOMETHING AN OBJECTIVE PERSON COULD REVIEW IN A BLINDED FASHION, THEY'D DETERMINE THAT, YES, THERE IS, IN FACT, IMPROVEMENT. THE RATE OF COMPLICATION IN THIS CASE WOULD BECOME A SECONDARY SAFETY END POINT. ANOTHER EXAMPLE, YOU KNOW, WE HEARD ABOUT ABILITY TO VISUALIZE TUMORS AND THERE'S SITUATIONS WHERE THE ABILITY TO DEFINE CORRECTLY WHAT TUMOR-FREE MARGIN IS CRITICALLY IMPORTANT AND IT'S WELL ACCEPTED. BREAST CANCER, SKIN CANCER, AND SO THERE, THE STUDY DESIGN WOULD BE VERY OBVIOUS AND IT COULD BE AN INTRAPATIENT STUDY WHERE AGAIN YOU DO STANDARD OF CARE, YOU DEFINE -- IF STANDARD OF CARE SAYS FOR THIS TYPE OF TUMOR YOU DO, I DON'T KNOW, 2 COUNCILMEMBE2-CENTIMETER MARGIN AND THEN YOU CAN GO AND ADD YOUR -- TURN ON THE BLUE LIGHT OR WHATEVER INVESTIGATION -- AND DETERMINE THERE'S ADDITIONAL TUMOR THAT THAT COULD BE HELPFUL. WE WOULD FIND THAT PERSUASIVE. SO YOU WOULD NOT HAVE TO HAVE A RATE OF COMPLICATIONS. FOR INSTANCE, IF IT'S BREAST CANCER, WE DON'T NECESSARILY NEED TO SEE RATE OF RE-OPERATIONS, SO THERE'S SOME GIVE AND TAKE THERE. IN THE CASE OF DEBULLING O DEBULKING OF WIDELY INFILTRATED TUMORS, IT GETS MORE COMPLICATED, BUT WE'RE WILLING TO ENTERTAIN PROPOSALS. DO YOU NEED TO HAVE PARALLEL ARMS, CAN DO YOU AN INTRAPATIENT CONTROL, WHAT WOULD BE THE PRIMARY END POINT? YOU WOULD WANT TO SEE INCREASED ABILITY TO -- INCREASED TUMOR MASS RESECTION, LESS RESIDUAL TUMOR IMAGING, SAFETY END POINTS HERE A CRITICAL, ARE YOU DOING MORE HARM TO THE PAINT BY TSH IF IT'S BRAIN TISSUE, ARE YOU CAUSING MORE ACUTE IMICATIONS? ARE YOU INDUCING INDICATION OF THE BRAIN, ARE YOU IND DUESING LOSS OF ORGAN FUNCTION, DISABILITY, CAN YOU -- SO FOR INSTANCE, IN WIDELY INFILTRATIVE TUMORS WHERE IT'S NOT CLEAR THAT THE BULKING IS CLINICALLY HELPFUL, YOU MAY HAVE TO SHOW THAT THERE IS SOME CLINICAL BEN FIRKTS AND IT MAY NOT EVEN BE SURVIVAL. IF IT'S BRAIN TUMORS AND THE PATIENT IS A RESULT OF THE BULKING PROCEDURE FEEL BETTER OR HAVE SOME OBJECTIVE CHANGE IN QUALITY OF LIFE, WE'RE WILLING TO LOOK AT THAT, BUT IF THERE'S SORT OF A SOFT END POINT THAT SHOWS BENEFIT BUT THEN YOU FOLLOW THESE PATIENTS AND THE SURVIVAL OF THESE PATIENTS TENDS TO BE SHORTLIVED, IF YOU HAVE A GLIOBLASTOMA AND YOU FIND THAT TIME TO RECURRENCE, OR TIME TO EVENT, TIME TO SURVIVAL WHEN YOU HAVE CANCER-FREE IS BETTER THAT, GIVES YOU ADDITIONAL CONFIDENCE. NOW WHAT HAPPEN FS THAT END POINT IS FAVORABLE BUT THEN YOU LOOK AT OVERALL SURVIVAL AND THERE'S NO DIFFERENCE. THAT BECOMES COMPLICATED. I THINK ONE OF THE RESEARCHERS HERE WAS ASKING THE VERY SAME QUESTION, I THOUGHT YOU WERE ASKING MORE IN TERMS OF CAN YOU DO ACCELERATED APPROVAL, CAN YOU APPROVE SOMETHING IN A BIOMARKET? WE'VE NEVER DONE IT FOR IMAGING DRUGS, AND IT WOULD BE PRETTY DIFFICULT TO JUSTIFY IN SITUATIONS WHERE YOU CAN FOLLOW PATIENTS AND YOU CAN HAVE A REASONABLE OUTCOME. SO WE PROBABLY WOULDN'T GO TO APPROVAL BUT AGAIN, WE COULD ENTERTAIN LOOKING AT PERSUASIVE DATA ON END POINTS FROM TIME TO EVENT AND THEN BE BACKED UP BY THE TIME OF THE SUBMISSION BY SURVIVAL DATA. SO AGAIN, IT'S SCIENCE, IT'S NOT ANYTHING ARBITRARY HERE. WE'RE TRYING TO SORT OF TAILOR THE STUDY DESIGN, THE END POINTS, TO WHAT IT WOULD TAKE OBJECTIVELY TO SHOW EVIDENCE THAT THIS DRUG HAS A THERAPEUTIC EFFECT, IT HAS A FAVORABLE EFFECT. SO I THINK I'LL STOP THERE AND AGAIN, THANK YOU FOR -- [APPLAUSE] >> SO I THINK BECAUSE THE TIME HAS GOTTEN AWAY FROM ME, WE'LL HAVE A 15-MINUTE BREAK BECAUSE THE CAFETERIA CLOSE AT 3:00, EXCUSE ME, 15 MINUTES, THEN WE'LL DO THE PANEL FOR THIS SESSION IMMEDIATELY AND THEN WE'LL FOLLOW IN TO THE NEXT SESSION. SO IS THAT CLEAR TO EVERYBODY? WE'RE GOING TO HAVE 15 MINUTES NOW AND THEN WE'RE GOING TO COME BACK AND DO THE PANEL THAT WAS WE'LL HAVE OUR PANELISTS FOR THE END POINTS PANEL, THEN WE'RE GOING TO GO DIRECTLY INTO THE NEXT TALK AND WE'LL START WITH PATRICIA LOVE ON THAT, WE WON'T HAVE A BREAK IN BETWEEN THEN. SO WE SHOULD START BY AGAIN INTRODUCING THE PANEL. I'M EVAN ROSENTHAL, I AM A HEAD AND NECK ONCOLOGIST AND SURGEON AT STANFORD UNIVERSITY. AND I'VE BEEN WORKING ON APT BODANTIBODY BASED IMAGING FOR A WHILE AND HAVE BEEN VERY INTERESTED TO KNOW HOW WE CAN ADVANCE THIS FIELD AS A WHOLE, SO I'M VERY GRATEFUL THAT EVERYBODY HAS COME HERE TO PARTICIPATE IN THIS, BOTH FROM FDA, NCI AND THEN, OF COURSE, THE COMPANIES AS WELL AS ACADEMICS WHO HAVE ALL MADE A MAJOR EFFORT TO COME HERE. THE OTHER THING I LIKE -- HOW THIS MEETING STARTED WAS ACTUALLY THROUGH THE OSN SOCIETY, WHICH IS PART OF THE WMIS, AND THAT GROUP THAT MIKE AND JIM RUN, WE HAD A PAM WHERE SEVERAL OF US WERE IN THE ROOM AND TALKING ABOUT THESE ISSUES AND REALIZED THAT WE REALLY COULDN'T MAKE ANY KIND OF DEFINITIVE STATEMENT WITHOUT THE FDA PRESENT AND ABOUT THE RIGHT PEOPLE. SO THE OPTICAL SURGICAL NAVIGATION SOCIETY, WHICH IS A PART OF THE WORLD MOLECULAR IMAGING SOCIETY, HAS A MEETING IN THE FALL, THE WMIS, AND AS PART OF THAT, IT HAS AN OSN SECTION, AND ACTUALLY LISA IS THE DIRECTOR OF THAT SOCIETY AND HAS BEEN VERY HELPFUL IN SUPPORTING THIS, BUT THAT'S WHERE THIS SORT OF CAME FROM, WAS OUR INABILITY TO ANSWER SOME OF THESE QUESTIONS. SO PAULA AND I AFTER THE CONFERENCE GOT TOGETHER AND TRIED TO MOVE THIS ALONG. >> HI, PHILIP DAVIS. I'M A NUCLEAR MEDICINE DOCTOR AND HAVE BEEN WITH THE AGENCY IN DIVISION OF MEDICAL IMAGING SINCE 2008 AT FDA. >> CARLA, POLICY ANALYST FOR THE EARLY FEASIBILITY PROGRAM, CDRH. >> MERRILL BIEHL, HEAD AND NECK SURGEON AT UNIVERSITY OF MINNESOTA, THERAPEUTICS. >> BARBARA SMITH, BREAST SURGEON AT MASS GENERAL AND I'M GOING TO MAKE A FEW COMMENTS. A COUPLE OF THINGS THAT I THINK WE PROBABLY ALL THINK ABOUT TO SOME EXTENT BUT I WANTED TO MENTION CONCRETE THINGS WE DO IN THE OPERATING ROOM AS SURGEONS WHO WILL BE USING THIS TECHNOLOGY THAT HAVE IMPLICATIONS FOR END POINTS. FIRST IS THAT THE TYPE OF TISSUE WE'RE DEALING WITH MAKES A HUGE DIFFERENCE ABOUT WHETHER WE CARE ABOUT IMAGING IN VIVO OR WHETHER WE CAN IMAGE IN EX VIVO SPECIMEN WHEN WE THINK ABOUT THINGS. IF THE TARGET THAT WE'RE OPERATING ON IS A SMALL ONE OR ANATOMICALLY FIXED, IT DOESN'T MATTER SO MUCH WHETHER WE'RE IMAGING IN THE PERSON OR OUT OF IT, BUT IF IT'S A PLIABLE TISSUE, WHERE OUR VIEW IS POOR OR CHANGES OVER TIME, BEING ABLE TO IMAGE IN VIVO IS HUGELY IMPORTANT BECAUSE A KEY POINT OF THE END POINT IS ARE WE GOING TO BE ABLE TO USE THIS INFORMATION IN WAYS THAT WILL HELP THE PATIENTS. SO IN BREAST SURGERY AS I DO, ONCE WE TAKE THAT LUMP ECTOMEE OUT OF THE PATIENT T TOTALLY CHANGES SHAPE. ANY ASSESSMENT WE GET OF THE SURFACE OF IT DOESN'T REALLY HELP US KNOWING WHERE TO GO BACK IN AND DO THE RE-EXCISION, SO BEING ABLE TO THINK ABOUT THAT, IF IT'S AN ENDOSCOPIC IMAGE OR LAPAROSCOPIC IMAGE, THE VIEW OF THE SURGEON IS ACTUALLY UNSTABLE OVER TIME. SO IF YOU HAVE TO TAKE A BIOPSY OUT AND LOOK AGAIN LATER, AFTER YOU'VE GOTTEN YOUR READOUT, YOU WON'T BE IN THE SAME PLACE. SO THOSE ARE THINGS WHEN YOU'RE THINKING ABOUT END POINTS HAVING YOUR USER AND YOUR ORGAN SYSTEM CLEARLY IN MIND WILL BE HELPFUL. THE OTHER THING IS THAT AS SURGEONS, WE ARE NOW GETTING COST OUTLINES, A LIST OF EVERY AMOUNT OF ANYTHING THAT WE SPENT IN THE O.R. SO EVERY TIME I DO A CASE NOW, I GET THIS MUCH DRUG, THIS MUCH DISPOSABLES, THIS MUCH OTHER THINGS, AND SO AS WE THINK ABOUT END POINTS AND AS WE THINK ABOUT HOW THESE DEVICES WILL BE USED, THE COST IS GOING TO BE SOMETHING THAT YOUR USERS AND YOUR HOSPITALS THAT WILL BE THINKING ABOUT USING THIS WILL BE THINKING ABOUT ALL THE TIME. THANKS. >> BETSY BALLARD, MEDICAL OFFICER IN DIVISION OF MEDICAL IMAGING, I'M THE BRIDGE FOR CDRH BECAUSE THAT'S WHERE I STARTED. >> I'M IN THE DIVISION OF MEDICAL IMAGING. FORTUNATELY THE FDA DOES NOT HAVE TO FACTOR IN COST CONSIDERATIONS. WE HAVE NO EXPERTISE IN THAT AT ALL, THANK GOD. >> I'M FROM THE CANCER IMAGING PROGRAM, I RUN THE CLINICAL TRIALS BRANCH AND MY GROUP OVERSEES IMAGING WITHIN CLINICAL TRIALS BOTH IN THE SMALL PHASE AND LARGE PHASE CONSORTIA AT NCI NCI. >> MY NAME IS TOM FROM THE UNIVERSITY OF MICHIGAN. I'M A GASTROENTEROLOGIST AND BIOMEDICAL ENGINEER, AND I'M INTERESTED IN EARLY DETECTION OF CANCER USING ENDOSCOPIC DETECTION WITH MOLECULAR IMAGING IMAGING. >> THANK YOU. YEAH, JIM. >> SO YOU WERE PROVOCATIVE TO ME AT LEAST THROUGH SOME OF YOUR COMMENTS ABOUT BREAST CANCER. SO CURRENTLY YOU TAKE OUT A LUMP, YOU'RE NOT SURE IF YOU GOT IT ALL, IT GOES TO PATHOLOGY, THEY LOOK AT 0.01% TO DETERMINE IF THE MARGINS WERE CLEAR OR NOT. DEPENDING ON THE SURGEON, ET CETERA THREA , THERE'S A WIDE RANGE OF THE NUMBER THAT COME BACK FOR REEXCISIONS BECAUSE THE MARGINS WERE NOT CLEAR, SO WHEN YOU GO BACK, THAT WOUND IS STARTING TO HEAL SO IT'S AN ENTIRELY DIFFERENT SHAPE THAN THE LUMP, SO IF YOU WERE ABLE TO DO IT EX VIVO BUT RAPIDLY WHILE THE PATIENT WAS STILL ON THE TABLE, WOULDN'T YOU STILL AT LEAST BE ABLE TO DIRECT, OKAY, THE NORTHERN HEMISPHERE OF THE LUMP REQUIRES MORE RESECTION, SO THIS IS GOING TO IMPACT THE QUALITY OF THE SURGERY AND THE REMOVAL OF ALL THE CANCER, EVEN THOUGH IT IS PLIABLE AND DOES MOVE? >> IT'S BETTER THAN NOTHING, BUT WE ACTUALLY DID A STUDY IN OUR GROUP WHERE WE LOOKED AT THE MAIN SPECIMEN AND THEN IT RESIZED THE ENTIRE CAVITY IN AN ORIENTED WAY, AND COMPARED WHAT YOU READ ON THE MAIN SPECIMEN WITH WHAT YOU READ -- IF YOU THOUGHT IT WAS SUPERIOR, WHAT CAME FROM SUPERIOR WHERE YOU'RE LOOKING IN THE CAVITY WHERE IT'S TOWARD THE PATIENT'S HEAD AND YOU CAN'T MAKE A MISTAKE, AND THERE WAS A HUGE VARIATION. JUST THAT THINGS CHANGE, WHAT WAS ON THE SIDE BECOMES TOP OR BOTTOM. SO YOU CAN -- IT CERTAINLY WOULD BE AN IMPROVEMENT BEYOND WHAT WE HAVE NOW, WHICH IS 20 TO 40% REEXCISIONS. AND ANYTHING HELPS. BUT IF YOU HAD A CHOICE, YOU WOULD PROBABLY WANT TO GET AS CLOSE TO THE -- SEEING IT IN VIVO AS YOU CAN FOR THAT PARTICULAR APPLICATION. >> WHAT SORT OF EVALUATING CLIP SHAVINGS? I KNOW EVERYONE TOANT DO IT BUT IDOESN'T DO ITBUT IT IS DONE. YOU KNOW EXACTLY WHERE THEY CAME FROM. >> SO YOU MEAN CLIP SHAVING, YOU MEAN TAKING A CERTAIN ORIENTATION OR PUTTING MARKINGS ON IT? >> A SURGEON I WORK WITH TAKES NINE PIECES OUT OF EVERY CAVITY, HE KNOWS EXACTLY WHERE THEY GO. >> THE SHAVES ARE PRETTY GOOD, BUT WHEN YOU GO BACK TWO WEEKS LATER, SOMETHING IN THE CONFIGURATION CAN CHANGE QUITE A BIT AND YOU END UP TAKING MORE. SO YOU CERTAINLY CAN MANAGE IT, BUT YOU END UP TAKING LARGER AMOUNTS OF TISSUE IF YOU CAN'T BE AS PRECISE ABOUT WHERE IT IS. >> YOU WOULDN'T IMMEDIATELY EXCISE MORE IF YOU KNEW THAT THE PATIENT SIDE OF SHAVING NUMBER 5 WAS HOT. >> IF YOU TOOK -- THAT'S PROBABLY THE NEXT BEST THING, IS TO TAKE MULTIPLE PIECE AND EXCISE EX VIVO AND GO BACK, BUT IT'S STILL -- YOU KNOW, THERE IS DATA THAT IT BECOMES MORE INACCURATE. >> I THINK THAT'S PART OF THE PROBLEM, IT'S A GROSSLY INACCURATE PROCESS RIGHT NOW. >> I HAD A QUESTION ON THE FDA SIDE. FOR THE CLINICAL END POINTS, WE HAVE TALKED A LOT ABOUT SURVIVAL AND OBVIOUSLY FOR DRUGS, THAT'S A GOOD WAY TO MEASURE OUT COME, BUT IN SURGERY, FROM ALL THE READINGS WE'VE DONE, VERY FEW TUMOR RESECTIONS RESULT IN BENEFIT, IF YOU LOOK AT HISTORICAL DATA. SO BY SETTING SURVIVAL AS THE CLINICAL OUTCOME, ARE WE SETTING THE BAR TOO HIGH FOR ANY AGENT TO BE APPROVED IN THIS CASE? >> I'M GLAD YOU ASKED THAT QUESTION, BECAUSE I THOUGHT THE POINT WE WERE TRYING TO MAKE WAS THE OPPOSITE, THAT WE DO NOT -- WE DO NOT NECESSARILY EXPECT -- OUTCOMES. SO THE EXAMPLE I DISCUSSED EARLIER WHERE YOU HAVE A PRIMARY TUMOR WHERE THE -- MAKING SURE THAT THE TUMOR MARGIN -- THAT THE MARGINS OF RESECTIONS ARE TUMOR-FREE, THAT'S AN IMPORTANT STAGING DECISION, AND SO FOR THAT ONE, WE WOULD NOT NECESSARILY REQUIRE CLEARLY SURVIVAL WAS NOT THE END POINT BUT THE -- RE-OPERATION WOULD NOT NECESSARILY BE AB OUTCOME THAT YOU WOULD NEED TO POWER THE STUDY ON. WE ALWAYS WOULD WANT TO SEE ALL THOSE OUTCOMES TO SEE IF THERE'S ANY SIGNAL THAT FOR SOME REASON THERE -- AS MY COLLEAGUE WAS SAYING, WE WOULD WANT COSMESIS, WE WOULD WANT FIRST EVENTS, ALL THOSE THINGS TO BE FACTORED IN, BUT THE MESSAGE I HOPE THAT I WAS CLEAR THAT WE ARE NOT REQUIRING SURVIVAL OUTCOMES. >> IF I WERE TO REPHRASE THAT, IT SOUNDS LIKE THAT THE FDA IS SAYING THAT IF YOU SHOW REDUCTION IN THE RATE OF POSITIVE MARGINS AND POSITIVE MARGINS ARE KNOWN TO CORRELATE WITH SURVIVAL, THAT, THEREFORE, YOU CAN MAKE THAT ASSUMPTION. IS THAT A FAIR STATEMENT? >> EXACTLY. EXACTLY. SO -- AND AGAIN, TO RE-EMPHASIZE, IN THE CONTEXT WHERE YOU HAVE DEBULKING SURGERY AND DEBULKING -- AND IT'S A CRITICAL ORGAN LIKE I MENTIONED IN THE BRAIN, FOR INSTANCE, AND YOU'RE NOT SURE WHETHER OR NOT MOVING MORE TUMOR IS CAUSING MORE DAMAGE BY CAUSING MORE DISABILITY AND IT DOESN'T RESULT IN ANY OTHER BENEFIT, THEN THAT WOULD -- >> RIGHT, SO TO REPHRASE THAT, THERE ARE CERTAIN TUMORS WHERE IT'S KNOWN IF YOU DEBULK THE TUMOR, YOU HAVE IMPROVED SURVIVAL, SO IN TUMORS WHERE THAT'S THE CASE, SHOWING YOU CAN ACTIVELY DEBULK MORE TUMOR, THAT WOULD BE VALUABLE. >> AND TO TAKE THE ANALOGY FURTHER, I WOULD REFER YOU TO PREVIOUS APPROVALS THAT WE'VE DONE WHERE YOU WOULD HAVE THE -- IT COULD BE AN INTRAPATIENT CONTROLLED STUDY, LET'S SAY, WHERE YOU IMAGE WITH THE STANDARD LIGHT AND THEN YOU CHART WHERE THE LESIONS ARE THAT YOU THINK YOU'RE GOING TO RESECT AND THEN YOU SWITCH ON THE INVESTIGATIONAL LIGHT AND YOU MAP AGAIN AND THEN YOU DETERMINE ON A PER-PATIENT BASIS, HOW MANY LESIONS WERE VISIBLE BOTH BY STANDARD AND BY INVESTIGATIONAL DRUG AND SO THE OVERALL BENEFIT WOULD BE THAT THE ADDITION OF THE INVESTIGATIONAL AGENT WOULD IMPROVE THE NUMBER OF PATIENTS IN WHOM YOU'RE ABLE TO IDENTIFY NEW LESIONS. AND FOR THAT PARTICULAR CASE, ANOTHER REFINEMENT WOULD HAVE TO BE THAT THERE WOULD HAVE TO BE SOME QUANTITATIVE MEASURES THAT THE NUMBER OF LESIONS THAT ONE HAS IDENTIFIED ARE LIKELY TO MAKE AN IMPACT SO THERE WOULD BE THAT REFINEMENT AS WELL. >> SO I WANT TO TALK A LITTLE ABOUT LUNG CANCER. I'M A LUNG CANCER SURGEON. BETWEEN THE TWO OF US, WE'VE DONE ABOUT 250 INTRAOPERATIVE IMAGING CASES. AND WHAT WE'RE FINDING IS, IF YOU TAKE THE WHOLE GROUP, THAT THERE'S THREE CATEGORIES OF BENEFIT, SO WE HAVE PATIENTS WHERE WE GO IN FOR STAGE ONE CANCER, THEN WE FIND THAT THERE'S STAGE TWO, BECAUSE WE FIND MAYBE LYMPH NODE INVOLVEMENT, OR THE SECOND SITUATION THAT'S VERY COMMON IS WE GO IN MINIMALLY INFAY VIF, WE CAN'T FIND IT, THEN WE TURN ON THE LIGHT SOURCE, WE FIND IT, AND WE AVOID HAVING TO DO A THORACOTOMY, WHICH IS AN OPEN OPERATION. THEN THE VERY THIRD COMMON SITUATION, WE GO IN WITH OUR STAPLER AND SUBTLY SEE IT GLOWING, TURN THE TUMOR OVER AND MAKE SURE WE HAVE A NEGATIVE MARGIN. SO EACH INDIVIDUAL EVENT IS NOT VERY HIGH. TOGETHER, ABOUT ONE OUT OF EVERY EIGHT TIMES, WE'RE CHANGING THE STANDARD OF CARE ON THAT PATIENT. CAN WE PUT THAT ALL TOGETHER AS A BODY OF WORK OR IS THAT THREE SEPARATE END POINTS -- >> YOU COULD HAVE COMPOSITE END POINTS. IT'S BASICALLY YOU'RE IMPROVING THE DELINEATION OF THE TUMOR AND YOU'RE IMPROVING THE RESECTION OR THE STAGING. >> SO SAYING NUMBER OF TIMES THAT MAN AMONGMENT HAS CHANGED BASED ON IMAGING WOULD BE A COLLECTIVE NUMBER SO THAT WOULD BE A COMPOSITE SCORE -- >> I'M NOT SURE I WOULD DEFINE IT AS CHANGE IN MANAGEMENT. I WOULD DEFINE IT AS AN ABILITY TO -- >> I WOULD SAY WE DID CHANGE THE MANAGEMENT, IF WE MOVE THE STAPLER OVER OR IF WE WENT IN AND THE PATIENT WAS STAGE 1 AND ALL OF A SUDDEN GETTING CHEMO BECAUSE WE SAW A SECOND SPOT -- >> I THINK PATIENT MANAGEMENT BRINGS US CLOSER TO THE NEED TO HAVE CLINICAL OUTCOME DATA, WHEREAS STRUCTURAL LIN YAITION, WE VIEW AS BEING INHERENTLY OBJECTIVE OUTCOME WITHOUT NECESSITY FOR CLINICAL OUTCOM. >> WOULD YOU SAY TO BRING SOME EXACT RIGOR TO THIS, IF WE HAVE TO DO IT AT THE BEGINNING OF THE TRIAL, BEFORE YOU START THE OPERATION, BASED ON THE BEST IMAGING DATA AVAILABLE, CAT SCAN, PET SCAN, THE SURGEON WRITES DOWN WHAT HE'S GOING DO, AND HOW THE OPERATION HAS CHANGED OR MANAGEMENT HAS CHANGED AFTER THE OPERATION, WOULD THAT BE A SUFFICIENT END POINT, PER SE? IF WAS CHANGED GOING INTO THE O.R. -- >> I THINK IT WOULD BE DIFFICULT, BECAUSE OF THE POTENTIAL FOR BIAS. SO THE CHANGE IN MANAGEMENT WOULD WORK IF YOU HAD A TEST THAT'S DONE AT BASELINE, AND THEN FOR INSTANCE LET'S SAY YOU HAVE ANATOMIC IMAGING AND YOU CAN -- [LOST AUDIO] WHAT YOU CAN DO IN THIS CASE, YOU CAN HAVE A BLINDED READER READING THE INFORMATION, AND THEN YOU COULD HAVE A PANEL OF ADJUDICATORS THAT SAY BASED ON THESE OBJECTIVE STANDARDS, BASED ON THIS ANATOMIC IMAGING INFORMATION, THIS WOULD HAVE BEEN THE APPROPRIATE PROCEDURE, WITH THIS ADDITIONAL TEST NOW, I GAINED THIS ADDITIONAL INFORMATION, AND AGAIN, BASED ON OBJECTIVE CRITERIA, THESE ADJUDICATORS CAN SAY NOW MY MANAGEMENT HAS CHANGED. SO UNDER THAT CIRCUMSTANCE, WE WOULD HAVE MORE CONFIDENCE THAT THERE'S NO BIAS. IF YOU HAVE -- YOU WOULD ALMOST HAVE TO DO A RANDOMIZED STUDY IN THE SITUATION WHERE YOU'RE THINKING ABOUT, AND THAT COULD BECOME VERY DIFFICULT, VERY MESSY AND VERY NOISY, SO YOU WOULD HAVE TO THINK IN TERMS OF HOW WOULD I CONTROL BIAS? AGAIN, THE BEST MANAGEMENT APPROACH WOULD BE MAYBE YOU CAN DO INTRAOPERATIVE IMAGING AND AGAIN LOOK AT THE NAKED EYE AND SAY THIS IS WHAT I SEE, AND THE LIGHT ON -- >> WOULD YOU ACCEPT THAT? >> WELL, NO, THERE WOULD HAVE TO BE AN INDEPENDENT PANEL TO AVOID BIAS. SO THE PANEL COULD SAY OKAY, BASED ON ALL THIS PRESPECIFIED BACTERIA, THIS IS WHAT -- THE CONTROL OF BIAS IS WHAT'S CRITICAL. >> HOW ABOUT -- SO OF THE THREE I NAMED, HOW ABOUT THE SOFTER END POINT, WHICH IS HOW MANY TIMES I AVOIDED HAVING TO OPEN THE PATIENT FOR A THORACOTOMY? THAT'S NOT A TRIVIAL POINT. HOW MANY TIMES I GO TO THE O.R., CAN'T FIND IT, I'M VISUALIZING T I PUT MY FINGER IN, I CAN'T FIND IT, I TURN ON THE LIGHT, I LOCATE IT, I NOW ALL OF A SUDDEN DO NOT HAVE TO OPEN THE PATIENT, I HAVE DO A MINIMALLY INVASIVE OPERATION, IT'S A SOFT END POINT PER SE. >> IF YOU WANT THAT SPECIFIC PLAY, YOU WOULD HAVE TO POWER THE STUDY TO SHOW THAT, IN FACT, IT REDUCES THE RATE OF INCREASING THE SURGERY FROM LOCAL TO MAJOR. SO IT WOULD BE A SPECIFIC CLAIM. BUT YOU COULD USE THAT OUTCOME AS A COMPOSITE END POINT, BUT YOU COULD NOT HAVE A SPECIFIC CLAIM THAT YOU ARE DECREASING THE RATE OF EXTENSION OF THE SURGERY. THAT WOULD REQUIRE AN ACTUAL OUTCOME TO GET THAT SPECIFIC CLAIM. SO THE CLAIM WOULD BE DIFFERENT. >> I DO WANT TO SAY THAT WE'RE TRYING NOT TO GO TOO MUCH INTO SPECIFICS OF SPECIFIC IND MEETINGS, BUT IN DEFENSE OF THE FDA, WE DO WANT TO GET WITHIN GENERAL -- AGGREGATE SERIES OF DATA POINTS WHICH I THINK THEY ADDRESSED. TOM, DID YOU HAVE A QUESTION? OR COMMENT ? >> I JUST WANT TO POINT OUT THAT A LOT OF WHAT WE'RE DISCUSSING HEERY LATES TO THE STAGING OF CANCER, AND MANY OF THE APPLICATIONS OF THERAPY IS APPLIED TO PATIENTS WITH VERY LATE STAGE, STAGE IV, AND IT'S VIRTUALLY IMPOSSIBLE TO GET ANY KIND OF GOOD OUTCOMES DATA AT THAT STAGE. SO THERE ARE ACTUALLY OTHER END POINTS, SOME OF THE WORK THAT I DO INVOLVE EARLIER STAGE, AND I THINK THIS IS REALLY WHERE MOLECULAR IMAGING IS GOING TO HAVE ITS GREATEST IMPACT BECAUSE THERE'S A LOT OF TECHNOLOGY THAT DOES REALLY WELL IN STAGE III AND STAGE IV, AND HIGH RESOLUTION CT, BUT OPTICAL IMAGING REALLY HAS ITS STRENGTHS IN AREAS OF THE EARLY STAGING, STAGE 1, STAGE 2, BECAUSE THE OTHER TECHNIQUES JUST DON'T HAVE THE RESOLUTION, SO ONE OTHER EXAMPLE I WANT TO POINT OUT WAS, WHEN WE DO ENDOSCOPIC RESECTION, ONE OF THE KEY END POINTS WE NEED TO KNOW IS HAS THE TUMOR INVADED BELOW A SERP DEPTH, WHERE WE CAN RESECT IT OR SEND THEM TO THE O.R. AND THAT, WE CAN ACTUALLY GET GOOD OUTCOMES WITH. >> PAUL. >> I WANTED TO MAKE A COMMENT THAT I WANT TO BOUNCE OFF OF LOU. I THINK WHAT'S HAPPENING HERE IS THAT PEOPLE AREN'T QUITE GETTING THIS POINT THAT YOU SHOULD GO FOR THE SIMPLEST AND MOST STRAIGHTFORWARD THING YOU CAN PROVE, EVEN IF SUBSEQUENT TO THAT, YOU USE INFORMATION FOR CLINICAL CARE, FOR CLINICAL DECISION-MAKING, YOU CAN -- IF YOU GOT AN INDICATION THAT SAID I SEE MARGINS BETTER, THE FACT THAT PEOPLE WOULD THEN USE THAT FOR CLINICAL CARE IS FINE. IT'S MUCH EASIER TO GET "I SEE MARGINS BETTER" THAN "EVERYBODY LIVES LONGER." >> BUT AGAIN, THE CLINICAL BENEFIT IN THAT SETTING WOULD BE CLEAR, BECAUSE WE HAVE A GOOD UNDERSTANDING THAT HAVING A CLEAN MARGIN DECREASES SURVIVAL, DECREASES RATE OF RE-OPERATION, SO WE'RE NOT DIRECTLY DEMONSTRATING THAT, WE'RE SORT OF MAKING INFERENCES BASED ON THE FACT THAT IT'S A CLEAN MARGIN, AND WE FEEL CONFIDENT IN MAKING THAT INFERENCE. >> SO PEOPLE DON'T HAVE TO PROVE WHAT THE CLEAN MARGIN MEANT? >> EXACTLY. EXACTLY. >> GO FOR THE SIMPLEST -- >> BUT AGAIN, IT DOESN'T HURT TO ADD ANOTHER END POINT WHICH YOU CAN HAVE A MULTIPLICITY OF END POINLTS BUT IPOINTS BUT IF YOU HAVE THE RI GHT ANALYSIS PLAN, YOU CAN PRESERVE THE ALPHA AND PROVIDED YOU WIN ON YOUR PRIMARY, YOU CAN THEN GO ON AND LOOK AT THE OTHERS. SO THERE'S ALSO AN ADVANTAGE TO USING MULTIPLE END POINTS AND POTENTIALLY GETTING ADDITIONAL CLAIMS FROM ONE STUDY. >> LOLITA. >> I WANTED TO SORT OF TAKE A STEP BACK, I KNOW WE'RE GETTING INTO SORT OF USEFUL AND IMPORTANT DETAILS ABOUT ACTUAL STUDY DESIGNS BUT I THINK ONE OF THE THINGS, SEVERAL OF THE FDA FOLKS SPOKE ABOUT, AND I THINK WE ALL AGREE, IS THE USE OF MULTICENTER EVALUATION FOR A VARIETY OF THESE AGENTS AND DEVICE, SO I JUST WANTED TO REMIND YOU THAT THAT'S ONE OF THE RESOURCES THAT NCI BRINGS TO THE TABLE, AND YOU HAVE MET -- CERTAINLY ME AND MY GROUP ARE AVAILABLE FOR DISCUSSIONS. WE HAVE HAD THE FIRST MULTICENTER OPTICAL IMAGING, OPTICAL DEVICE EVALUATION, IT IS NOT IN THE SURGICAL NAVIGATION BUT FOR ASSESSMENT OF RESPONSE TO THERAPY IN BREAST CANCER, SO BRUCE TROMBERG'S STUDY WAS DONE THROUGH AKRON IN A MULTICENTER SETTING AND THAT WENT QUITE WELL. SO I THINK THIS WAS MENTIONED BEFORE, SO -- AKRON IS SPECIFICALLY FUNDED TO PERFORM IMAGING STUDIES AS THE PRIMARY AIM. ALSO, THOUGH, WE NEED TO KEEP IN MIND THAT ALLIANCE, WHICH IS ONE OF OUR OTHER LIN CA CLINICAL -- THE SURGICAL ONCOLOGIST GROUP, SO THERE ARE A LOT OF FOLKS HERE OTHER THAN I IN MY BRANCH WERE QUITE INVESTED IN LOOKING AT SOME OF THESE AGENTS AND DEVICES THAT YOU WOULD LIKE TO WORK ON, AND WE HAVE THAT PARALLELLED WITH PHARMACEUTICAL COMPANIES ROUTINELY DOING -- WITH US SO I WANTED TO SORT OF MAKE A PLUG FOR THEIR RESOURCES AVAILABLE AND FOLKS INTERESTED WITHIN THE LARGER CLINICAL TRIALS NETWORK, SO WE WOULD LOVE TO HEAR FROM YOU. >> DO WE HAVE THE TO A PHASE 1 AT YOUR INSTITUTION AND THE PHASE 2 OR IS IT SUFFICIENT THAT WE DID A PHASE 2 AND YOU'LL HELP US -- >> ROUTINELY, SO WE HAVE TWO DIFFERENT WAYS TO G SO PHASE 1 DEFINITELY YOU HAVE TO HAVE THE DATA FOR AND PUBLISHED THE, BUT FOR INSTANCE, IN THE ECOG AKRON, THEY HAVE A GROUP, A SUBCOMMITTEE WHICH IS CALLED EXPERIMENTAL IMAGING SCIENTISTS' COMMITTEE, SO THEY WILL DO THE SMALLER PHASE 2 AND FEASIBILITY, AND WE ALLOWED THAT SIMPLY BECAUSE IT'S SO HARD TO GET FUNDING. AND TO GET SORT OF MOMENTUM TO DO SOME OF THIS EARLIER PHASE TWO WORK. WE ALSO HAVE THE R01 THAT WE MENTIONED BEFORE. SO THAT'S THERE. BUT FOR GENERALLY, IT TENDS TO BE PHASE TWO AND HIGHER AND THE SIZE AS TO WHEN YOU CAN START IS REALLY UP FOR NEGOTIATION. IN FACT, FOR INSTANCE, WE JUST HAVE THROUGH THE ECOG AKRON FOLKS A REPEATABILITY FOR DIFFUSION AND DYNAMIC CONTRAST ENHANCED IMAGING IN MR, JUST TO LOOK FOR REPEATABILITY IN 30 CASE, SO THIS IS THE KIND OF THING THAT'S NOT GOING TO GET A LOT OF EXCITEMENT, SO THAT WAS 30 CASES BUT WE DID THAT AS A LARGER NCTN EVALUATION, AND THEN OF COURSE WE HAVE THE ONES WITH THE HUNDREDS AND -- SEVERAL HUNDREDS. >> WE'VE DONE A PHASE 1, WE HAVE A GUY, WE SAY LET'S DO A PHASE 2, WE SAY WE CAN PROVIDE THE DYE, WOULD YOU HELP US PROVIDE CAMERAS AT THE OTHER SITE? BECAUSE THAT'S THE MOST EXPENSIVE PART ABOUT THIS STUDY. >> AND IT MAY BE THAT THEY CAN'T COMMIT TO THAT AND IT MAY BE SOMETHING THAT YOU NEED TO -- >> RIGHT, SO THAT IS SOMETHING YOU CAN -- SO WHAT HAS HAPPENED WITH THAT IS, USUALLY WE COULD POTENTIALLY HELP THE CAMERA COMPANY HOLD AN IDE FOR AN EVENT, BUT IF IT'S A COMMERCIALLY AVAILABLE CAMERA, I THINK FINDING A GROUP OF INTERESTED PHYSICIANS WHO ALSO HAVE THOSE CAMERAS MAY BE THE BETTER WAY TO GO. >> SO LET ME SHIFT THE CONVERSATION A LITTLE BIT TO SOME OF THE PHRASES THAT BETSY WAS USING EARLIER, AND I THINK REALLY PEAKED A LOT OF INTEREST AS WELL, AND THAT'S ESSENTIALLY A LITTLE WHAT BARBARA WAS SAYING TOO, AND THAT IS WHAT IS THE STANDARD OF CARE TODAY AND HOW DO YOU -- WHAT IS THE FALSE NEGATIVE RATE AND IMPACT OF THAT. TODAY WE'RE TALKING ABOUT CONTRAST ENHANCED SURGERY, AND THAT'S REALLY COMPARED TO CONTRAST -- THAT'S REALLY ALL THAT SHOW IS. AND OF COURSE THEY ACTUALLY HAVE ALIGNED CERTAIN TYPES OF PHYSICIANS WITH CERTAIN CHARACTERS IN THE GAME OF THROANS SO GENERAL SURGERY IS TIELAN LANISER, THE MEDICAL STUDENT IS ARIA, UNLIKELY TO BE LEFT ALONE AND SHE'LL STAB WITH YOU A NEEDLE. SO WHAT BETSY WAS SAYING ABOUT ABNORMAL VERSUS NORMAL, AND THIS IS WHERE -- SO IF YOU SAY THAT FOR -- HISTOLOGY, THAT'S THE MAIN THING THAT CAN BE SAID AT A VERY SPECIFIC LEVEL IN PATHOLOGY, BUT IN THE CLINICAL ARENA, IT'S MUCH HARDER TO DETERMINE THAT IN REALTIME, SO IN OTHER WORDS, THE CURRENT STANDARD OF CARE IS US KIND OF FEELING AROUND, LOOKING WHERE WHAT MIGHT BE TUMOR, WHAT MIGHT NOT BE TUMOR, SO IS A FALSE NEGATIVE WHAT THE SURGEON PURR PERCEIVES AS A FALSE NEGATIVE OR IS IT BASED ON HISTOLOGY, I GUESS IS THE QUESTION, OR HOW IS THAT VIEWED? IN OTHER WORDS, IS FLUORESCENCE -- AND I DON'T KNOW IF ANYBODY HAS A WAY TO COME AT THAT. >> THIS THIS CASE, THERE WOULD HAVE TO BE CLINICAL FOLLOW-UP. I DON'T KNOW HOW ELSE YOU COULD DETERMINE THAT -- IT BECOMES A SELF FULFILLING PROPHECY, CAN YOU NOT HAVE THE CLINICAL DIAGNOSIS BE THE TRUE STANDARD, THERE HAS TO BE AN INDEPENDENT OBJECTIVE STANDARD, AND TYPICALLY IT'S PATHOLOGY AND/OR CLINICAL FOLLOW-UP. >> >> SO THE GOLD STANDARD -- [INAUDIBLE] -- OVEREXPRESSIONS TO NOT CORRELATE TO CANCER. I MEAN, IT MAY BE RELATED TO IT BUT THAT'S NOT THE GOLD STANDARD. SO WE'RE REALLY LOOKING AT TWO VERY, VERY DIFFERENT THINGS, AND TO THE EXTENT THAT THIS PARTICULAR TARGET REFLECTS THE LIKELIHOOD OF CANCER IS WHAT YOU'RE LOOKING AT IN REALTIME WITH IMAGING. >> BUT TO GO TO FOLLOW UP AND PATIENT SURVIVAL, IT'S VERY DIFFICULT TO DO, IT'S FIVE YEARS OUT AND IT'S EXPENSIVE, BUT YOU COULD DO DIRECTED -- AND WORK WITH THA PATHOLOGY TO CORRELATE THAT MARKER TO THE PATHOLOGY THAT THEY SEE, SO THEY MAY BE TAKING MORE SECTIONS, BUT IT WOULD PROVE THAT THIS IS GIVING YOU WHAT YOU WANT. >> FOR APPROVED PRODUCTS, EVALUATION OF NEURODEGENERATIVE DISEASE, SO THE AMYLOID IMAGING AGENTS OR THE -- SCANS, SO BASICALLY THAT IS BASED ON PRE-CLINICAL -- CLINICAL DATA WHERE YOU'RE ACTUALLY SHOWING THAT YOU CAN LOCALIZE THE DEPOSITION OF AMYLOID TO A TRUE STANDARD WHERE YOU ACTUALLY GET THE SCAN AND YOU HAVE THE PATIENT COME TO AUTOPSY, YOU CAN DETERMINE THAT, OR IT CAN ALSO BE CLINICAL FOLLOW-UP SUCH THAT AT THE TIME YOU ASSESS THE PATIENT, YOU DON'T HAVE A DIAGNOSIS BUT YOU FOLLOW THE PATIENT, FOR INSTANCE, FOR PARKINSON'S, YOU DON'T KNOW WHETHER IT'S ESSENTIAL TREMOR OR PARKINSON'S DISEASE. SO YOU LOOK AT THE SCAN AND THEN YOU FOLLOW UP TO PATIENTS FOR TWO YEARS AND THEN THE DIAGNOSIS BECOMES CLINICALLY MANIFEST SO IT'S THE FINAL CLINICAL DIAGNOSIS THAT BECOMES THE TRUE STANDARD. >> I THINK WE HAVE TIME FOR ONE MORE QUESTION. >> ONE QUESTION HERE, I WANT TO BRING IT BACK TO BREAST. WE'RE HEARING ABOUT MARGIN PROBE, AS AN APPROVABLE DEVICE WITH A GREAT APPROVAL AND WE HAVE A BREAST SURGEON HERE. WHEN I LOOK -- I LOOK AT THE SPECIFICITY AND SENSITIVITY AND IT'S ABYSMAL. HOUR, THE REDUCTION IN RE-EXCISION AND RE-OPERATION IS THE APPROVAL END POINT. GETTING TO THE POINT ABOUT THORACIC AS WELL, APPROVABLE VERSUS COMMERCIAL SUCCESS, SOMETHING THAT ACTUALLY HELPS THE PATIENT, IS THAT A TECHNOLOGY, DO YOU KNOW THE TECHNOLOGY, DO YOU USE IT, ARE YOU COMFORTABLE IN THE RE-EXCISION RATE FOR IMAGING AGENTS AS WELL? >> CERTAINLY IN BREAST IF YOU CAN REDUCE RE-EXCISIONS OR THE VOLUME OF THE EXCISION, THAT'S GOOD. I THINK THE SPECIFICALLY EXAMPLE YOU SHOW REALLY HAS MINIMAL IMPACT ON CLIP CAL USE, AND I DON'T THINK IT'S VERY WIDELY USED BECAUSE OF THAT. SO I THINK IN LOOKING FORWARD, WHAT YOU WANT, YOU WANT THINGS THAT WILL GIVE YOU A MEANINGFUL REDUCTION IN SOME BAD END POINT LIKE RE-EXCISION OR RECURRENCE OR WHATEVER, AND AS I MENTIONED BEFORE, IT HAS TO BE SOMETHING THAT'S GOING TO FIT IN THE SUITE OF THINGS THAT A PHYSICIAN IS DOING WITH THE PATIENT AND THE OVERALL COST, REDUCING REEXCISION SAVES MONEY OVERALL SO THOSE KINDS OF THINGS ALL COME TOGETHER, BUT A SMALL REDUCTION IN RE-EXCISION MAY NOT BE ENOUGH. >> OKAY. I'D REALLY LIKE TO THANK THE PANELISTS, IT'S BEEN A GREAT DISCUSSION AND THEN WE'LL HAVE THE NEXT PANEL -- OR THE NEXT SPEAKER COME UP, SO THANK YOU VERY MUCH, EVERYBODY, FOR HELPING OUT. >> GOOD AFTERNOON. THIS IS THE LAST SESSION, THE LAST PRESENTATION, SO WE'LL JUST GO THROUGH THIS IN ABOUT 10 MINUTES, AND THEN OPEN IT UP FOR FURTHER DISCUSSION. PPATRICIA LOVE FROM THE OFFICE OF COMBINATION PRODUCTS, DEPUTY DIRECTOR. BEFORE GOING INTO THE MAJOR PART OF THE DISCUSSION, JUST WANTED TO ADDRESS A COUPLE OF HALLWAY CONVERSATION QUESTIONS ABOUT WHAT IS THE OFFICE OF COMBINATION PRODUCTS, HOW DID WE GET HERE AND SO FORTH. SO THE OFFICE OF COMBINATION PRODUCTS WAS ESTABLISHED IN 2002 AS PART OF THE MEDUFAH LEGISLATION. WE ARE LOCATED IN THE OFFICE OF THE COMMISSIONER, PART OF THAT LOCATION CONCEPT IS OBVIOUSLY TO ALLOW US TO BE OBJECTIVE AS WE LOOK AT ISSUES THAT ARE RAISED ACROSS THE DIFFERENT CENTERS, AND PARTICULARLY THESE ARE THE CENTERS RELATED TO MEDICAL -- HUMAN MEDICAL PRODUCTS, DRUGS, BIOLOGICS AND DEVICES. I'LL TALK A LITTLE BIT IN THE NEXT FEW MINUTES, I'M SORRY, I HAVE TO REMEMBER WHAT I'M SUPPOSED TO DO, TO LOOK AT WHAT ARE SOME OF THE PATHWAYS. YOU'VE HAD SOME CONVERSATION TODAY ABOUT THE FACT THAT THESE OPTICAL IMAGING AGENTS AND DEVICES ARE COMBINATION PRODUCTS, WE'LL TALK A LITTLE BIT ABOUT THAT. THEY MAY OR MAY NOT BE AND THERE'S BEEN SOME ELUSION TO THAT DURING THE DISCUSSION. ALSO I'LL TALK QUICKLY ABOUT THE BLENDING OF THESE PRODUCTS, WHAT ARE SOME OF THE DEVELOPMENTAL IMPLICATION AND SOME PRACTICAL CONSIDERATIONS. SO AS WAS MENTIONED EARLIER, MOST IMAGING DRUGS ARE NOT COMBINATION PRODUCTS AND THOSE WERE THE PETs AND THE MRI AND OTHER PRODUCTS THAT WERE IDENTIFIED, BUT THERE ARE SOME EXCEPTIONS EVEN IN THOSE REALMS, BUT THE OPTICAL IMAGING PRODUCTS TEND TO BE COMBINATION PRODUCTS, AND IN THAT CONTEXT, WE'LL TALK A LITTLE ABOUT WHAT THAT MEANS, BUT STILL, EACH TIME THERE IS A PRODUCT THAT COMES TO THE AGENCY FOR DISCUSSION, WE STILL GO THROUGH THE PROCESS OF SAYING IS THIS A DEVICE ALONE, IS THIS A DRUG ALONE, OR IS THERE SOME TYPE OF LIMITED REFERENCE LABELING AND WE'LL TALK ABOUT THAT. SO THERE'S SOME LABELING JARGON THAT IS OFTEN USED. WE DON'T TRULY HAVE REGULATORY DEFINITIONS HERE SO THIS IS JUST A LITTLE BIT ABOUT HOW WE AT LEAST CONVERSE AMONG OURSELVES ABOUT THIS. THERE IS GENERAL LABELING, DOES NOT RESTRICT THE DEVICE OR THE DRUG TO USE WITH EACH OTHER OR OTHER PRODUCTS AS WAS ADDRESSED EARLIER TODAY. SOMETHING WE TEND TO CALL ONE-WAY LABELING, SO THAT'S WHERE BRAND JUG A IS USED WITH DEVICE A BUT THE DEVICE IS NOT PARTICULARLY BRANDED FOR A PARTICULAR DRUG, IT CAN BE USED WITH ANY OTHER DRUG BASED ON CHARACTERISTICS. OBVIOUSLY YOU COULD THINK ABOUT THAT IN THE REVERSE, AND THEN WE HAVE WHAT'S OFTEN AS TWO-WAY LABELING. THE COMBINATION PRODUCT WHERE BRAND NAME A DRUG -- BASED ON THAT -- DRUG A IS FOR USE WITH BRAND DEVICE A, AND BRAND DEVICE A IS USED FOR BRAND DRUG A. SO THAT'S THE FULL COMBINATION PRODUCT WITH CROSS LABEL. WHEN WE MAKE SOME OF THESE ASSESSMENTS, THOUGH, THAT USUALLY IS THE FIRST STARTING POINT OF SOME OF THESE DISCUSSIONS, BUT WHEN YOU HAVE A PRODUCT THAT IS ALREADY APPROVE APPROVED, ALREADY ON THE MARKET, WE'RE LOOKING TO SEE IF THE NEW USE THAT'S BEING PROPOSED EITHER BY THE DRUG OR THE DEVICE IS CONSISTENT OR DOES IT DIFFER IN SOME WAY FROM THE APPROVED OR CLEARED LABELING. AND THAT'S THE INDICATION FOR USE. BUT WE ALSO LOOK AT DOSE, RATE OF ADMINISTRATION OF THE DRUG, THE ROUTE, THE METHOD OF ADMINISTRATION, REGIMENT, DOSAGE FREQUENCY, SOME OF THOSE OTHER THINGS THAT WERE ADDRESSED EARLIER ABOUT REPEAT DOSING AND ALL THE OTHER THINGS THAT ONE MIGHT NEED TO KNOW IN TERMS OF HOW THOSE PRODUCTS ARE USE DOLLARS TOGETHER. WHICH ALSO LOOK AT IMAGING MODALITY DIFFERENCES THAT MIGHT COME TO BEAR. FOR THE DEVICE, SIMILAR KIND OF QUESTIONS, WHAT IS THE MODALITY, EXPOSURE RATE DIFFERENT, THERE WAS DISCUSSION EARLIER TODAY ABOUT LASER SAFETY, SO ALL THOSE QUESTIONS COME INTO BEAR WHEN WE'RE LOOKING AT THE LABELS, LOOKING AT WHAT IS ALREADY APPROVED, WHAT IS ALREADY CLEAR, APPROVED AND EVIDENT. WHEN I SAY CLEAR, I DON'T MEAN IN THE SENSE OF CLEARED, 5, 10Ks, BUT SUFFICIENTLY EXPLICIT IN WHAT WE NEED TO DO AND CHANGE. AND THAT CHANGE IS OFTEN LABELED FOR -- THAT MIGHT NOT BE NECESSARY BASED ON THE NEW DATA YOU'D BE DEVELOPING. WHAT IS A COMBINATION PRODUCT? IT IS IDENTIFIED MORE SPECIFICALLY IN THE REGS, CERTAINLY IDENTIFIED IN THE STATUES, BUT THE REGULATIONS GET MORE INFORMATION. COMBINATION PRODUCTS COMPRISED OF TWO OR MORE COMMONLY -- A DEVICE WITH A BIOLOGIC, TODAY NOT SO MUCH OF AN ISSUE IN TERMS OF CURRENT DISCUSSION BUT WE COULD HAVE A DRUG AND A BIOLOGIC THAT IS YOUR IMAGING PRODUCT AS WELL AS IT MIGHT BE USED WITH A DEVICE SO WE COULD CONCEIVABLY HAVE ALL THREE IN THIS PARTICULAR CONTEXT AS YOUR COMBINATION PRODUCT. THE DEFINITION IS BROKEN OUT INTO THREE DIFFERENT MAIN AREAS, THOSE THAT ARE CHEMICALLY OR PHYSICALLY COMBINED INTO A SINGLE EPT IT, NOT WHAT WE'RE DISCUSSING TODAY, THE CLASSIC EXAMPLE OF THAT IS THE DRUG ALLUDING STENT. THERE ARE THINGS THAT ARE CO-PACKAGED THAT WEREN'T DISCUSSED TODAY WITH THE EXAMPLES EARLIER ON THE SPY IMAGING PRODUCT THAT IS COMPRISED OF A COPACKAGE THAT HAS THE DISPOSABLE DRUG AND THE DISPOSABLE DEVICE CONSTITUENT PART, SO THAT IS CONSIDERED A FORMAL COMBINATION PRODUCT. OUR OFFICE WAS INVOFFED IN THAT. THEN THERE ARE THOSE THAT ARE SOLD SEPARATELY AND LABELED FOR USE. THE E3s AND E4, THEY'RE TWO DIFFERENT DEFINITIONS WE'LL TALK ABOUT, BECAUSE THAT'S ALSO PART OF TODAY. SO THE E3 HAS TO DO WITH PRODUCTS WHERE ACCORDING TO AN INVESTIGATIONAL PLAN, SO WE GET AN IDE OR PRESUBMISSION WHERE A PRODUCT IS BEING DEVELOPED FOR USE WITH SOMETHING ELSE. THEY'RE BOTH NECESSARY, THEY'RE BOTH REQUIRED TO ACHIEVE THE INTENDED USE, BUT ONE OF THESE PRODUCTS IS ALREADY APPROVED AND ON THE MARKET. AND WHEN WE GO THROUGH THE LABELING ANALYSIS, AS I WAS MENTIONING ERLGIER, TO SEE WHAT IS IT THAT MIGHT NEED TO CHANGE, IF IT'S APPARENT THAT THE LABELING OF THE APPROVED PRODUCT WOULD NEED TO BE CHANGED BEFORE -- I DON'T KNOW WHAT -- WHAT IS THIS? SOMETHING WANTS TO INSTALL SOME ITEMS HERE. SHOULD I JUST HIT "CLOSE"? OKAY. WE DON'T WANT TO DO THAT WHILE WE'RE IN THE MIDST OF A PRESENTATION. OKAY. SO IF THE LABELING OF THE APPROVED PRODUCT, BE IT THE DRUG OR THE DEVICE, NEEDS TO CHANGE IN ORDER FOR US TO BE ABLE TO APPROVE THE NEW USE THAT'S BEING PROPOSED AND HAS TO BE DONE TO REFLECT EITHER THAT NEW USE WHATEVER IN THAT CONTEXT, THAT WOULD BECOME A COMBINATION PRODUCT. WE COULD NOT GET THE PRODUCT, THE NEW PRODUCT TO MARKET UNTIL WE MAKE THE CHANGE IN THE OTHER PRODUCT. AS SOMEONE WAS MENTIONING EARLIER, WE CAN'T REQUIRE THE CHANGE TO THE OTHER PRODUCT, SO WHAT THAT WOULD MEAN UNFORTUNATELY IS THAT WE COULD NOT MOVE FORWARD WITH THE APPROVAL OR CLEARANCE OF THE PRODUCT THAT HAS BEEN DEVELOPED AND IS REQUESTING A CHANGE, WE COULD NOT DO SO UNTIL WE ARE ABLE TO ACHIEVE A CHANGE. THERE ARE SOME OTHER APPROACHES, WE CAN TALK ABOUT SOME OF THAT IN THE PANEL DISCUSSION, BUT WE DO TRY TO FACILITATE THIS PROCESS THAT THE EXTENT THAT WE CAN. WHEN I SAY PROCESS, I MEAN THE PROCESS OF GETTING THE PRODUCT TO THE MARKET, PARTICULARLY ONE THAT HAS A POTENTIAL BENEFIT FOR THE PUBLIC HEALTH. THE OTHER PART OF THIS DEFINITION IS IT RELATES TO INVESTIGATIONAL PRODUCT, SO THIS IS WHERE BOTH THE DRUG AND THE DEVICE ARE INVESTIGATIONAL, AND WE ARE ANTICIPATING THAT THEY BOTH WILL BE REQUIRED TO BE USED TOGETHER TO ACHIEVE THE INTENDED PURPOSE AND OBVIOUSLY WE WOULD MOVE TO DETERMINE HOW ARE WE GOING TO DO THAT, BUT THEY WOULD BE STILL CONSIDERED A COMBINATION PRODUCT. THE JURISDICTION DISCUSSION THAT WAS RAISED EARLIER, WE DO HAVE IN THE REGULATIONS A SECTION THAT DESCRIBES WHAT WE ARE TO DO TO DETERMINES JURISDICTION. IT IS BASED ON THE PRIMARY MODE OF ACTION. SO ONE THING ABOUT THE OFFICE OF COMBINATION PRODUCTS, WE DETERMINE IS IT A DRUG DEVICE, BIOLOGIC OR COMBINATION PRODUCT AS A WHOLE, AND IF IT IS, WE ARE RESPONSIBLE FOR ASSIGNING THAT PRODUCT TO -- IF WE CANNOT DETERMINE THE PRIMARY MODE OF ACTION, WE DO HAVE AN ALGORITHM THAT CONSIDERS PRECEDENTS WHERE THEY'VE ALREADY BEEN ASSIGNED AND IF THEY HAVE NOT BEEN ASSIGNED ANYWHERE OR THERE ISN'T ONE PARTICULAR SITE, THEN WE LOOK TO QUESTIONS ABOUT SAFETY AND EFFECTIVENESS. LET'S JUST TALK FOR THE MOMENT ABOUT THE PRIMARY MODE OF ACTION. SO THE FIRST THING WE DO IS LOOK AT WHAT IS THE MODE OF ACTION OF A PRODUCT, AND THAT'S THE MODE OR MECHANISM BY WHICH IT -- THAT IS IDENTIFIED IN THE REGULATION AND THAT ACTION IS BASED ON WHETHER OR NOT IT'S A DRUG ACTION, IN QUOTES, IT'S REALLY MORE A DEVICE ACTION AND THE DEVICE DEFINITIONS, OF COURSE, IN THE REGS SAY IT IS NOT ACHIEVED -- AND THE BIOLOGICS DEFINITION IS VERY SPECIFIC FOR CERTAIN TYPES OF PRODUCTS. THE PRIMARY MODE OF ACTION IS THE SINGLE MOST IMPORTANT MODE OF ACTION, THERAPEUTIC ACTION OF THE PRODUCT, THAT MODE OF ACTION THAT PROVIDES THE MOST THERAPEUTIC ACTION, AND THAT HAS ITS OWN DEFINITION WHICH IS THE ACTION THAT MAKES THE GREATEST CONTRIBUTION TO THE OVERALL INTENDED THERAPEUTIC EFFECT. SHOULD YOU WISH TO LOOK FURTHER INTO THIS, AND THEY'RE ALL AVAILABLE ON THE COMBINATION PRODUCTS WEBPAGE. THAT LEAD CENTER IS YOUR POINT OF CONTACT FOR ALL DISCUSSIONS RELATED TO THE COMBINATION PRODUCTS, SO IF YOU ARE ASSIGNED TO CDRAs TO NEIL'S GROUP AND HE'S GOING TO WORK WITH CDER AND EVEN IF THERE ARE QUESTIONS ABOUT THE DRUG DEVELOPMENT PRO SE THOSE QUESTIONS WOULD BE FILTERED THROUGH THE CDRH PROCESS USING THE CDRH MECHANISM. THERE WAS A QUESTION ABOUT THE IND AND IDE. JUST WANT TO ELABORATE ON THAT JUST A LITTLE BIT. SO FOR A COMBINATION PRODUCT, WE APPLY WHATEVER REGULATIONS ARE NECESSARY OR APPROPRIATE ON THE BASIS OF THAT LEAD CENTER USING THAT PARTICULAR LEAD CENTER OF THE EVALUATION MECHANISM. WE USE THEIR PROCEDURES FOR COMMUNICATION AND SO FORTH, BUT WHATEVER DATA ARE NEEDED FOR BOTH THE DRUG OR THE DEVICE ARE SUBMITTED IN THE CONTEXT OF THAT ONE APPLICATION. BOTH CENTERS WORK TOGETHER TO ADDRESS THAT AND WE'LL COME TO THAT A LITTLE BIT MORE IN A MINUTE. IT'S A COLLABORATIVE REVIEW. WHEN WE SAY COLLABORATIVE, THAT MEANS ESSENTIALLY THAT EACH CENTER IS THE EXPERT FOR THEIR CONSTITUENT PART. WE CALL THE DRUG AND THE DEVICE CONSTITUENT PARTS. WE'VE USED THE TERM COMPONENTS IN A MORE JARGONED PERSPECTIVE BUT THE CONSTITUENT PART IS THE TERM IDENTIFIED IN THE REGULATION, SO IF YOU HEAR US TALK ABOUT THAT, THAT'S WHAT WE MEAN. BUT WHEN THE COMBINATION PRODUCT IS ASSIGNED TO THE OTHER CENTER, ITS CLASSIFICATION DOESN'T CHANGE. SO IF IT'S ASSIGNED TO CDRH, WE'RE NOT REVIEW AGO DEVICE, WE'RE REVIEWING A COMBINATION PRODUCT. THAT PRODUCT DEVELOPMENT MUST APPLY TO THE APPLICABLE REGULATIONS AND REQUIREMENTS FOR BOTH CONSTITUENTS WITHOUT BEING CONTRARY OR CONFOUNDING. AND THE TWO CENTERS WORK TOGETHER TO TRY TO MAKE SURE THAT THAT DEVELOPMENT IS CONSISTENT AND APPROPRIATE, BUT IT'S NOT STOPE R. STOVE PIPED OR JUST ARBITRARILY DUPLICATIVE, SO TWO CENTERS MIGHT HAVE ASKED THE SAME QUESTION IN A DIFFERENT WAY BUT THEY'RE REALLY GETTING TO THE SAME INFORMATION, THE CENTERS WOULD WORK TO TRY TO FIGURE OUT WHAT IS THE BEST WAY TO HELP YOU IN PROVIDING THAT INFORMATION IN ONE COHESIVE PACKAGE INSTEAD OF DOING TWO BLINDED IN-PARALLEL DEVELOPMENT STRATEGIES, IF THAT IS NOT REALLY CONDUCIVE TO EFFICIENCY OR EFFECTIVENESS ON EITHER SIDE, OUR SIDE OR YOUR SIDE. SOME OF THAT GOES TO THE STANDARDS YOU'VE HEARD FROM BOTH CENTERS TODAY IN TERMS OF HOW DO YOU GET TO THAT DEVELOPMENT. THERE WERE DISCUSSIONS ABOUT THINKING ABOUT WHAT'S THE DOSE AND THE APPROPRIATE DOSE FOR THE DRUG, AND THERE WERE CONSIDERATIONS ON WHAT'S THE APPROPRIATE DOSE FOR THE DEVICE, IF YOU CAN DEVELOP A STANDARD AND APPROACH THAT EVALUATES BOTH OF THESE TOGETHER, A NEENING EXERCISEX-ER SEISE. ALSO FOR COMBINATION PRODUCTS IN MOST SITUATIONS WE REALLY ONLY NEEN ONE MARKETING APPLICATION, AND THAT COULD EVEN BE FOR THESE LARGER FIXED DEVICES THAT ARE, IF YOU WILL, CAPITAL EQUIPMENT VERSUS THINGS USED IN OUR DISPOSABLES, THERE ARE MANY DIFFERENT WAYS TO APPROACH THIS AND AGAIN DURING THE DEVELOPMENTAL MEETINGS, THERE ARE CONVERSATIONS TO TRY TO HELP CLARIFY THAT. IF YOU DO CHOOSE TO USE TWO MARKETING APPLICATIONS AND THAT'S OTHERWISE ACCEPTABLE, THEN WE WOULD ALSO HAVE CONVERSATIONS ABOUT WHAT'S THE BEST WAY TO DO THAT, AND I THINK SOME OF THAT GOES TO SOME OF THE QUESTIONS EARLIER ABOUT WHAT IF I WANT TO DO ONE DRUG AND THEN DEVELOP IT IN SOME OTHER WAY FOR ANOTHER DEVICE OR THE DEVICE FOR USE WITH OTHER DRUGS. AGAIN, THAT MIGHT BE SOMETHING THAT STILL STAYS UNDER ONE MARKETING APPLICATION OR IT MIGHT BE THE USE OF TWO. WE HAVE A LOT OF LEGACY PRODUCTS THAT WERE DEVELOPED MANY YEARS AGO UNDER TWO MARKETING APPLICATIONS AND THAT OCCURRED LONG BEFORE THE OFFICE OF COMBINATION PRODUCTS WAS ESTABLISHED AND SOME HAVE CHOSEN TO STAY WITH THEIR APPROACH, SOME COMPANIES THAT HAD TWO CHOSE TO CHANGE TO ONE. SO IT REALLY DEPENDS ON YOUR BUSINESS DECISIONS, BUT THE AGENCY WILL WORK TO TRY TO TALK THROUGH THOSE ISSUES ON A PRODUCT-SPECIFIC BASIS. BECAUSE IT REALLY IS PRODUCT-SPECIFIC RELATED TO THE ISSUES AND QUESTIONS THAT ARE RAISED FOR EACH ONE. AND THEN FROM A POST MARKET PERSPECTIVE, IF IT'S A COMBINATION PRODUCT, THERE ARE CERTAIN REQUIREMENTS, WE'VE TRIED TO STREAMLINE THE DP POST MARKET GMPs FOR COMBINATION PRODUCTS AS A WHOLE WITHOUT REQUIRING DUPLICATIVE GOOD MANUFACTURING PRACTICES, WE'VE TRIED TO STREAMLINE THAT TO MAKE IT SIMPLER AS WELL, THAT IS REVIEWED DURING THE MARKETING APPLICATION STAPLING AND ALSO AGAIN TO LOOK AT HOW WE INSPECT THE PRODUCTS POST MARKET AND SO FORTH. s NOW WHAT WOULD HAPPEN IF YOUR PRODUCT WAS NOT A COMBINATION PRODUCT, IF YOU HAD THE ONE-WAY LABELING OR THE GENERAL LABELING? SOME OF THE SPECIFIC REGULATORY REQUIREMENTS THAT ARE ASSOCIATED WITH COMBINATION PRODUCTS GO AWAY, BUT THE CENTERS STILL CONTINUE TO WORK TOGETHER BECAUSE AS YOU HAVE HEARD FROM TODAY'S DISCUSSION, THESE PRODUCTS ARE USED TOGETHER, THEY'RE LABELED SOMEHOW OR ANOTHER TO ACHIEVE THAT CO-USE TOGETHER, SO THE DIVISIONS WOULD STILL HAVE SCIENTIFIC AND TECHNICAL QUESTIONS THAT THEY NEED TO DISCUSS WITH EACH OTHER, DEPENDING UPON THE PARTICULAR PRODUCT. OFTEN TIMES THEY'LL COME TO OUR OFFICE DURING THE ROUX VEE AND SAY WE THINK THIS IS GOING TO BE A ONE-WAY LABEL BUT WE'RE NOT EXACTLY SURE, PLEASE LET US KNOW IF IT'S TRULY A COMBINATION PRODUCT OR IS IT TRULY A DEVICE ALONE OR A DRUG ALONE, OR WHAT DO WE NEED TO DO TO TRY TO FIND OUT. SCIENTIFIC OR TECHNICAL QUESTIONS THAT MIGHT EXIST, STILL LOOK AT THE LABELING ISSUES, AND OVERALL TRY TO MAKE SURE WE'RE ALWAYS CONSISTENT AND TRANSPARENT. SO WITH THAT, THIS IS THE CONTACT INFORMATION FOR THE OFFICE OF COMBINATION PRODUCTS, YOU MAY EMAIL ANY QUESTION TO THIS OFFICE, THIS IS OUR WEBSITE AND THIS IS MY PERSONAL CONTACT INFORMATION AT FDA. THANK YOU. [APPLAUSE] >> ARE THERE ANY QUESTIONS FOR PATRICIA? >> I HAVE A QUESTION JUST ABOUT THE TIMING. SO SMALL BIOTECHS, TIMING IS EVERYTHING, MONEY, YOU USUALLY ONLY GET ONE SHOT, END POINT OF SOME SORT. MY QUESTION IS, IF YOU DO COMBINATION, DO YOU GUYS REALLY TRY TO KEEP THE REVIEW TIME AND REGULATION DOWN TO THE SAME TIME FRAMES AS EITHER OF THE SEPARATE ONES WOULD BE? >> ABSOLUTELY. IN FACT, THAT'S ONE OF OUR RESPONSIBILITIES, IS TO ENSURE THAT. WE MONITOR THE CONSULT THAT THEY GO BACK AND FORTH IF THERE ARE ISSUES THAT ARE RAISED, WE DO TRY TO WORK WITH THE TWO CENTERS TO RESOLVE THEM WITHIN THE TIME FRAME. WE ALSO WORK WITH EACH OF THE CENTERS TO TRY TO ENSURE THAT THE CONSULTS, THE RESPONSES FROM THE OTHER CENTER ARE PROVIDED IN A TIMELY MANNER. THE CENTERS THEMSELVES HOST THEIR OWN MEETINGS, AND HAVE THEIR OWN TIME LINES THAT ARE IDENTIFIED TO ACHIEVE THE REVIEW TIME OUTCOME, THERE ARE A NUMBER OF MILESTONE MEETINGS ALONG THE WAY, AND THAT INFORMATION IS SHARED ACROSS THE CENTERS AND THE CENTERS WORK TOGETHER TO FIGURE OUT WHAT DO THEY NEED TO DO TO MEET THOSE. THE AGENCY IS RESPONSIBLE FOR MEETING THE TIME LINES OF THE AGENCY, NOT JUST THE PADUFAH OR MADUFAH TIME LINES BUT ALL OF THEM THAT APPLY. >> JOHN FINGLER. DID YOU SAY THAT THE WAY PRODUCTS ARE DETERMINED TO BE COMBINATION PRODUCTS IS FIRST AND FOREMOST BASED ON PRECEDENCE? >> NO. NO. IT'S BASED ON THE SPECIFIC INFORMATION OF THE INFORMATION THAT IS PROVIDED AND THE DATA. THESE ARE ALL PRODUCT-SPECIFIC DECISIONS. SOMETIMES PRECEDENCE DOES COME IN. THAT'S WHEN WE CANNOT MAKE A DETERMINATION ON THE BASIS OF THE PRIMARY MODE OF ACTION. THE FIRST AND FOREMOST REQUIREMENT IS PMOA. IF WE MAKE THE DECISION ON PMOA, WE STOP. >> THANK YOU. >> IN OTHER WORDS, THE ALGORITHM ONLY COMES INTO PLAY WHEN THE PMOA CANNOT BE DETERMINED. >> OKAY. LET'S MOVE ON TO THE PANEL. WE CAN HAVE THE PANELISTS COME UP AND PAULA IS GOING TO MODERATE FOR US. I WANT TO THANK EVERYBODY FOR COMING TODAY AND AS THE FINAL PANELISTS COME UP, I DO WANT TO PUT A PLUG IN FOR THE WORLD MOLECULAR IMAGING SOCIETY MEETING, IT'S GOING TO BE IN NEW YORK, AND THE WEDNESDAY BEFORE THAT MEETING IS GOING TO BE THE OPTICAL SURGICAL WORKSHOP. ANY OTHER COMMENTS ON THAT? IMAGING 20/20 IS ALSO CURRENTLY IN SEPTEMBER -- >> THE THIRD WEEK OF SEPTEMBER. >> JACKSON HOLE, MAYBE SIMILAR -- >> OKAY. LET'S START HERE AND IDENTIFY OURSELVES. >> MY NAME IS CHRISTY, I'M THE PRODUCT JURISDICTION OFFICER WITH THE CENTER -- I REPRESENT CDER'S POSITION ON PRODUCT AND CLASSIFICATION ISSUES AND WORK VERY CLOSELY WITH THE OFFICE OF COMBINATION PRODUCTS AND THE MEDICAL REVIEW DIVISIONS WITHIN THE CENTER ON MAKING THESE PRODUCT DETERMINATIONS. >> MY NAME IS JAMES BERTRAM. I'M CHRISTY'S COUNTERPART IN CDRH AND I'VE BEEN WITH THE AGENCY SINCE 2009. >> PATRICIA LOVE, OFFICE OF COMBINATION PRODUCTS, HAVE BEEN WITH THAT OFFICE SINCE 2003, BEEN WITH THE AGENCY MUCH LONGER THAN THAT. >> BRANCH CHIEF, GENERAL SURGERY DEVICE, BRANCH ONE. >> DIVISION OF MEDICAL IMAGING PRODUCTS IN CDER. >> SO LET'S OPEN UP FOR QUESTIONS. UNLESS THERE'S SOME COMMENTS -- I WAS CURIOUS MYSELF ACTUALLY AS TO HOW MANY PRODUCTS HAVE BEEN CLASSIFIED AS COMBINATION. >> LET'S SAY LAST YEAR. >> EVEN THAT'S A LITTLE DIFFICULT, BUT LET'S PUT IT THIS WAY. WE HAD APPROXIMATELY -- THIS IS TRULY OFF THE TOP OF MY HEAD SO PLEASE DON'T QUOTE ME. I THINK WE HAD ORIGINALLY SUBMISSIONS PROBABLY OVER 300 COMBINATION PRODUCT ORIGINAL SUBMISSIONS AND OVER A THOUSAND CROSS CENTER CONSULTS BACK AND FORTH DURING THE REVIEW PROCESS. THAT, I CAN -- >> THAT'S A LOT. >> I HAD A QUESTION, AND IT'S -- ONE OF THE THINGS THAT I THINK MAKES THE FIELD DIFFICULT FOR SOME COMPANIES AND SOME PEOPLE TO ENTER IS THE FAILURE OF 5ALA TO GET APPROVED IN THE UNITED STATES, AND I'M JUST -- AND I DON'T HAVE A LOT OF INFORMATION ABOUT THAT SO I DON'T KNOW IF THIS IS SOMETHING THAT YOU CAN COMMENT ON, BUT IT'S BEEN APPROVED IN SOME OF THE OTHER EUROPEAN OR I BELIEVE IN OUR CANADIAN NEIGHBORS. AND THIS IS MOSTLY OUT OF IGNORANCE, IS THERE SOME -- HAS THIS EVER BEEN BROUGHT FORWARD AND IT'S ONE OF THINGS THAT PEOPLE SAY IF 5ALA CAN'T MAKE IT IN THE U.S. HOW CAN OTHER THINGS? THAT'S WHY I'M SORT OF BRINGING IT UP. >> BY LAW, WE CANNOT COMMENT ON PENDING ISSUES. WE CANNOT ACKNOWLEDGE THAT WE HAVE AN IND, SO I WOULD ASK THAT YOU ASK THE SPECIFIC COMPANY. >> OKAY, THANK YOU. >> AND JUST ANOTHER POINT, WE'VE HEARD MANY PEOPLE COMMENT ABOUT WHY HASN'T THE FDA APPROVE X, Y OR Z? THEY CAN'T APPROVE ANYTHING UNTIL SOMEBODY SUBMITS AN APPLICATION. >> 5ALA, I DON'T KNOW WHAT YOU KNOW PUBLICLY, THEY'RE TRYING TO RAISE FUNDS TO ACTUALLY GET THE STUDIES DONE TO SUBMIT, IS WHAT I HAVE HEARD, UNLESS ANYBODY ELSE HERE IS FROM THE COMPANY, IT'S NOT CONFIDENTIAL INFORMATION. >> WHICH MEANS THEY HAVE NOT PUT IN -- SO THERE'S NOT FAILURE TO APPROVE IT. >> [INAUDIBLE] >> CLOSER TO THE MIC. >> [INAUDIBLE] >> IT DOESN'T APPEAR TO BE ON. >> THIGH, PAUL. THANK YOU, PAUL. VERY STIMULATING. AS A PRACTICAL MANNER, I HOPE THE PANEL COULD MAYBE HELP COMPANIES IN THIS ISSUE OF A MARKETING APPLICATION. THIS MORNING WE HEARD THAT THERE'S INTEREST IN PERHAPS A SINGLE APPLICATION, WHICH SOUNDS GOOD ON THE SURFACE, IF YOU HAVE A COMBINATION PRODUCT, WHEN IS THE BEST TIME TO START TALKING TO THE REVIEWED DIVISION, THE LEAD DIVISION ABOUT WHAT TYPE OF MARKETING APPLICATION SHOULD COME FORWARD? SHOULD IT BE A SINGLE APPLICATION, AND IF SO, WAS IT A PMA OR NDA OR BLA OR WHO -- DOES THE COMPANY DECIDE THAT, DOES THE COMPANY, AND WHEN IS THE RIGHT TIME? IS THAT INTO PHASE 1? THE REASON I SAY THAT -- I'M HUMBLED BY THE EFFORT THAT REQUIRES MANY MONTHS IF NOT YEARS CANDIDLY INTO GETTING THOSE APPLICATIONS TOGETHER, AND THE EXPECTATIONS FOR THE NDA, THE FORMAT, EVERYTHING IS VERY DIFFERENT FROM A PMA, AND CAN WE TALK ABOUT THAT? >> SURE. >> I WILL PROVIDE MY PERSPECTIVE OR OBSERVATION AND THEN ASK LOU AND NEIL TO COMMENT AS WELL. FROM MY PERSPECTIVE, I THINK THE EARLIER THE BETTER, AT LEAST TO RAISE THE QUESTION. THAT REVIEW DIVISIONS MIGHT SAY GIVEN A PARTICULAR PRODUCT AND ITS STATE YOUR NAME OF DEVELOPMENT, THAT SOME OF THOSE DISCUSSIONS MIGHT BE A LITTLE EARLY, AT LEAST FROM THE PERSPECTIVE OF NAILING DOWN THE OPTIONS, BUT AT LEAST HAVING SOME EARLY DISCUSSIONS. NOW EARLY IN A WAY DEPENDS UPON HOW DEVELOPED THE PRODUCT IS AT THE TIME YOU FIRST APPROACH THE AGENCY, SO IF YOU'RE STILL IN A VERY EARLY CONCEPT STAGE, YOU'RE LOOKING PRIMARILY AT PRE-CLINICAL DEVELOPMENT FOR THE DRUG IS NOT ESTABLISHED, THE DEVICE IS CONTINUING TO CHANGE, THAT MIGHT BE A LITTLE EARLY. BUT WE COULD AT LEAST HAVE SOME CONCEPTUAL DISCUSSION ABOUT THE DIFFERENT APPROACHES BUT TO REALLY GET IN TO MORE CONCRETE DISCUSSION, IT'S PROBABLY, I WOULD SAY, AROUND PHASE 2 FROM THE DRUG DEVELOPMENT STANDPOINT AND AT LEAST AFTER YOUR FEASIBILITY STUDY, PROBABLY FROM THE DEVICE PERSPECTIVE, BUT I'LL SEE WHAT MY COLLEAGUES SAY. >> I WOULD AGREE WITH THAT, I THINK AFTER THE FEASIBILITY STUDY, YOU'LL PROBABLY HAVE ENOUGH INFORMATION SO WE COULD GIVE YOU SOME REASONABLE GUIDANCE TO MOVE FORWARD. AS FAR AS FORMATTING, THIS IS STILL AN EVOLVING PROCESS FOR US BUT WE HAVE NO OBJECTION UNDER THE PMA FILING THAT IF YOU WANT TO SUBMIT THE DRUG INFORMATION IN THE NDA FORMAT, WE HAVE NO ISSUE WITH THAT BECAUSE DEVICE FOLKS ARE TO THE GOING TO BE REVIEWING THE DRUG STUFF. SO WE WILL BE HANDING IT OFF TO THEM AND THEY WILL BE REVIEWING IT AS PART OF THE PMA. >> AGREEING WITH WHAT EVERYBODY'S SAYING, THAT WE ACTUALLY STRONGLY RECOMMEND THAT BEFORE YOU START YOUR PHASE 3 STUDIES THAT YOU HAVE FINALIZED YOUR DRUG, YOUR FORMULATION, YOUR DEVICE, BECAUSE THE CHANGING IT AFTER YOU START OR EVEN WORSE AFTER YOU COMPLETE THE STUDIES COULD INTRODUCE ALL KINDS OF PROBLEMS AND AT A VERY MINIMUM THE NEED FOR BRIDGING STUDIES TO BRIDGE THE CLINICAL TRIAL PRODUCTS, WHAT THE COMMERCIAL PRODUCT IS GOING TO BE. >> SO SOMETHING THAT DR. LOVE SAID, HOWEVER, IMPLIED THAT AFTER THE FACT, >> NOT SEPARATE. JOINED. >> IF YOU'VE GOTTEN A COMBINATION APPROVAL AND YOU'VE MARKETED IT AND SO ON AND SO FORTH AND THEN YOU DECIDE I'D LIKE TO MORE GENERALIZE YOUR DEVICE -- >> THERE ARE TWO ISSUES. WHAT I WAS THINKING TO WAS ACTUALLY THE REVERSE EXAMPLE WHERE HISTORICALLY A COMPANY LONG BEFORE THESE OTHER PROCESSES WERE CLARIFIED WHERE A COMPANY HAD AN NDA AND A 510K AND COULD CHOOSE TO EITHER CONTINUE OR JOIN TO ONE MARKETING APPLICATION AND BASICALLY THEY'RE RELYING ON THEIR OWN PRIOR DATA, WE'RE JUST ALLOWING THE REGULATORY PATHWAY TO MOVE FORWARD AS ONE. SPLITTING RAISES A DIFFERENT QUESTION BECAUSE WE HAVE APPROVED THE COMBINATION PRODUCT UNDER ONE MARKETING APPLICATION. IF YOU ARE SPLITTING OUT SOMETHING, IF IT IS NO LONGER A PART OF THE COMBINATION -- >> IT'S STILL PART OF THAT. >> UNDERSTAND. IF IT'S NO LONGER A PART OF THE COMBINATION PRODUCT, THEN IT CAN FOLLOW ITS OWN SEPARATE PATHWAY, IT'S OWN LIFE CYCLE, ITS WHATEVER, SO LET'S SAY THE SAME DEVICE YOU WANTED TO HAVE AS GENERAL USE, SEPARATE AND APART FROM THIS ONE COMBINATION PRODUCT APPROVAL, YOU WANT TO USE IT FOR EVERYTHING ELSE FOR SOME DIFFERENT INDICATION AND THERE ARE ENOUGH DRUGS OUT THERE ON THE MARKET TO ALLOW THAT, THAT WOULD BE A GENERAL DEVICE, IT WOULD HAVE A SEPARATE INDICATION. A SEPARATE INDICATION, A SEPARATE APPLICATION. SPLITTING OFF FROM ONE MARKETING APPLICATION MAY NOT BE NECESSARY, IF YOU WANT TO ADD OTHER THINGS. IT'S MORE WHAT WAS MENTIONED DURING THE DAY ABOUT SUM MENTAL APPLICATIONS. THE WAY DO YOU THAT IN PART DEPENDS UPON THE REGULATORY PATHWAY THAT IS BEING USED, SO IF IT'S A PMA OR AN NDA, LET'S JUST SAY FOR EXAMPLE IT MIGHT HAVE BEEN, THEN WE FOLLOW THE PATHWAY OF THE PRODUCT THAT IS ALREADY APPROVED AND WHAT THE REGULATORY REQUIREMENTS ARE FOR THAT. IF IT'S A 510K THEN IT MIGHT BE VERY DIFFERENT. >> I COULD SEE A SMALL COMPANY, THEIR CONCERN IS TO GET SOMETHING ON THE MARKET AND QUICKLY AND THEN GENERALIZE IT. >> MY QUESTION IS SAY THAT A COMPANY AT THE SIDES TO GO INTO HAVING AN NDA FOR THE IMAGING AGENT AND PMA FOR THE DEVICE, AND AT SOME POINT, THERE IS SIGNIFICANT CHANGE TO THE DEVICE, THERE'S NEW OPTICS, NEW -- NO, BUT NEW OPTICS, SOME SUBSTANTIAL CHANGE TO THE DEVICE, WHAT WOULD BE THE APPLICATION TO THE NDA [ >> AGAIN, THAT DEPENDS, WHAT IS THE CHANGE, BUT IF THESE ARE APPROVED AS A COMBINATION PRODUCT, YOU ARE IN EFFECT CHANGING THE COMBINATION PRODUCT. SO THE QUESTION BECOMES WHAT ARE THE CHANGES, WHAT ARE THEY AFFECTING, WHAT DATA DO WE NEED TO EVALUATE. SO IF THE CHANGE IMPLICATED THE DRUG IN SOME WAY, THEN WE MAY NEED DATA RELATING TO THAT. IF THE CHANGE IS ONLY LOOKING AT THE DEVICE AND WE THINK WE CAN EVALUATE IT ONLY WITHIN THE PMA POST MARKET CHANGE APPROACH, THEN WE COULD DO THAT, BUT IT REALLY DEPENDS ON THE SPECIFICS OF WHAT'S HAPPENING. >> THIS MAY BE A CASE WHERE CONSULTATION EARLY WOULD BE A GOOD IDEA. >> YES. >> AND THAT'S ALWAYS A GOOD IDEA ACTUALLY. >> I HAVE A QUESTION ABOUT PARTS OF DEVICES. LOTS OF DEVICES ARE BUILT IN A MAD LAR FASHION. MODULAR IF SHON. CAN YOU YOU HAVE A COMBINATION OF A BROADER USE OF THE INSTRUMENT IS NOT LINKED TO THAT COMBINATION PRODUCT? >> THAT'S A PRETTY VAGUE QUESTION. [LAUGHTER] SO I CAN GIVE YOU AN EQUALLY VAGUE ANSWER. THAT IT REALLY DEPENDS ON THE DETAILS OF THAT SITUATION. SO IF IT'S COMPLETELY INDEPENDENT, THIS MODULE, IF YOU WILL, WE COULD ASSESS THAT MODULE INDEPENDENTLY AND SEE IF YOU HAVE ADEQUATE INFORMATION TO SHOW THAT IT WILL MEET WHATEVER MARKETING GOALS YOU'RE TRYING TO ACHIEVE. >> WHAT I MEANT BY A MODULE, SAY YOU HAVE A CAMERA SYSTEM, AND A CAMERA SYSTEM HAS A MODULE THAT HAS A DIFFERENT WAVELENGTH OR FILTERS THAT WE TALK ABOUT THESE TYPE OF MODIFICATIONS. BUT EVERYTHING ELSE WAS THE SAME, AND THAT MODULE COULD BE MANUFACTURED INDEPENDENTLY. IS THAT A PERFECTLY REASONABLE APPROACH? >> THE ENTIRE SYSTEM IS THE COMBINATION PRODUCT. THE FILTER WAS ORIGINALLY PART OF THE COMBINATION PRODUCT, YOU'RE MAKING A CHANGE TO THE FILTER BUT THE CHANGE IS OUTSOURCED TO ANOTHER MANUFACTURER WHO'S GOING TO SEND IN THAT CHANGE AND IT'S STILL PART OF THE SYSTEM? IS THAT WHAT YOU'RE DESCRIBING? >> SAY YOU HAVE A SYSTEM AND IT HAS THREE PARTS. AND ONE PART, YOU CAN PLUG IN. YOU CAN UNPLUG IT AND REPLACE THAT PART WITH DIFFERENT FILTER, FOR EXAMPLE, AND RATHER THAN LINKING IT TO THE WHOLE SYSTEM, YOU JUST WANT TO LINK IT TO THAT MODULE. >> THE MODULE WOULD HAVE TO HAVE ITS OWN APPLICATION. >> THAT'S WHAT I'M SAYING BUT THAT'S A PERFECTLY REASONABLE APPROACH. >> I NOTED THIS MORNING WHEN I WAS TALKING ABOUT -- THE CORAL STARCH THING USES A CAMERA THAT IS 510K APPROVED. EVEN THOUGH THAT DEVICE WAS PMA. CLEARED. PART OF THE QUESTION, WHAT HAPPEN FS THE C CD CAMERA THAT'S 510K APPROVED HAS A MODIFICATION? THAT'S WHERE YOU'RE GOING? SO SOMEBODY PUTS IN A SUPPLEMENT FOR THE 510K APPROVED CCD CAMERA, WHICH GOES INTO THE PMA APPROVED DEVICE. WHOA. I BET IT HAPPENS ACTUALLY FAIRLY OFTEN. >> WE HAVE TO LOOK AT IF THAT CHANGE IS GOING TO AFFECT THE PERFORMANCE OF THE COMBINATION PRODUCT AND IT'S GOING TO CHANGE THE CLINICAL EFFECT OF THE COMBINATION PRODUCT, WE JUST HAVE TO ASSESS WHAT THOSE DETAILS ARE. IT'S REALLY HARD TO GIVE YOU A BLANKET ANSWER -- WE ALSO HAVE A GUIDANCE DOCUMENT THAT TALKS ABOUT DECIDING WHEN YOU NEED A NEW 51 510K FOR AN ALREADY MARKETED DEVICE THAT HAS A 510K. I WOULD ASK YOU WALK YOUR DECISIONS THROUGH THAT FLOW CHART ABOUT WHETHER IT'S TECHNOLOGY OR LABELING OR BIOCOMPATIBILITY AND WALK THROUGH THE FLOW CHART TO SEE WHERE YOU END UP, WHERE IT'S NEW SUBMISSION OR -- >> I THINK THERE'S SOMETHING ANALOGOUS IN DRUGS, WHERE EVEN IF YOU DON'T HAVE COMBINATION PRODUCTS, YOU HAVE A FINISHED PRODUCT AND THERE MAY BE MULTIPLE COMPONENTS THAT GO INTO THAT PRODUCT. IT COULD BE A CHANGE IN THE STOPPER OR A CHANGE IN THE GLASS VIAL. THERE'S COR CORRESPONDING APPLICATION THAT THE MANUFACTURER OF THE FINISHED PRODUCT IS RESPONSIBLE FOR COMMUNICATING WITH THE FDA, CHANGES TO ALL THE COMPONENT PARTS THAT MIGHT AFFECT THE SAFETY AND EFFICACY PROFIT DUCT. MAYBE THE STOPPER HAS SOME EXTRACTIBLES THAT CAN CAUSE SOME PROBLEMS OR MAYBE THE CLOSURE SYSTEM IS IMPAIRED AND NOW THE PRODUCT ALL OF A SUDDEN IS NO LONGER STERILE. SIMILARLY, THE MANUFACTURER THAT IS SUPPLYING THE COMPONENT IS ALSO RESPONSIBLE FOR GIVING THE MANUFACTURER OF THE FINISHED PRODUCT THE INFORMATION THAT THEY NEED IF NECESSARY TO UPTAKE THE NDA FOR MAJOR CHANGES THAT MAY IMPACT AGAIN THE SAFETY AND EFFICACY OF THE PRODUCT. >> OUR PMA PROCESS HAD THE SAME SORT OF THING FOR DESIGN CHANGES, THOSE NEED TO BE REPORTED TO THE AGENCY, THEY GET REVIEWED TO SEE IF IT REQUIRES FURTHER SUBMISSION TO THE AGENCY FOR FURTHER REVIEW. >> CAN I ASK THE QUESTION IN A MORE BROADER WAY THAT FOR EXAMPLE, COULD YOU HAVE AB AGENT APPROVED, THE DRUG APPROVED AS A COMBINATION PRODUCT WITH A LASER SPECIFYING JUST THE WAVE LENGTH AND THEN A SET OF FIL FILTERS, IN OTHER WORDS, YOU'RE NOT SPECIFYING THE DEVICE, YOU'RE JUST SPECIFYING A RANGE, YOU'RE NOT FOCUSED SO MUCH ON THE SPECIFIC DEVICE, YOU'RE JUST SIMPLY SAYING THIS DRUG, FOR A COMBINATION, CAN BE USED WITH THIS RANGE OF MISSION ECK EYE TAITION WITHOUT SPECIFYING THE DEVICE SPHWHR. IN SOME CONTEXT, IT MAY BECOME IMPORTANT TO HAVE A SPECIFIED LEGALLY RESPONSIBLE PERSON THAT IS PRODUCING THE PRODUCT, BECAUSE THEN WHAT IF THE PRODUCT IS CRITICAL, FOR INSTANCE, IN THE CONTEXT OF DRUGS, THE FDA WILL GO AND INSPECT THE DRUG OF THAT CRITICAL COMPONENT, I'M NOT SURE HOW IT WORKS IN DRUGS. SO IF IT'S CRITICAL TO VERIFY THAT THE QUALITY OF THE COMPONENT, DRUG OR DEVICE, IS CRITICAL, THEN IT WOULD NEED TO BE SPECIFIED. MAYBE NOT IN THE LABEL BUT MAYBE IN SOME PORTION OF THE APPLICATION. >> THERE MAY BE MULTIPLE APPROVED DEVICES THAT FIT THAT WAVELENGTH, SO THEN -- >> AS LONG AS THEY'RE CLEARED. YOU'RE TALKING ABOUT CLEARED DEVICES. >> CORRECT. SO IN OTHER WORDS, YOU'RE NOT ASSIGNING A SINGLE DEVICE, YOU'RE ASSIGNING A RANGE. IS THAT AN ACCEPTABLE APPROACH? >> I THINK THAT GOES TO ONE OF THE EXAMPLES ON SLIDE WHERE IT SAID GENERAL USE PRODUCT POTENTIALLY, THAT IS NOT A COMBINATION PRODUCT, SO THAT'S BROAD LABELING AND YOU'RE LOOKING AT THE DRUG SAYING MY DRUG CAN BE USED WITH DEVICES WITH ALL THESE DIFFERENT WAVELENGTHS. OR DEVICES THAT ARE WITHIN A CERTAIN BANDWIDTH. AND HAVE X, Y, Z CHARACTERISTICS CHARACTERISTICS. THAT'S CONCEIVABLY POSSIBLE AND -- WIT BUT AS WAS DISCUSSED EARLIER TODAY, THERE ARE A NUMBER OF SCIENTIFIC AND TECHNICAL QUESTIONS THAT GO INTO THAT AND THE DATA WOULD NEED TO BE PROVIDED TO SUPPORT SUCH LABELING. IF THE DATA WERE NOT AVAILABLE, THEN THE DIVISIONS WOULD LOOK TO SEE WHAT IS THE MOST APPROPRIATE APPROACH. MAYBE IT MIGHT NOT BE -- MAYBE WE WOULDN'T IDENTIFY JUST THAT, IT MIGHT IDENTIFY THE THREE OR FOUR, FIVE, WHATEVER NUMBER OF DIFFERENT DEVICES THAT WERE ACTUALLY STUDIED AND FOR WHICH THERE ARE DATA TO DEMONSTRATE THAT THEY'RE OKAY, BUT MAYBE IT'S NOT A FULL BROAD LABEL. THERE ARE A NUMBER OF DIFFERENT POSSIBILITIES BASED OP THE DATA. >> BUT I TAKE IT THAT WOULD NOT BE A COMBINATION PRODUCT. >> NO, THAT'S NOT A COMBINATION. THEY'RE EITHER ONE-WAY LABELING OR BROAD GENERAL LABELING. >> THAT'S IMPORTANT. >> THAT'S WHAT'S DONE WITH, FOR EXAMPLE, PET AGENTS AND PET MACHINES. YOU CAN'T GET A PET IMAGE WITHOUT A PET MACHINE AND A PET LABEL. >> IT'S INDICATED FOR USE FOR POSITRON EMISSION TO MOGRAPHY AND THAT'S ALL IT SAYS. >> IT'S JUST DATA DRIVEN. PART OF THE PROCESS THAT WE GO THROUGH, AS I MENTIONED, THERE'S A PROSPECTIVE LOOK AT WHAT ARE THE EXISTING LABELS AND DO THEY NEED TO CHANGE, BUT THEN DURING THE REVIEW, THERE'S ANOTHER ASSESSMENT BASED ON THE DATA THAT ARE PROVIDED THAT AT THE END OF THE DAY WILL ALSO INFORM LABELING DECISIONS. >> TYPICALLY IN THE CONTEXT OF LET'S SAY A PET IMAGING AGENT, THERE WILL BE MULTICENTER TRIALS AND THERE WILL BE MULTIPLE PLATFORMS AND I THINK WE'VE BECOME A LITTLE BLAZE AND WE DON'T LOOK TO SEE WHETHER THERE'S ANY SPECIFIC HARDWARE THAT PERFORMS DIFFERENTLY, IT FALLS OUT IN TERMS OF DO WOULD HE SEE SIGNALS THAT ARE ANOMALOUS IN TERMS OF SAFETY AND EFFICACY. BUT IN DATA, WE'RE GENERALIZE ACROSS PLATFORMS. >> WHAT IF YOU HAVE A NEW IMAGING DEVICE THAT USES AN OLD DRUG AND OLD DYE THAT'S BEEN IN CLINICAL PRACTICE FOR A HUNDRED YEARS? >> WE HAVE A LOT OF THOSE. [LAUGHTER] >> ICG. >> IS THAT A COMBINATION DEVICE? >> AGAIN, IT DEPENDS UPON THE SPECIFICS. SO IF YOU LOOK VERY -- IF YOU LOOK EXACTLY AT, LET'S SAY ABOUT THE DRUG LABEL, I'M NOT GOING TO MENTION BRAND NAMES RIGHT NOW, SO IF YOU LOOK AT THE DRUG LABEL LABEL, AND THE NEW DEVICE FALLS WITHIN INDICATIONS ALREADY WITHIN THAT LABEL OR FALLS WITHIN OTHER ASPECTS OF WHAT'S IN THAT LABEL, THEN IT'S ESSENTIALLY A GENERAL LABEL AND YOU CAN GO AHEAD AND JUST DEVELOP THE DEVICE BY ITSELF. THEN WE GO THROUGH THE PROCESS OF DO WE NEED ONE-WAY LABELING OR CROSS LABELING? IF WE NEED CROSS LABELING, IT'S EITHER THE DISCUSSION THAT OCCURRED EARLIER, WHEN DR. MARZELO WAS TALKING ABOUT APPROACHING OAR THE OTHER COMPANY, OR HELD BY THE APPLICANT THAT HAS THE LEAD BASED ON THE COMBINATION PRODUCT AND THEY DO A CO-PACKAGE AND THAT INDICATION THEN ONLY EXISTS IN THE COPACKAGE, IT DOES NOT EXIST IN THE STANDALONE DRUG LABELING. >> I WISH I HAD THE ANSWER. I HAVE A RELATED QUELL TO THAT. IT'S A GREAT QUESTION, I'VE BEEN WAITING ALL DAY TO ASK THIS QUESTION ACTUALLY. BUT IF WE JUST CONSIDER THE MOLECULES THEMSELVES, AND I'M A MOLECULE DESIGNER, SO IF WE THINK ABOUT A MATRIX, WE CAN SIMPLIFY THE AGENT PERSPECTIVE DOWN TO A 4 BY 2 MATRIX, WHERE YOU HAVE EITHER AN OL OLD OR ACCEPTED CARRIER AND AN OLD OR ACCEPTED FLUOROFOR, OR YOU COULD HAVE A NEW CARRIER AND AN OLDER ACCEPTED FLUOROFLOOR OR YOU COULD HAVE NEW BOTH. MY QUESTION TO THE AGENCY IS, ARE THESE REVIEWED THE SAME OR CAN YOU GIVE US SOME GUIDANCE? IF I WAS STARTING A COMPANY OVER AGAIN, WHICH IS THE EASIEST ONE TO DO? BECAUSE IT SEEMS LIKE IF YOU'RE OLD, OLD, YOU'LL HAVE A MUCH HE'DIER PATH TO GETTING INTO APPROVAL IN CLINICAL TRIALS. >> WHAT DO YOU MEAN CARRIER? >> TARGETING MOLECULES, NOW SO YOU COULD HAVE AN ANTIBODY OR A SMALL MOLECULE. SO IN OUR CASE -- >> YOU'RE TALKING A -- ENTITY? >> ABSOLUTELY. SO EITHER AN ANTIBODY OR A CARRIER OF THE FLUOROFOR, SO THERE'S FOUR DIFFERENT SCENARIOS THERE. AND DOES THE AGENCY LOOK AT THAT WHEN THESE PROPOSALS COME IN, THESE APPLICATIONS COME IN, OR DOES IT NEVER EVEN ENTER IN TO THE EQUATION? THAT'S WHAT I'M TRYING TO FIND OUT. I'VE BEEN TRYING TO EAPS THIS QUESTION FOANSWER THISQUESTION FOR OVER A YEAR NOW. >> GO TO IT, JAMIE. >> I'M NOT SURE IF I FULLY UNDERSTAND THE QUESTION BUT I'LL TAKE A STAB AT ANSWERING ANYWAY. SO EACH ONE WOULD BE A NEW MOLECULAR ENTITY PRESUMABLY, AND EACH ONE WOULD HAVE TO BE REVIEWED FROM SCRATCH IN TERMS OF HOW STABLE IS THE PRODUCT, IS THE ABILITY TO BIND TO -- IS THE PURPORTED MECHANISM OF ACTION STILL AFFECTED, DOES IT STILL BIND TO THE RECEPTOR WHERE IT BINDS, DOES THE STUFF ASSOCIATE IN VIVO, HOW DOES IT BOY BIODISTRIBUTE, WHAT IS THE CHEMICAL STABILITY, WHAT IS THE STORAGE CONDITIONS, BLAH, BLAH, BLAH, AND YOU HEARD FROM MY COLLEAGUE ABOUT EXREE PREE CLINICAL, THEN THERE WOULD HAVE TO BE SAFETY CHARACTERIZATION, DHOS NEW MOLECULE NEED PRE-CLINICAL CHARACTERIZATION. SO CAN YOU LEVERAGE SOME OF THE INFORMATION. ONE THING WE NEGLECTED TO MENTION ALSO, THERE'S THIS OPPORTUNITY TO DO THIS EXPLORATORY IND. IF YOU'RE FORTUNATE ENOUGH TO HAVE A MICRO DOSE TYPE OF PRODUCT WHERE YOU CAN ACTUALLY IN CLINICAL STUDIES INVESTIGATE A NUMB WE ARE OER OF CANDIDATES THAT POTENTIALLY COULD BE USEFUL. SO YOU COULD BE CREATIVE AND YOU COULD DO MICRO DOSE STUDIES, EVEN IF YOUR INTENDED DIAGNOSTIC USE WILL REQUIRE HIGHER DOSES IF YOU WANT TO GET SOME DATA ABOUT BIODISTRIBUTION OR BINDING OR FEASIBILITY STUDY, SO THERE ARE ARE -- BUT THE BASIC CONCEPT, YOU WOULD HAVE THE RIGHTS TO WHATEVER APPLICATION YOU'RE ABLE TO DEVELOP, THERE IS THE POTENTIAL TO LEMPLEG SOME INFORMATION THAT WE MIGHT HAVE, BUT THE REQUIREMENT WOULD BE THERE BE DATA FOR THIS NEW MOLECULAR ENTITY. >> WOULD THERE BE A LITTLE MORE COMFORT IF YOU HAD TWO WHICH ARE WELL-KNOWN, YOU HAD A TOTALLY NEW -- >> YES, AND I THINK AN EXAMPLE WAS DISCUSSED THIS MORNING WHERE THAT IS, IN FACT, THE CASE IN TERMS OF PRE-CLINICAL. >> BUT THERE WHAT YOU'RE DOING IS LEVERAGING EXISTING KNOWLEDGE ABOUT SIMILAR DRUGS. >> YES. >> THERE'S STILL NEW CHEMICAL ENTITIES. THERE'S JUST A HIGHER LEVEL OF COMFORT THERE. >> ALSO I'M SUGGESTING THAT YOU SHOULD BE SMART AND LOOK AT THE MOST PROMISING CANDIDATES AND DO WHATEVER YOU CAN BEFORE YOU CHOOSE WHICH ONE YOU'RE GOING TO DEVELOP. >> GOING BACK TO THE MARKETING APPLICATIONS IN THE CLINICAL IMAGING DATA ITSELF, DENNIS MILLER FROM BLAZE BIOSCIENCE. COULD YOU MAYBE GIVE ANY SORT OF COMMENTS OR GUIDANCE TOWARDS HOW DO WE ACTUALLY SUBMIT ALL THIS IMAGING DATA? WE'RE STARTING TO GET TO A POINT WHERE WE'RE RECORDING THE SURGERIES, SO WE HAVE HOURS AND HOURS OF VIDEO, YOU START MULTIPLYING IT BY PATIENTS, IT'S OVERWHELMING US AND DO I EVEN NEED TO BE SUBMITTING THAT TYPE OF INFORMATION? >> MY BOSS, MY PREVIOUS BOSS HAD A LOT OF FORESIGHT AND DETERMINED THAT WE WOULD SOON BE INUNDATED WITH IMAGING DATA. SO WE DON'T ARCHIVE IMAGING DATA BUT WE DO INSPECT IT. SO WE RELY BASICALLY ON INSPECTION TO VERIFY THE VALIDITY AND THE QUALITY OF THE DATA. WE ALSO PUT A LOT OF IMPORTANCE ON THE WAY THAT THE STUDY IS DESIGNED IN TERMS OF HOW THE IMAGES ARE ACQUIRED, HOW THE QUALITY OF THE IMAGES IS VERIFIED, IF THERE'S GOING TO BE INDEPENDENT ASSESSMENT, HOW THAT INDEPENDENT ASSESSMENT IS DONE, THEN WE JUST LOOK AT THE DATA. WE DON'T ACTUALLY -- WE MAY AT TIMES REQUEST SOME IMAGES JUST FOR THE PURPOSE OF FAMILIARIZATION BUT WE DON'T ARCHIVE, IT'S NOT EACH PART OF EVEN PART O F THE OFFICIAL DATA SUBMISSION. >> THIS MIGHT BE DISCUSSED AS YOUR PRENDA MEETING AS WELL. >> ABSOLUTELY. >> YOU COME TO TALK TO US AND WE HAVE A GUIDANCE ON HOW -- WHAT WE CALL AN IMAGE CHARTER, AND I'M SURE THIS IS NOT MEANT TO BE AN ENDORSEMENT BUT THERE'S A NUMBER OF COMPANIES THAT YOU CAN CONTRACT, THEY CAN MANAGE ALL THIS IMAGING ASPECT CH YOUR TRIAL. MORE QUESTIONS, MORE COMMENTS? >> I HAVE A RATHER MUNDANE ONE THAT FOLLOWS UP ON THE QUESTION THAT WAS JUST ASKED. CURRENTLY THERE ARE COSTS ALLOWED FOR, FOR EXAMPLE, A NON-COMPLICATED BREAST CANCER SURGERY OR A NON-COMPLICATED COLON CANCER SURGERY, AND THIS IS, I GUESS, DETERMINED BY THE CENTER OF MEDICARE SERVICES. HOW DO WE COLLECTIVELY AS A GROUP INTRODUCE THE CONCEPT OF FLUORESCENCE GUIDED SURGERY TO THIS ORGANIZATION SO THAT THEY APPRECIATE IT AND REALIZE IT SHOULD BE AS A REIMBURSEMENT? >> THIS IS A DIFFICULT THING TO DO. >> >> I THINK THAT'S AN IMPORTANT POINT TO RAISE, AND IT SORT OF TIES BACK TO THE CONCEPT I WAS MENTIONING EARLIER OF THE CONCEPT OF CLINICAL STUDIES. SO IF CMS IS INTERESTED, FOR INSTANCE, IN PATIENT MANAGEMENT OUTCOME, THAT WE AT THE FDA WOULD BE INTERESTED IN WORKING WITH YOU TO DESIGN A STUDY THAT, AGAIN, WOULD CAPTURE DATA THAT WE COULD USE FOR APPROVAL, BUT THAT POTENTIALLY COULD ALSO SATISFY OTHER REGULATORY REQUIREMENTS. BUT THIS IS SOMETHING THAT EACH SPONSOR WOULD HAVE TO DO ON THEIR OWN, IN OTHER WORDS, IT'S NOT AS THOUGH THE TWO REGULATORS WOULD TALK TO EACH OTHER. YOU WOULD HAVE TO TAKE THE INITIATIVE. >> WOULD YOU HAVE TO GET A CPT CODE ESTABLISHED THROUGH YOUR SOCIETY FIRST BEFORE YOU COULD GO TO CMS? >> YOU'RE NOT ASKING AN EXPERT THERE. YOU GENERALLY GO TO CMS AFTER YOU HAVE AN FDA APPROVAL, AND THEY WANT COST-EFFECTIVENESS, OUT COME, SO ON AND SO FORTH. WITHOUT MAKING THEM TOO COMPLICATED, YOU CAN GATHER IT AS YOU GO. >> THERE WERE NUMEROUS ATTEMPTS OVER THE YEARS, I WAS INVOLVED IN ONE, FROM 2001 TO 2004, WHERE WE TRIED TO COLLABORATE WITH CMS, THEY WOULD COME TO OUR INDUSTRY MEETINGS AND WE WOULD TRY TO DEVELOP PROTOCOLS FOR VARIOUS DEVICES THAT WOULD MEET BOTH OUR NEEDS, WHICH IS SAFETY AND EFFICACY, AND THEIR NEEDS, WHICH IS REASONABLE AND NECESSARY. SO DIFFERENT BARS. AND WE HAD LIMITED SUCCESS BACK THEN, OF COURSE THIS WAS 15 YEARS AGO, SO WE HAVE A NEW INITIATIVE THAT'S TRYING TO REINVIGORATE THAT PROGRAM, SO I WOULD SAY COME TO US AND ASK US EARLY, WE MAY GET INVOLVED IN THAT PROGRAM, SO CMS MAY JOIN IN IN OUR MEETINGS AND YOU CAN TALK DIRECTLY TO THEM ABOUT GETTING THE INFORMATION NECESSARY TO SHOW REASONABLE AND NECESSARY. >> I THINK ALSO LIKE FDA AND THE TWO MAJOR DIVISIONS WE'RE TALKING ABOUT HERE, CMS DOES POST THEIR DELIBERATIONS WHEN THEY HAVE FINISHED THEM. GO LOOK AT SOME THINGS WHICH ARE REIMBURSED AND SEE WHAT IS REQUIRED TO GET THERE. >> PRESS DEPTH IS VERY IMPORTANT IN ALL REGULATORY ASPECTS. >> THE OTHER POINT I THINK I WANTED TO UNDERSCORE IS YOU DON'T HAVE TO GO THROUGH AN FDA FORMAL PROCESS TO INVITE CMS. YOU CAN INVITE ANY EXPERT OR ANY AGENCY THAT YOU WANT TO COME TO OUR MEETINGS. SO THAT COULD BE SOMETHING WORTHWHILE. WE WOULD WELCOME THEIR PARTICIPATION, >> MY QUESTION RELATES TO, AGAIN, LABELING A DRUG BY ITSELF OR A DEVICE BY ITSELF LIKE A GENERAL LABELING FOR THE DRUG, AND SAY THAT YOU CONDUCT YOUR CLINICAL TRIAL AND YOU NEED A DEVICE TO CONDUCT THE CLINICAL TRIAL, SO YOU'RE GOING TO HAVE TO FINISH YOUR CLINICAL TRIAL AND YOU'RE GOING TO HAVE YOUR END POINT SENSITIVITY, SPECIFICITY OR REDUCE, REEXCISION, WHATEVER IT IS, BUT IT'S REALLY TIED UP TO THE DRUG IS REALLY TIED UP TO THE SPECIFICATIONS OF THAT PARTICULAR DEVICE, ALTHOUGH YOU'LL WANT TO TIE UP THAT DRUG TO THAT DEVICE. WHEN YOU HAVE YOUR LABELING FOR THE DRUG, DO YOU HAVE TO SAY -- DO YOU HAVE TO SPECIFY ANOTHER DEVICE OR DO YOU HAVE TO SPECIFY THE METRICS OR THE SPECIFICATIONS THAT THE DEVICE HAS TO HAVE IN ORDER TO MEET THOSE END POINTS THAT YOU ALREADY ESTABLISHED? >> AGAIN, I THINK IT GOES BACK TO THE SPECIFICS. IF YOU THINK THERE ARE ENOUGH DEVICES THROUGHOUT THERE WHERE THAT PARTICULAR INFORMATION IS ACCESSIBLE, SO SOMEONE COULD LOOK AT A DEVICE LABEL AND GET THAT INFORMATION, THAT'S ONE QUESTION TO ASK. SECONDLY, IT WOULD NEED TO BE SOME INFORMATION SHOWING THAT THOSE ARE THE CRITICAL IDENTIFYING FACTORS. TO ENSURE CONSISTENCY AND THE RESULTS. THAT WAS SOME OF THE DISCUSSION FROM THIS MORNING. SO IT REALLY AGAIN COMES DOWN TO WHETHER YOUR DATABASE SUPPORTS BROAD LABELING. AND SO IN YOUR EARLY DEVELOPMENT DISCUSSIONS, LET'S STEP BACK A BIT, WE HAVE EARLY DEVELOPMENT DISCUSSIONS DURING PRESUBMISSIONS, WHY YOU WANT TO COLLECT, WHY YOU THINK THOSE ELEMENTS ARE CRITICAL, AND WHAT YOU WANT TO DO AS A STANDALONE DRUG, LET'S SAY, THAT WOULD BE COMING IN THROUGH THE PRE-IND, IND PROCESS, AGAIN DISCUSSING THE SAME THINGS, AND YOU LAY OUT WHY YOU THINK YOU COULD SUPPORT AND HOW YOU WOULD SUPPORT A BROAD LABELING CLAIM, THE TWO CENTERS WOULD DISCUSS WHAT DATA WOULD BE NECESSARILY TO DO SO, AND WHETHER THE INFORMATION OR THE TECHNOLOGY IS AVAILABLE TO EVEN LOOK AT WHETHER OR NOT THESE THINGS ARE THE SAME OR DIFFERENT. AND BASED ON THAT DATABASE, THEN THEY WOULD MAKE THOSE ASSESSMENTS ON WHETHER OR NOT YOU COULD ACHIEVE THAT GOAL. IF NOT, THEN IT WOULD PROBABLY BE ABLED AT LEAST ONE-WAY LABELING. IF NOT, THE AT THE VICE IS ALREADDEVICE IS ALREADYOUT THERE TO DO THI S, IT MIGHT JJUST BE ONE-WAY LABELING TO BE SURE. >> I WON'T MENTION THE NAME BUT IT'S FOR USE IN PULMONARY VENTILATION IMAGING, SO, YOU KNOW, WE KNOW THAT IT CAN BE USED WITH ANY DOSE CALIBRATOR, SO WE DON'T SPECIFY THE DOSE CALIBRATOR, WE SAY ANY SUITABLE -- WE KNOW IN THIS PARTICULAR CASE THIS, RADIOACTIVE MATERIAL IS A GAS, AND SO THE TRANSFER DEVICE IS REALLY CRITICAL FOR THE SAFETY AND EFFICACY OF THE PATIENTS AND SO WE ACTUALLY SPECIFY WHAT THE TRANSFER DEVICE IS. THEN FOR IMAGING, YOU USE SPECT IMAGING, ANY BLACK FORM WOULD BE SUITABLE SO WE DON'T MENTION WHAT THE PLATFORM IS. SO THAT'S AN EXAMPLE OF WHERE BASED ON SAFETY AND EFFICACY CONCERNS, WE DO OR DO NOT SPECIFY THE DEVICE. >> SUPPOSE SOMEONE COMES IN WITH A DRUG AND THEY HAVE USED A SINGLE DEVICE ONLY, MOST OF THE PET TRIALS, THEY'RE MULTICENTER, IF THERE'S ONLY ONE DEVICE THAT YOU USED IN YOUR ENTIRE CLINICAL TRIAL, WHAT WOULD THAT DO? >> YOU WOULD HAVE TO PROVIDE DATA THAT THE PERFORMANCE WOULD BE SIMILAR WITH OTHERS AND IF YOU DON'T, YOU KNOW, WE MAY REQUIRE THAT YOU DO SOME BRIDGING STUDIES. WE'VE EVEN HAD SITUATIONS WHERE THE TEST ITSELF WAS NOT APPROVED BUT WE SPECIFICKED IT ANYWAY, BECAUSE IT WAS CRITICAL TO PICK UP THE PATIENT POPULATION FOR WHICH THIS DRUG WOULD WORK. >> IT'S BEEN A LONG DAY. ARE THERE ANY OTHER QUESTIONS? I REALLY WOULD LIKE TO THANK THE FDA FOR TAKING A BIG GRILLING TODAY. >> I THINK THE PLEASURE IS OURS. I REALLY APPRECIATE THE DISCUSSION, AND WE WELCOME THIS EXCHANGE AND WE LOOK FORWARD TO SEEING MORE OF YOU COME TO MEETINGS TO CONTINUE THE DEVELOPMENT OF YOUR PRODUCTS. THANK YOU. >> AGREED. LET'S CONTINUE TO COLLABORATE. >> THANK YOU ALL FOR COMING. >> I'D LIKE TO MAKE ONE ANNOUNCEMENT REALLY QUICKLY. -- IS GOING TO BE WRITING THIS UP SO IF YOU SEE AN EMAIL FROM HER, PLEASE OPEN IT. DON'T DELETE IT. SHE'S GOING TO TRY TO SUMMARIZE SOME OF THESE STATEMENTS IN ONE OR TWO PAPERS THAT WE'LL ALL PARTICIPATE IN. SO THANK YOU VERY MUCH. >> AND I HAVE SOMEBODY'S USB UP HERE.