IPPCR: FDA Product Regulation



MY NAME IS CHRIS JONECKIS,
ASSOCIATE DIRECTOR FOR VIEW MANAGEMENT IN THE CENTER FOR BIOLOGICS AT FDA AND MY TALK IS GOING TO COVER, I GUESS THE MATERIAL IN THE CHAPTER. REALLY, IT'S A REGULATION OF DRUGS AND BIOLOGICAL PRODUCTS IN THIS COURSE. I'M GOING TO COVER SOME OTHER THINGS THAT AREN'T IN THE CHAPTER, WHICH ARE SORT OF MODERN AND UP TO DATE AND THINGS WE'RE DOING NOW. SO IT'S PRETTY STRAIGHTFORWARD WHAT IT COVERS AND DOESN'T COVER. SO WE HAVE, FINALLY, CENTRALIZED CAMPUS OVER AT WHITE OAK SILVER SPRING, ABOUT THE SIZE OF A MID-SIZED UNIVERSITY, ABOUT 10,000 OR SO INDIVIDUALS THERE, PERIODICALLY AND IT'S A VERY NICE CORPORATE FEEL AND LOOK IF YOU WILL, AND FIELD-ENABLED RESEARCH LABORATORIES AND LOOKS LIKE THIS, AND TILE, IT'S A LITTLE BIT BIGGER NOW. BUT IT BRINGS US OVER FOR THE FIRST TIME IN A LONG TIME AND IT'S REALLY GOOD FOR COLLABORATION BETWEEN SOME OF OUR RESEARCHERS AND REVIEWERS IN THE VARIOUS CENTERS. WE'RE ONE OF YOUR CENTER CENTERS, CLEARLY AND WE'RE STUCK UNDER THE HEALTH AND HUMANSERSES, WE'RE STUCK HERE. FDA. WE WORK CLOSELY WITH NIH AND WITH THE CMS. CDC AT TIMES ON A LOT ISSUES, AND VARIOUS OTHER AGENCIES AS NECESSARY. A WHOLE VARIETY OF ISSUES. AND THIS IS THE SLIDE FROM LAST YEAR, THIS IS A PROBLEM WITH MY SLIDE. DR. HAMBURG IS NO LONGER THE COMMISSIONER IN. OUR ACTING COMMISSIONER IS WILLIAM OSTROF. AND DR. ROB KALEFF IS NOMINATED AS OUR CURRENT COMMISSIONER AT PRESENT. WE ARE COMPOSED AROUND VARIOUS CENTERS AND THAT INCLUDES THE CENTERSES SHOWN HERE, THE OFFICE OF REGULATORY AFFAIRS IS ESSENTIALLY OUR INSPECTION ARM OF THE GOVERNMENT — OR THE FDA, IF YOU WILL. THEY DO A LOT OF INSPECTIONS OF THE VARIOUS MANUFACTURING FACILITIES AND STUFF. [INDISCERNIBLE] MED AND THEY SHARE RESPONDENT WITH THE CAPTAIN OF AGRICULTURE FOR THE REGULATION OF FOOD SUPPLY. OUR NEWEST CENTER IS THE CENTER FOR TOBACCO PRODUCTS. OUR MISSION IS RELATED TO ENSURING SAFE MEDICINES AND DRUGS AND DEVICES AND SO. THEIR MISSION IS SLIGHTLY DIFFERENT, GIVEN THE NATURE OF THE PRODUCTS THAT THEY REGULATE. SO THE MISSION OF THE FDA IS THE PROTECTION OF THE HEALTH BY ENSURING THE SAFE, AND EFFICACY OF SECURITY. ALTHOUGH WE HAVE DONE WORK IN THAT BEFORE HAND. WE'RE RESPONSIBLE FOR ADVANCING THE PUBLIC HEALTH, BY HELPING SPEED INNOVATION. I'VE BEEN THERE FOR ABOUT 21 YEARS, ALL IN THE CENTER FOR BIOLOGIC. AND I HAVE SEEN QUITE A FEW CHANGES IN THAT TIME PERIOD. NEVER INTENDD TO STAY THERE, BUT I KEEP DOING MORE INTERESTING THINGS EACH YEAR I'M THERE. SO IT'S BEEN QUITE REWARDING. WE CAN DO WHAT WE CAN ON OUR SIDE, IF WE WILL, TOO REGULATE THESE PRODUCTS AND SUPPORT THE INDIVIDUALS, THAT DEVELOP THESE PRODUCTS, SO WE'RE IN PART, IF YOU WILL, WE'RE ARE A PART OF THAT HUGE PUZZLE. THE IMPORTANT PHRASE HERE IS TO PROTECT THE PUBLIC HEALTH AND [INDISCERNIBLE] TO MINORS, THE HOOK THAT ALLOWS THE CENTER FOR TOBACCO TO PERFORM ITS REGULATORY ROLE. WE ALSO HAVE A LARGE ROLE IN COUNTER TERRORISM, WORKING REALLY CLOSELY WITH BARTA AND OTHER AGENCIES. THERE ARE CLEARLY, IN MY CENTER, A LOT OF VACCINES, A LOT OF DRUGS — EXCUSE ME — A LOT OF BIOLOGICS IMPORTANT RELATED TO MULTIPLE COUNTER TERRORISM, POTENTIAL VEHICLES. AND AGAIN, FOSTERING DEVELOPMENT OF MEDICAL PRODUCTS TO RESPOND TO — WE DEAL WITH PUBLIC HEALTH THREATS ALL THE TIME. THE LATEST ONE WOULD BE THE XECA VIRUS. — ZICA VIRUS. THOUGH THE AGENCY MOBILE MOBILIZES AND COORDINATES ITS ACTIVITIES, ACROSS THE BOARD. SO WE ARE ALSO RESPONDING TO CREATE HUMAN MERGING PUBLIC HEALTH 38. SOME MAKE THE NEWS LIKE OTHERS DO, AND PERHAPS THOSE AREN'T AS PROMINENT BUT ARE AS IMPORTANT AS WELL. THESE THREE CENTERS, CENTER FOR BIOLOGICS, DRUGS AND DEVICES, REALLY FORM THE MEDICAL PRODUCTS AND REGULATE THOSE THREE TYPES OF PRODUCT THAT IS CLOSELY INTERACT. ONE OF THE MOST IMPORTANT AND INTERESTING AND CHALLENGING FIELDS OVER THE YEAR CITIZEN DEVELOPMENT OF COMBINATION PRODUCTS. COMBINATION PRODUCTS ARE A MIXTURE OF A BIOLOGIC DRUG, A DRUG OR DEVICE, OR BIOLOGIC DEVICE, THESE ARE CLEARLY AT FOREFRONT OF MANY FOREFRONTS AND INTERACTIONS BETWEEN THE TWO, ESPECIALLY FOR EXAMPLE, BIOLOGICS AND DEVICES ARE INCREDIBLY CHALLENGING. UNFORTUNATELY, BUT REALITY IS THAT TRAGIC EVENTS THROUGHOUT THE HISTORY OF THE REGULATION OF PUBLIC HEALTH IN THIS COUNTRY, ESPECIALLY AS RELATED TO DRUGS, BIOLOGICS AND DEVICES AND THIS ONE FOCUSES ON DRUGS AND LI LOGICS, IS PRECIPITATED BY TRAGEDY. SOME TRAGIC EVENTS ARE SHOWN HERE. WHAT GAVE US THE BIOLOGIC CONTROLS ACT OF 19 INTERIOR 2, HAD TO DO WITH CONTAMINATED HORSE SEAROOM. TETANUS ANTISERUM WAS RAISED AND ADMINISTERED IN POARCE HORSES TO PRODUCE THE ACTUAL ANTISERUM FOR THE PRODUCT. AND THE HORSE JIM, WHICH WAS ACTUALLY NAMED JIM, WAS CONTAMINATED AND RESULTED IN THE DEATH FROM TETANUS BECAUSE THE HORSE WAS CONTAMINATED IN AVIETTE OF CHILDREN ACROSS THE COUNTRY. THAT PRECIPITATED THE BY LOGICALS CONTROL ACT OF 1982. WHICH IS THE SECOND OLDEST BIOLOGICAL OR ACTUAL DRUGAC IN THE WORLD, AT LEAST IN MODERN HISTORY. ALL KINDS OF WORTHS CLAIMS, THERE ARE TONS OF EXAMPLES, THAT LED TO THE FOOD AND DRUG ACT IN 1906, WHICH REQUIRED THEM TO HAVE SOME LEVEL OF SAFETY. NOT EFFICACY. THERE WAS A REALLY TRAGIC EVENT WITH GLYCOL CONTAMINATION OF [INDISCERNIBLE] WHICH LED TO THE FEDERAL FOOD AND DRUG COSMETIC ACT OF 1938 AND THE CUTTER INCIDENT WHERE 268 CHILDREN WERE CONTAMINATED WITH THE VACCINE AGAINST POLIO. THIS CREATED A DIVISION OF BIOLOGICAL STANDARDS WHICH WAS ORIGINALLY HOUSED AT NIH. IT WASN'T UNTIL MANY YEARS LATER, THEY I DON'T UNDERSTAND AND BECAME UNDER THE FOOD AND DRUG ADMINISTRATION. SO THE CENTER FOR BIOLOGICS, UP UNTIL THE LAST FEW YEARS WAS HOUSED AT N.I.H. CAMPUS, REALLY HAS ITS ORIGINS IN THE LABORATORIES, ACTUALLY, THAT CAME OUT OF NIH. WHEREAS THE DRUGS CAME FROM A WHOLE SERIES OF LABORATORIES AND DIFFERENT LEGISLATIVE APPROACHES. HERE'S SOME MORE. THE MORE RECENT ONE, WHICH LED TO THE KEY FAULT OFIN' ACT OF 1962. IT DOESN'T JUST HAVE TO BE SAFE, IT HAS TO HAVE SOME DEMONSTRATION OF EFFICACY. MORE RECENTLY, SINAI POISONING, TYLENOL CAPSULE, WHICH LED TO THE ANTI-TEMPERING ACT OF 1993, AND THERE HAVE BEEN REGULATIONS RELATED TO COUNTERFEITING, WHICH HAS LED TO SOME RECENT LEGISLATION NOT SHOWN ON THIS SLIDE, RELATED TO TRACING THE, IT'S CALLED THE CHAIN, IF YOU WILL, THE CHAIN OF PRODUCTS AS THEY'RE MARKETED FROM THE PREFERRURE, ALL THE WAY THROUGH ITS CENTRAL AMERICA TO THE END CONSUMER, THAT'S LED TO A WHOLE SERIES OF LEGISLATION AS WELL AND A WHOLE SERIOUS OF ADDITIONAL REGULATION, WHICH ACTUALLY HAS TO TRACE F YOU WILL, THE HISTORY OR THE DISTRIBUTION OF THESE VARIOUS PRODUCTS. THIS IS A VERY COMPLEXED SLIDE, WHICH I CAN EASILY SUMMARIZE BY SAYING, AND THESE ARE THE VARIOUS PRODUCTS, EITHER DRUG OR BIOLOGIC. AND THESE ARE SOME OF THE REGULATORY AUTHORITIES THAT ACTUALLY EXIST. I'M NOT SURE, THIS CHART MAY BE IN THE CHAPTER THAT WAS WRITTEN BY SOME FOLKS IN THE CENTER FOR BIOLOGICS. THE EASIEST WAY TO THINK ABOUT THIS IS TO SAY THAT BECAUSE THE WAY THE LAWS ARE WRITTEN, ALL BIOLOGICS ARE ACTUALLY CONSIDERED DRUGS SO THEREFORE, THEY'RE COVERED BY ALL THE REGULATIONS FOR THE MOST PART, THAT A BIOLOGICAL PRODUCT WOULD HAVE. IN ADDITION, THERE ARE SOME VERY SPECIFIC LEGISLATION THAT ACTUALLY COVERS BIOLOGICS. AND SO HERE ARE A WHOLE SERIES OF LEGISLATIONS, IF YOU WILL, UP HERE THAT COVER THE REGULATION OF BIOLOGICS AND BASICALLY, FOR THE MOST PART, WITH THE EXCEPTION OF THE YENISH ERIC DRUG STATUTES, ALL THE — YENISH ERIC DRUG S.S, ALL THE DRUGS PRETTY MUCH COVER BIOLOGICS, AND THE BIOLOGICS HAVE THE PUBLIC HEALTH SERVICE ACT, WHICH COVERS BIOLOGICS. WITH THE EXCEPTION OF THOSE, MOST OF THE LEGISLATION COVERS BOTH TYPES OF MEDICAL PRODUCTS, AND I'LL COVER SOME OF THESE IN A LITTLE BIT MORE DETAIL. ONE OF THE MORE RECENT LEGISLATION THAT WAS PASSED WAS THE BIOLOGICAL PRICE COMPETITION AND INNOVATION ACT OF 2010 AND WHAT THAT REALLY GAVE US WAS A PATHWAY KNOWN AS "BIOSIMILARS." SO FOR MANY, MANY YEARS, WE HAD THE LEGISLATION THAT ALLOWED FOR THE GENERIC EQIVALENCE OF DRUGS. DRUGS ARE PRODUCED BY MU MANUFACTURERS, THEY ABOUT THROUGH PATENT PROTECTIONS, WHICH WE REALLY DON'T GET THAT MUCH INVOLVED W UNTIL THEN, EVERY — UNTIL THE PASSAGE OF THIS BIOLOGICAL PRICE COMPETITION ACT, EVERY BIOLOGIC, BASICALLY HAD TO HAVE ITS OWN NEW APPLICATION. THIS, ALLOWS FOR A PATHWAY OF BIOSIMILAR PATHWAY APPLICATION WHICH ALLOWED US TO REFERENCE THE INNOVATOR PRODUCT, THE PRODUCT THAT WAS NORM LEGALLY PASSED AND APPROVED UNDER ITS OWN SET OF DATA. ALLOWED US TO BASICALLY REFERENCE THOSE INNOVATIVE PRODUCTS TO RELY ON SOME OF THAT INFORMATION THERE AND AS A RESULT OF THAT, THAT PATHWAY HAS BEEN EXPANDING OVER THE LAST SEVERAL YEARS SINCE 2010. IT DID SOME OTHER THINGS ABOUT DEFINING WHAT IS THE BIOLOGICAL PRODUCT AND TALKED ABOUT GIVING SOME EXCLUSIVITY PROVISIONS. SO ONE OF THE BENEFITS OR PROVISIONS A CHEMICAL DRUG, YOU CAN'T HAVE A GENERIC MADE FOR SO MANY YEARS ON THE MARKETINGS BECAUSE OF PATTEN PROTECTION, SIMILAR THING WOULD WITH LI LOGIC. IT ALLOWED EXCLUSIVITY PROVISION THAT IS NO ONE COULD CREATE A BIOSIMILAR PRODUCT OF THE INNOVATOR PRODUCT FOR SEVERAL YEARS AFTER THAT INNOVATOR PRODUCT WAS APPROVED. BUT THIS IS ANOTHER GOOD EXAMPLE OF HOW A LEGISLATIVE INITIATIVE HAVE CAUSED US TO BASICALLY FROM SCRATCH, ALMOST, THINK ABOUT WHAT IS THAT MEAN TO SET UP HOW YOU'RE GOING TO REGULATE THESE PRODUCTS AWAY. DOES IT MEAN FOR OUR POLICY, OUR LEGAL APPROACH. WHAT DOES IT MEAN FOR ALL THE GUIDANCE, THAT WE HAVE TO USE TO TELL WORLD CAFE, IF YOU WILL, AND ANYONE WHO'S INTERESTED ABOUT HOW WE'RE GOING TO APPROACH THIS PROBLEM. HOW ARE WE GOING TO INTERPRET THIS LEGISLATION. AND IT REALLY STARTED FROM THE GROUND UP, AND IT WAS A MAMMOTH AMOUNT OF WORK. THERE ARE MANY, MANY PRODUCTS, PHILADELPHIAING THE BIOSIMILAR PATHWAY, FOR THOSE INNOVATOR PRODUCTS THAT ARE NO LONGER COVERED BY PATENTS. AND TO DATE, I BELIEVE, ONLY ONE HAS BEEN ACTUALLY APPROVED FOR MARKETING AUTHORIZATION WE HAVE USED SOMETHING CALLED "USER FEES" AN APPROACH USED IN SEVERAL GOVERNMENT AGENCIES, WHERE IS CERTAIN PEOPLE PAY FEES IN RESPONSE, THEY GET WHAT'S KNOWN AS A "FEE PER SERVICE." SO THE FIRST USER FEE THAT WE HAD WAS NOT ACTUALLY SHOWN HERE, IS BRING DRUG USER FEE ACT. WE APPROVED THE FIFTH VERSION OF WE HAD THE BIOSIMILAR USER FEES AND SO ON, AND SO FORTH. EVERY FIVE YEARS, THESE GO UP FOR NEGOTIATION AND THE FDA AND INDUSTRY NORTHS THESE WITH INPUT FROM VARIOUS CONSUMER GROUPS AND OTHER THINGS. IT REQUIRES CERTAIN SERVICES ARE COVERED BY FEES. AND OTHER SERVICES ARE NOT. AT LEAST IN TERMS OF INDIVIDUAL WHO IS SUBMIT CERTAIN APPLICATIONS MAY HAVE TO PAY A FEE OR IN SOME CASES, THEY ARE WAIVED. FOR EXAMPLE, IND'S DO NOT HAVE TO PAY FEES. INVESTGRATIONAL NEW DRUG APPLICATION: HOWEVER, THE MARKETING AUTHORIZE, A DLA, FOR EXAMPLE, BIOLOGIC LICENSE APPLICATION THAT WOULD FALL UNDER PDUFA. AND CERTAINLY ABOUT ALL THE NEW INNOVATIVE DRUGS WOULD HAVE TO PAY A MARKETING FEE FOR THEIR MARKET APPLICATION. THERE ARE EXCEPTIONS LIKE GOVERNMENT INSTITUTIONS WHEN, ACTUALLY PUT THESE FORWARD. IF YOU HAVE A TRUE ORPHAN PRODUCT, YOU DON'T HAVE TO 58 FEE. IF YOU'RE A MALL BUSINESS. YOU CAN ACTUALLY GET A WAIVER. SO THERE ARE EXCLUSIONS BUILT INTO THE WALL, WHICH COMPANIES AND, SYSTEM HAVE TO PAY THOSE FEES BUT THOSE FEES FROM PDUFA REALLY FUND A LOT OF OUR PROGRAMS. THESE FEES WOULD BE USED TO PAY FOR REVIEWERS, WHO WORK WITH IND'S OR OTHER POST APPROVAL KIND OF THINGS. SO IT'S ACTUALLY BEEN REVOLUTIONARY. WHAT THIS GAVE US 26 YEARS AGO IS A LOT MORE PREDICTABILITY. IT GAVE US FUNDING TO EXPAND THE AMOUNT OF REVIEWER THAT IS FDA NEEDED AND INSPECTS AND EVERYTHING ELSE. RIGHT NOW, IT COVERS ROUGHLY, ABOUT HALF OF OUR OPERATING EBBING PENCES, GIVE OR TAKE. SO IT'S A SUBSTANTIAL POURING OF OUR REVENUE AND GIVES PREDICTABILITY AND THEY'RE VERY STRUCTURED AND IT ALLOWED, YOU KNOW, MORE FORMALIZED MEETINGS TO OCCUR AND SO ON AND SO FORTH. SO THEY ARE A VERY INVOLVED BUT GAVE US A LOT OF FOUNDATION AND STRUCTURE. WE'RE DOING THE SIXTHTH VERSION, FOURTH VERSION, SECOND VERSION AS WE SPEAK. SO HERE'S ONE EXAMPLE, AUTISMIFIED PRODUCT LIFE CYCLE, IF YOU WILL. THERE'S ONE IN THE BOOK CHAPTER WHICH WE'LL TALK ABOUT LATER. THIS IS A SIMPLE ONE, AND HOPEFULLY, MOST PEOPLE SHOULD BE FAMILIAR WITH THIS. THERE'S SOME KIND DISCOVERY CALLED A PRECLINICAL PHASE. WE CALL IT A PRE-IND OR PRE-INVESTIGATAL NEW DRUG APPLICATION. THAT WILL BE THE FIRST EXPERIENCE YOU MAY HAVE WITH F.D.A. WE GO THROUGH CLINICAL DEVELOPMENT, WHICH IS TRADITION TRADITIONALLY, KNOWN PHASE 1 THROUGH 3, WE HAVE A MARKETING AUTHORIZATION, A BIOLOGICAL LICENSE APPLICATION THAT YOU WOULD SUBMIT AND IF APPROVED, WOULD ALLOW YOU TO MARX THAT DRUG OR LI LOGIC, AS AN APPROVED DRUGS. WE HAVE A LARGE POST APPROVAL ISSUE WHERE WE CAN REGULATE INTERACT WITH THE COMPANIES FOR LOTS OF CHANGES. MOST OF THE DISCOVERY PRECLINICAL IS DONE IN A COMPANY'S OR INVESTIGATOR'S SPHERE, IF YOU WILL. WE HAVE ABILITIES TO HAVE MEETINGS THROUGHOUT THESE ENTIRE PROCESSES AND INTERACTIONS. YOU CAN, REQUEST, FOR EXAMPLE, A PRE-IDN. YOU WOULD COME IN AND REQUEST A MEETING FOR PRE-I.N.D. THESE ARE THE ISSUES I WISH TO TALK ABOUT. SO ON AND SO FORTH. AND THE VARIOUS MEETINGS ARE CLASSIFIED. WE HAVE TO GIVE YOU A MEETING WITHIN SO MANY MONTHS AND YOU HAVE TO [INDISCERNIBLE] WITH PACKAGES AND SO FORTH. BUT PRE-IND'S ARE USEFUL, ESPECIALLY FOR NOVEL PRODUCTS OR PRODUCTS THAT ARE CHALLENGING, NEW REGULATORY THINGS THAT WE HAVE SEEN, THAT WE HAVEN'T HAD TO ADDRESS. THAT HAPPENS A LOT IN BIOLOGICS, ACTUALLY, SO YOU WOULD REQUEST A PRE-IND MEETING. WE HAVE A NEW GENE THERAPY PRODUCT. WE'RE REALLY NOT SURE WHAT'S THE APPROPRIATE PHARMACOLOGY THAT WE NEED TO FOLLOW. THAT MAY BE A SUBJECT OF A PREIND MEETING. HOW ARE WE GOING TO DETERMINE THE POTENCY OR THE BIOLOGICAL ACTIVITY. SO THOSE TYPES OF MEETINGS ARE HELD AT A PRE-IND MODEL. THOSE ARE THE ONLY ZACHS WE WOULD HAVE AS AN AGENCY AT THAT POINT IN TIME. SO IF YOUR BIOLOGIC REQUIRED YOU TO SUBMIT AN IND, YOU WOULD SUBMIT IT AT THIS PHASE. LAW REQUIRES US TO ACT WITHIN 30 DAYS OF YOU SUBMITTING THAT INVESTIGATIONAL DRUG APPLICATION TO BASICALLY, STOP YOU FROM GOING INTO YOUR CLINICAL STUDY. WE HAVE 30 DAYS TO, IT'S ACTUALLY ONE OF THE FEW LAWS THAT'S WRITTEN THAT WAY. WE HAVE TO PUT YOU ON TO CLINICAL HOLDS, AND I'LL COVER NA IN A MINUTE OR YOU CAN PROCEED INTO CLINICAL STUDIES AT THAT POINT. TRADITIONALLY, YOU GO THROUGH THESE PHASES, WHICH WE'LL TALK ABOUT AND ASSUMING THAT YOUR BIOLOGICAL PRODUCT SHOWS EFFICACY AND SAFETY AND YOU CAN CONSISTENTLY MANUFACTURE AND MEASURE THE PRODUCT, YOU WOULD APPLY FOR A BLA. LI LOGICAL LICENSE APPLICATION. IF APPROVED, WE WOULD THEN HAVE INTERACTION WITH US, DURING THE POST LICENSING PHASE. YOU'RE GOING TO BE MAKING MANUFACTURING CHANGES. THERE'S GOING TO BE OTHER SAFETY COMMITMENTS YOU HAVE MADE DURING THE B.L.A. STAGE, PERHAPS RELATED TO PEDIATRICS OR CERTAIN SUBPOPULATIONS AND THOSE STUDIES, AS WELL AS ANNUAL REPORTS WOULD COME IN AND WE WILL CONTINUE TO HAVE THOSE INTERACTIONS WITH YOU. AGAIN, AS YOU ALL KNOW A VERY SMALL PERCENTAGE OF IND'S, ACTUALLY MAKE IT TO THE BLA STAGE AND ALTHOUGH WE'RE ONLY GOING TO TALK ABOUT LI LOGICS. WHAT I'M TELLING YOU, ALSO APPLIES TO YOU CAN DOCTORS. THE VICES ARE A LITTLE BIT DIFFERENT. THEY HAVE DIFFERENT REGULATORY AUTHORITIES. DON'T AUTOMATICALLY ASSUME WHAT I'M TELLING YOU, APPLIES NECESSARILY TO DRUGS. SO THAT'S ONE WAY IN WHICH YOU'RE GOING TO TALK WITH US, AND INTERACT WITH YOU THOUGHT ALL OF THESE AREAS AND WE'LL HAVE — YOU'LL HAVE CERTAIN MEETINGS AT KEY DEVELOPMENTAL POINTS DURING YOUR INVESTIGATION AT TRIALS AS WELL. OKAY. I'M NOT GOING TO GO THROUGH THIS. THERE'S A WHOLE SERIES OF REGULATIONS THAT ARE LISTED HERE THAT TALK ABOUT LABELING AND ADVERTISING. IF YOU'RE STARTING OUT IN AN INVESTIGATIONAL AREA, THIS IS GOING GOING TO BE THE MOST IMPORTANT ONE. THE INVESTIGATIONAL. REGULATION THAT IS FOCUS ONLY ON BIOLOGICS AND THERE'S A LEGAL DEFINITION FOR WHAT A LI LOGIC IS. IF YOU'RE NOT SURE, THERE ARE PROCESSES CALLED "DESIGNATION PROCESSES" WHERE YOU CAN SAY, YES OR MY PRODUCT IS A BIOLOGIC. OR NO, IT'S A DEVICE. THESE THESE ARE THE EDUCATION LAYING THAT IS DERIVE FROM OUR LAWS. AND WE PROMULGATE THROUGH FORMAL PROCESSER THAT SAY, THIS IS HOW WE'RE INTERPRETING THE LAW AND I'LL EXPLAIN THAT IN A SECOND. WHEN YOU GET TO OTHER AREAS, THAT ARE ALSO VERY IMPORTANT. ENVIRONMENTAL IMPACT CONSIDERINGS. PROTECTION OF HUMAN SUBJECTS, CLEAR, WHICH IS PERSON IN YOUR EARLY IND STAGES, FOOTAGE DISCLOSURE BY CLINICAL INVESTIGATORS, THAT'S BECOME A GREATER PROM NANCE. IN ORDER TO HAVE AN IND. YOU HAVE TO GO THROUGH AN INSTITUTIONAL REVIEW BOARD AND THAT WILL BE LOOKED AT AS PART OF YOUR IND. AND IF YOU'RE DOING CERTAIN TYPES OF NONCLINICAL LABORATORY STUDY THAT IS IMPACT A SAFETY, YOU'LL HAVE TO FOLLOW THE GOOD LABORATORY PRACTICE SECTIONS. AGAIN, THEY'RE LIKE ANY KIND OF GOVERNMENT REGULATION. THEY'RE GENERALLY VERY PRESCRIPTIVE. BUT THIS IS THE REALLY IMPORTANT SLIDE YOU'RE GOING TO NEED TO LOOK AT AND THINK ABOUT. WE REALLY HAVE VERY FEW LAWS, AS I'VE SEEN YOU ON PREVIOUS SLIDES. THERE'S MANY OF THEM OVER TIME, BUT THEY'RE VERY BROAD AND GENERALLY, NOT TERRIBLY SPECIFIC. OCCASIONALLY, THAT INCH WHATS. WE PROMULGATE, AS I MENTIOND TO YOU, THROUGH A WHOLE NOTICE AND COMMENT AND RULE MAKING PERIOD TO DETERMINE THOSE REGULATIONS. THOSE THINGS THAT ARE EVENTUALLY PUBLISHED IN THE FEDERAL REGISTER EVERY YEAR OR PERIODICALLY, AS THEY ARE PROMULGATED. SO THE REGULATIONS AGAIN, ARE MORE PRESCRIPTIVE, IF YOU WILL, THAT TELL US HOW WE'RE GOING TO INTERPRET THE LAWS. WHAT FDA ALSO DOES, THERE ARE THOUSANDS OF THESE, IS PROMULGATE WHAT IS KNOWN AS GUIDANCE. THAT ALSO GOES THROUGH A PERIOD OF COMMENT AND NOTICE. OUR REGULATIONS ARE, YOU KNOW, THIS IS THE LAW AND YOU OF COURSE, HAVE TO FOLLOW THE LAW. THE REGULATIONS FOLLOW THE LAW, AND YOU GENERALLY NEED TO FOLLOW THOSE, WITH RARE EXCEPTIONS. THE GUIDANCE PRETTY MUCH TRIBES TO ANYONE WHO'S INTERESTED, THISES OUR CURRENT THINKING ON HOW YOU CAN PLY WITH THE REGISTER REPORTSES AND LAW. IT IS NOT A REQUIREMENT. WHEN YOU LOOK AT A GUIDANCE, THERE ARE OTHER WAYS IN WHICH YOU FEEL YOU CAN COMPLY WITH THAT REGULATION OR LAW, THAT'S COMPLETELY FINE. THE GUIDANCE DOES BIND FDA IN THAT IF THAT GUIDANCE IS APPLICABLE AND HERE'S A WAY YOU CAN APPROACH THE SITUATION OF THE PROBLEM AND YOU FOLLOW THAT, THEN WE HAVE TO SAY THAT'S ACCEPTABLE. THE ONLY EXCEPTION WOULD BE IF THERE'S A SAFETY ISSUE OR IT'S NOT SCIENTIFICALLY VALID OR WHAT WE'RE SAYING REALLY DOESN'T BELONG TO YOUR PARTICULAR PRODUCT OR CLASS OF PRODUCT. THE OTHER THING THAT HAS BECOME IMPORTANTLY INCREASING OVER THE LAST YEAR ARE STANTIALS, AND THESE STANDARDS ARE — ARE STANDARDS, AND THERE ARE THESE STANDARDS DEVELOPMENT ORGANIZATIONS. THEY ARE EXTERNAL TO THE FDA, ALTHOUGH MANY TIMES, WE INTERACT WITH THEM X PROVIDE INPUT INTO THOSE STANDARDS. WHAT ATTAINDER IS, AND A GOOD EXAMPLE MAY BE WELL, IT USED TO BE IN THE OLD DAYS F I FILED A CERTAIN STANDARD AND I BASICALLY DID MY STERILITY THIS WAY FOR CERTAIN TYPES OF PRODUCTS, IT WAS GENERALLY CONSIDERED ACCEPTABLE. SO THAT WOULD BE AN EXTERNAL STANDARD, PROMULGATED BY AN ORGANIZATION THAT WE FELT COMFORTABLE, SO IT APPLIED TO YOUR SITUATION, YOU COULD USE THAT STANDARD. THERE ARE A LOT STANDARDS BEING DEVELOPED. ANOTHER EXAMPLE WOULD BE HOW YOU KWAN STATE CERTAIN TYPES OF MARKER SURFACE MARKERS USING [INDISCERNIBLE] TOMETRIES. AND IF YOU FOLLOW THAT STANDARD AND IT'S APPLICABLE TO YOUR PARTICULAR SITUATION, IT CAN BE USED FOR TO YOU KWAN STATE HOW YOU'RE GOING TO MEASURE CERTAIN RECEPTORS ON THE SURFACE OF THE CELL AND SO O. AND THE STANDARDS ARE VERY BROAD. THEY ARE IN ALL AREAS. THEY ARE IN CONTENT AREAS, IF YOU WILL, TECHNICAL AREAS ABOUT HOW YOU MANUFACTURE A PRODUCT. THERE ARE ALSO CLINICAL STANDARDS, AND I'LL TALK ABOUT AT THE END, THERE ARE ALSO STANDARDS NOW THAT YOU HAVE TO FOLLOW, IN ORDER TO SUBMIT SUBMISSIONS ELECTRONICALLY. SO THESE ARE VERY USEFUL FOR US AND IN THE MEDICAL PRODUCTS AREA, THE DRUGS AND THE BIOLOGICS. WE HAVE TYPICALLY BEEN USING THESE MORE AND MOREOVER THE YEARS. LASTLY, THERE ARE INTERNAL THROUGHOUT AGENT, OUR VARIOUS POST NATALS AND OUR PRECEDENCE, SO OUR POLICIES, A LOT OF THESE MAY RELATE TO PROCESS. FOCT'S. THOSE ARE PUBLICLY SO IF YOU REALLY WANT TO SEE HOW YOUR APPLICATION IS GOING TO BE ADDRESSED OR YOU OR YOU FILE FOR A MEET IT DETAILS HOW WE'RE GOING TO HANDLE YOUR REQUEST FOR A MEETING AND SO ON AND SO FORTH. THE PRECEDENCE THAT RELATE TO HOW WE'RE GOING TO HANDLE YOUR PARTICULAR PRODUCT WHEN THERE'S AN ISSUE RELATED TO POTENCY, HOW DO I DETERMINE POTENCY FOR THIS SUBSET OF A CELL, THAT'S GOING TO BE HARDER TO FIND. YOU MAY SEE IT IN SOME OF THE REVIEWS SO THE REVIEWS OF A BLA OR MARKING APPLICATION ARE POSTED AND THEY'RE FREELY AVAILABLE. IN A PUBLIC ADVISORY COMMITTEE, THEY MAY BE DISCUSSED THERE. IN A LOT CASES YOU WON'T SEE THAT GUIDANCE, HOW CAN YOU APPLY THE REGULATIONS, STANDARDS IS A WAY YOU CAN COMPLY WITH POLICIES AND STANDARDS. AND THE THING THAT'S REALLY CRITICAL, TOO IS TO LOOK AT WHAT THIS LAW SAYS, WHAT IS THE CURRENT SCIENCE SAYING AND WHAT'S THE RISK. THERE'S BEEN A GREATER EMPHASIS OVER THE LAST SEVERAL YEARS ON RISK AND THE PUBLIC COMMUNICATION. RISK TO A PRODUCT. RISK TO SUBPOPULATIONS OF PATIENTS. WE DEAL WITH FROM FOR BIOLOGICS. OF THINGS THAT ARE LITERALLY IN THE LABORATORY, AND IN THE CLINICS. WE ARE RIGHT AT THE CUSP OF SCIENCE. SO HOW WE USE ALL THESE THREE THINGS, ARE IMPORTANT. IT'S IMPORTANT THAT YOU LOOK AT THE INDIVIDUAL SCIENCE AND RISK FOR EACH PRODUCT OR CLASS OF PRODUCTS COMING ACROSS THE BOARD TO MAKE THOSE DETERMINATIONS. THIS COVERS WHAT I JUST SAID, I'M NOT GOING TO GO THROUGH T. IT'S A RECOMMENDATION. WE FOLLOW A PROCESS, KNOWN AS GOOD GUIDANCE THAT ALLOWS FOR PUBLIC COMMENT. YOU CAN FIND ANY OF THESE ON THE VARIOUS WEBSITES, AS THEY COME THROUGH. SO WHAT'S AN I.N.D. IT'S THE FIRST THING YOU'RE GOING TO FILE, AND IF A DRUG OR BIOLOGICAL USED IN THE CLINICAL INVESTIGATION, DOES NOT APPLY TO USE OF AN APPROVED PRODUCT, UNDER THE PRACTICE OF MEDICINE. THAT CAN GET A LITTLE DICEY AT TIMES WHAT, IS AND WHAT IS NOT. YOU ARE EXEMPT FROM ALL THE PREMARKETING REQUIREMENTS. THEREFORE, IF YOU VETERANNA I.N.D. YOU CAN SHIP IS LAWFULLY IN INTERSTATE COMMERCE. ANYTHING THAT GOES IN INTERSTATE COMMERCE OR ANYTHING THAT'S USED IN THE MANUFACTURER OF YOUR INVESTIGATIONAL NEW DRUG, AND INTERSTATE COMMERCE, GIVES US OUR REGULATORY AUTHORITY. YOU FILE AN I.N.D. THIS IS JUST A COVER PAGE, WHICH IS ACTUALLY TOO OLD YOU CAN HAVE A DISCUSSION WITH US WHETHER IT DOES OR DOES NOT. INTERNATIONAL CONFERENCE FOR HARMONIZATION. WE ADOPT THESE GUIDANCES, FROM THE: ANDIA PAN SO IF YOU'RE GOING TO CONDUCT A CLINICAL STUDY, IT'S THE LEVEL OF THIS GUIDANCE WILL PRETTY MUCH FOLLOW THE SAME APPROACH. AND IT TALKS ABOUT VARIOUS THINGS, RELATED TO CLINICAL TRIALS, WHAT MAJOR THINGS SHOULD BE IN AN I.N.D. WHAT INVESTIGATOR'S BROCHURE SHOULD LOOK LIKE. SO I SUGGEST YOU LOOK AT THOSE IF YOU'RE REALLY GETTING INTO CLINICAL TRIALS. SUBPART B TALKS ABOUT ALL THE THINGS UP HERE WHICH I'M GOING TO COVER IN DETAIL A LITTLE BIT MORE. WHAT HAS TO BE IN ONE. THERE ARE TONS OF GUIDANCES OUT THERE. THAT REALLY TELL YOU WHAT YOU NEED TO PROVIDE IN THAT, RELATED TO THE YOUR CLINICAL STUDIES, RELATED TO YOUR INVESTIGATOR'S BROCHURE AND WE'LL COVER THESE IN A FEW MINUTES. SO PHASE 1 STUDY. TRADITIONALLY, AND IN ADDITION IS OFTEN CHANGING A LOT THESE DAYS W GREATER EMPHASIS ON ORPHAN PRODUCTS WHERE THERE ARE HALLER NUMBER OF PATIENTS OR BECAUSE WE HAVE UNMET MEDICAL NEEDS FOR DRUGS AND BIOLOGICS. SO THIS CLASSIC WAY OF DEVELOPING THINGS IS NOT NECESSARILY THE SAME. THEY MAY BE ACCELERATED OR THE VARIOUS PHASES MAY BE COMBINED. IF YOU WANT TO TAKE SOMETHING AWAY FROM THIS COURSE, THAT'S SORT OF WHAT WE'RE SEEING IN MANY AREAS. BUT TYPICALLY ANDING FROMALLY LOOKS A PHASE 1 STUDY WOULD BE A VERY SMALL NUMBER OF SUBJECTS. FIST OR LES, MAYBE A LITTLE BIT MORE. THE REAL FOCUS IS, IS IT TOLERABLE. AND DO YOU GET ANY EVIDENCE OF ACTIVITY OR EFFICACY. AND YOU MAY BE DOING SOMETHING ABOUT THE ELATION, WHICH IS HARD WHEN YOU'RE EXERTING A BIOLOGICAL EFFECT WITH YOU CAN DOCTORS. IF YOU SUCCESSFULLY NAVIGATE THOSE STUDIES, YOU MAY HAVE A PHASE 2 STUDIES. ALL THESE AGAIN, YOU'RE GOING TO FOCUS ON SAFETY, THROUGHOUT THE CLINICAL DEVELOPMENT, AND YOU'RE GOING TO BE LOOK AT SOME EVIDENCE OF EFFICACY. IS IT WORKING AND STILL BEING SAFE. AGAIN, STILL DOING SOME MORE [INDISCERNIBLE] ESCALATION AND YOU'RE TRYING TO FIGURE OUT, WHAT AM I LOOKING FOR, HOW AM I ASSESSING THAT ACTIVITY AND SO O. PHASE III AGAIN, IS OFTEN USED TO BE CALLED THE PIVOTAL STUDIES, IF YOU WILL, BECAUSE THEY ARE REALLY GOING TO FORM YOUR BASIS FOR YOUR MARKETING APPLYING. AND HOW THEY'RE DESIGNED REL DEPENDS ON HOW THESE ARE LISTED HERE THEY WERE GOING TO CONFIRM YOUR CLINICAL BENEFIT, REALLY DEFINE THE BENEFIT RISK RELATIONSHIP AND GIVE SOME SENSE OF LABELING. LABELING IS VERY CRITICAL TO THAT PRODUCT FOR MULTIPLE REASONS. PIVOTAL SAFETY AND EFFICACY STUDIES, REALLY FORM THE BASIS FOR THE MARKETING APPLICATION. AND AGAIN, THE GENERAL PRINCIPLE HERE IS YOU'RE ALWAYS ASSURING THE SAFETY AND THE RIGHTS OF THE SUBJECTS, WHICH WHY WE'RE REQUIRING INSTITUTIONAL REVIEW BOARDS, WHICH WHY WE'RE GOING TO LOOK AT YOUR INVESTIGATOR'S BROCHURE, AND FILE AN ANNUAL REPORT OR IN THE CASE OF IMMEDIATE RETURNS REALITIED TO SAFETY OR ADVERSE EVENTS. AND PHASE 2 AND 3, THE QUALITY OF THE DATA IS ADEQUATE FOR THE ADEQUACY AND SAFETY. WE'LL BE USUALLY, PHASE 1 AND 2 STUDIES, OCCASIONALLY, PHASE III STUDIES ON HOLD, UNTIL YOU ADDRESS THE ADDRESS WE'RE RAISING, FOR SAFETY REASONS. IT'S RARE WE PUT SOMETHING ON FOR THE TRIAL THAT WOULD NOT BE ADEQUATE TO ASSESS THE EFFICACY OF THAT PRODUCT. OCCASIONALLY, IT DOES HAPPEN. BUT IT CAN. SO WHAT WOULD BE THE GROUND FOR PUTTING A STUDY ON PHASE 1. THEY'RE ALL LISTED HERE AND PRETTY STRAIGHTFORWARD. IT'S AN UNREASONABLE SIGNIFICANT RISK OF INJURY OR ILLNESS. SO IN OTHER WORDS, IF YOU CAN THINK ABOUT IT BEING A RISK BENEFIT ALMOST. THE CLINICAL INVESTIGATIONS ARE NOT QUALIFIED BY SCIENTIFIC TRAINING EXPERIENCE. YOU REALLY WANT TO TRY SOMETHING THAT IS NO SCIENTIFIC BASIS FOR THE EFFECT YOU THINK IT'S GOING TO HAVE. THE INVESTIGATORS PRO SURE IS MISLEADING, ERRONEOUS, IMMATERIAL OR INCOMPLETE. HOPEFULLY, THAT WON'T GETS BECAUSE THAT'S GOING TO YOUR REVIEW BOARD. OF THE IND DOESN'T CONTAIN INFORMATION TO ASSESS THE RISKS. WELL, YOU DIDN'T DO, YOU KNOW, ESSENTIALLY, PHARMACOLOGY STUDIES THAT WE NEED TO DO FOR THIS TYPE OF PRODUCT AND THAT'S A REALLY PROBLEM WE CAN'T MAKE ANY ASSESSMENTS ON WHAT THAT IS. YOU CAN'T TOLD US WHAT THE [INDISCERNIBLE] ARE IN EUROPE IF YOU CONDUCTED THATTED CLINICAL TRIALS IN EUROPE OR THE LIFE LIFE-THREATENING DISEASES AFFECTS GENDER AND THE TRIAL EXCLUDES GENDER. PEDIATRIC POPULATIONS. GENDERS HAVE BECOME A GREATER EMPHASIS ON CLINICAL TRIALS AND STUDIES AND I'LL TALK A LITTLE BIT MORE ABOUT THAT. SO THOSE WILL BE THE REASONS THAT WE WOULD SAY, YOU CAN'T GO INTO CLINICAL HOLD. AGAIN, PHASE 2 AND 3, ANYTHING I JUST MENTIONED OR AGAIN, THE TRIAL IS REALLY DEEFFICIENT IN THE DESIGN ANSWER THE QUESTION. YOU HAVEN'T POWERED THE TRIAL TO ANSWER THAT. AND ESPECIALLY FOR BIOLOGICAL PRODUCTS. WHERE LOOKING AT SAFETY AS WELL AS REPRODUCIBILITY FROM RAW MATERIALS OR VIRAL BANKS. IT'S A BIOLOGIC, SO IT'S HIGHLY VARIABLE. HOW ARE YOU PRODUCING THIS, WHAT ARE YOU DOING, WHAT'S THE CHARACTERIZATION OF THE PRODUCT. WHAT ARE THE TRAITS YOU HAVE TO SHOW AND BE REPRODUCIBLE, EACH AND OVER TIME YOU MAKE T. PROCESS VALIDATION AND TESTING. AGAIN, THIS IS DONE, SORT OF INCREMENTALLY, YOU HAVE TO HAVE ENOUGH TESTING ON THE INITIAL PRODUCT AND THE PHASE 1 STUDY TO ENSURE THE SAFETY. BUT YOU DON'T HAVE TO NECESSARILY CHARACTERIZE YOUR PRODUCT. CHARACTERIZING YOUR PRODUCT MEANS, OKAY. IT'S, YOU KNOW, IT'S A REDOMINANT BIOLOGICAL PROTEIN AND IT HAS THE FOLLOWING SECONDARY STRUCTURES AND SO O. SO IT'S VARIABLE. DEPENDS WHAT WE KNOW ABOUT YOUR PRODUCT. HOW REPRESENTABLE IS TO OUR EXPERIENCE AND THINGS WE KNOW, AND THINGS OF THAT NATURE. AS YOU MOVE FORWARD THROUGH THE PHASES AND YOU MOVE THROUGH D.L.A. AFTER THE ACCIDENT YOU NEED TO NAIL DOWN THESE THINGS. YOUR PHASE 1 MATERIAL HAS TO BE MANUFACTURED IN COMPLIANCE WITH WHAT'S CALLED GOOD MANUFACTURING PRACTICES, AND THAT'S SPECIFIC REGULATIONS AND THERE'S A PLETHORA OF GUIDANCE THAT TELL YOU WHAT THAT MEANS. IT STARTS OUT AT PHASE 1. THERE ARE SPECIFIC REGULATIONS, THE 211 REGULATION, BUT YOU DO HAVE TO FOLLOW THE GM P'S, YOU DON'T HAVE TO FOLLOW THE REGULATIONS FOR THE PHASE 1 STUDY. THESE TWO 11 REGULATIONS WERE REALLY MEANT FOR MARKETING WHEN YOU HAVE ALL OF THESE THINGS WORKED OUT. AND THERE ARE SPECIFIC REGULATION THAT IS DON'T APPLY TO THE EARLY PHASE OF MANUFACTURING, WHERE YOU'RE TRYING TO FIGURE THINGS OUT. THERE'S A CLEAR GUIDANCE THAT TALKS ABOUT THAT. BUT THAT'S BEEN THE ISSUE OVER THE LAST FIVE, 10 YEARS AGO. SO HERE'S AN EXAMPLE OF A SMALL LABORATORY SET UP, VERSUS PERHAPS A COMMERCIAL KIND OF AN APPROACH. BUT YOU STILL HAVE INSURE THE SAFETY, STABILITY OF A PRODUCT. IF THERE ARE POTENTIAL VIRAL CONTAMINANTS, YOU STILL NEED TO ASSURE THOSE. SO IT DEPENDS UPON WHAT THE PRODUCT IS AND WHAT IS NECESSARY TO ASSURE THAT SAFETY. AGAIN, SOME OF OUR BIOLOGICS LIKE VACCINES ARE MUCH MORE LIMITED TO THE PHARMACOLOGY. THERE'S LESS THAT RELATES TO A PHARMACOLOGY LIKE A DRUG MOLECULE, BUT THERE MAY BE SOME. SO A LOT THAT DATA MAY HAVE TO BE DEVELOPED. THE EFFECTS YOU DON'T WANT FOR REDOMINANT BIOTECHNOLOGY PRODUCTS, IS ALSO VERY PRODUCT — RECOMBINANT BIOTECHNOLOGY PRODUCTS IS ALSO VERY IMPORTANT. THERE'S A TON OF THINGS RELATED TO THE TRIAL DESIGN AND ANALYSIS. AGAIN THAT, STARTS PHASE 1 AND THE DISCUSSIONS ABOUT HOW ARE
ARE YOU GOING TO PROCEED WITH THIS. ARE YOU DOING ESCALATION ON POPULATIONS YOU'RE GOING TO LOOK AT. YOU SUBMIT INFORMATION ON THAT, YOU NEED TO FOLLOW THE BIOMONITORING. AND WE'LL TALK ABOUT THAT AND AGAIN, ESPECIALLY PEDIATRIC DEVELOPMENT, WHICH WILL COVER IN A MINUTE AND INCLUSION OF DEMOGRAPHIC SUBGROUPS. IN PARTICULAR, THE PEDIATRIC DEMOCRAT GRAPHIC SUBGROUPS ARE A GREATER CONCERN AT LOOKING AT WHAT IS YOUR PRODUCT, WHAT ARE YOU INTENDING TO TREAT. COULD IT BE USED IN THE PEDIATRIC POPULATION AND OTHER DEMOGRAPHIC SUBGROUPS. IS THERE A TRIAL REPRESENTATIVE OF A POPULATION THAT WOULD BE USED IN THOSE PRODUCTS. GOOD CLINICAL PRACTICES. I'M NOT FIGURE GOING TO GO THROUGH THIS, BUT THIS TALKS ABOUT KEY I THINK THISES, PROTECTING THE RIGHTS OF THE SUBJECTS IT GIVE US YOU A GOOD FEEL FOR THAT UNDERSTANDING OF WHAT YOU NEED IN THESE CLINICAL STUDIES, WITHOUT GETTING TO THE REGULATIONS AND THINGS OF THAT NATURE. AND THIS IS COVERED HERE. AGAIN, NOTICE THE IRB APPROVAL AS WELL. YOUR INVESTIGATORS ARE QUALIFIED. YOU'LL GIVE US SOMETHING ABOUT YOUR INVESTIGATORS. ARE THEY QUALIFIED MEDICAL FOLKS WITH THE RIGHT TRAINING AND EXPERIENCE TO RUN THESE TRIALS. YOUR DATA'S GOING TO BE PROTECTED AND SO ON. AND THERE ARE ALL KINDS OF HIPAA LAWS THAT AN INVESTIGATOR MAY HAVE TO COMPLY WITH AND SO ON. PROTECTING THE CONTACTORRITY OF RECORDS, USING INVESTIGATIONAL — PROTECTING THE CONFIDENTIALITY OF RECORDS, USING INVESTIGATIONAL PRODUCTS AND GM P'S AND SO O. SO A SPONSOR IS AN INDIVIDUAL WHO ACTUALLY SUBMITS THE I.N.D. APPLICATION. BEING BE A DRUG COMPANY, BY LOGICAL COMPANY OR AN INVESTIGATOR, SOMEONE WHO DOES CLINICAL RESEARCH, FOR EXAMPLE, AN INVESTIGATOR IS THE INDIVIDUAL AT THE CLINICAL SITE WHO IS ACTUALLY RESPONSIBLE FOR THAT TRIAL AT THAT SITE. SO AN INVESTIGATOR'S RESPONSIBILITY IS CONDUCTING THAT TRIAL AT THEIR SITE, ADHERING TOULE AT INVESTIGATIONAL PLANS AND REGULATIONS, MAKING SURE THERE'S APPROPRIATE HUMAN SUBJECTS PROTECTION. TYPICALLY, MAKING SURE INFORMED CONSENT IS OBTAINED. ALL THE CASE HISTORIES RECORDED AND THOSE REQUIREMENTS ARE RETAINING RECORDS FOR THOSE PERIODS OF TIME. TWO YEARS IS A GOOD SENSE AS TO WHAT THAT MEANS, ALTHOUGH THERE ARE DIFFERENCES. THEY ARE RESPONSIBLE FOR CONTROLLING AND DISPOSITION OF THE INVESTIGATIONAL PRODUCTS, OFTEN TIMES, THE HOSPITAL PHARMACY, BUT MAYBE NOT. AND THEY HAVE TO MAKE VARIOUS REPORTS, TOO THAT SPONSE ARE AND LISTED HERE. PROGRESS REPORT SAFETY REPORT, FINANCIAL REPORT. FINANCIALAL DISCLOSURE. A SPONSOR, THEY'LL TYPICALLY HAVE MULTIPLE SITE ANDS THEY'LL COMPILE ALL THAT, AND SUBMIT THAT TO US. IF YOU'RE AN INVESTIGATOR SPONSOR, IT IS YOUR RESPONSIBILITY TO PROVIDE ALL OF THIS INFORMATIONS TO. SO THE SPONSOR, THE INDIVIDUAL WHO SUBMIT THAT IS IND. WHAT IS THEIR RESPONSIBILITY? WELL, THEY'RE GOING TO SELECT THE INSTITUTIONS AND THE INVESTIGATORS THAT CAN PROVIDE ALL THE PI'S SO THEY CAN GET REVIEWED BY THE VARIOUS BOARDS. THEY ARE GOING TO NOTIFY SUBMISSION OF APPLICATIONS AND THEY'RE GOING TO BE THE ONCE TYPICALLY, COMMUNICATING US, NOT VARIOUS INVESTIGATORS AT THE SITES THEY SENDA AUDITORS AROUND TO MAKE SURE THAT INVESTIGATIONAL SITE IS IN COMPLIANCE WITH FOLLOWING THAT PLAN. YOU WILL HAVE INDIVIDUALS FROM A LI LOGICAL COMPANY, VISITING YOUR SITE. INFORM THE FPI'S AND FDA'S OF ADVERSE RISK DRUGS. WE DIDN'T FIND IT IN THIS INVESTIGATIONAL SITE, BUT WE FOUND IT EVERY YEAR. ADEQUATE MONITORING, THAT WILL BE AN AUDIT. INTERACTION WITH FDA. ACTS AS AN INVESTIGATOR IF YOU'RE NOTING THOSE THINGS, YOU MAY BE BARRED IN PARTICIPATING IN OTHER INVESTIGATIONS AND THAT OCCASIONALLY HAPPENS. NOTIFICATION OR SUSPENSION. YOU DECIDE YOU DON'T WANT TO DO THE STUDY ANYMORE. AND THERE'S A VARIETY OF TRIALS, TOO GET FILTERED UP. THEY TAKE RESPONSIBILITY BUT THE INVESTIGATOR CONDUCTS AT THE SITES BUT ARE EQUALLY RESPONSIBLE FOR MANY THINGS. SOME OTHER RESPONSIBILITIES. KEEP THE PI'S INFORMED REGARDING SAFETY AND SO O. THAT'S THE PRINCIPAL INVESTIGATORS. ADVERSE EVENT REPORTING. THINGS HAPPEN AT SITE THAT USUALLY FUNNEL IT UP. QUALITY CONTROL, STANDARD OPERATING PROCEDURES FOLLOWED RELATED TO THE CLINICAL STUDIES. TRIAL AND DATA MANAGEMENT. YEAH, WE'LL BE AT THE SPONSOR SITE. HAVE THEY EMPLOYED A CROAUDITTINGLY AND PROVIDING THE INVESTIGATIONAL PRODUCT TO THE SITE AS WELL. WITH THE FDA AMENDMENTS ACT OF 2007. THERE'S NOW THE CLINICAL TRIALS REGISTRY, CLINICALTRIALS.GOV AND THE REQUIREMENTS FOR POSTING CLINICAL TRIALS AT VARIOUS PHASES OF DEVELOPMENT, AND THEY ARE THIS, ANDY WE ASSURE, AS PART OF OUR REVIEW, THAT THEY ARE IN FACT, COMPLYING WITH THAT AND THEY HAVE TO INCLUDE THE CERTIFICATION FORMS WITH THAT AS WELL. SOME OF THE SITES ARE UP THERE AGAIN, THERE'S AN EXAMPLE OF SOMETHING THAT'S EVOLVED OVER TIME AND SO O. MONITORING, AGAIN, WE HAVE TALKED ABOUT ALL THAT AS WELL. VOIGHT RIGHT OF THE VARIOUS INDIVIDUALS. REPORT THAT THE DATA IS ACCURATE. SPONSORS REQUIRED TO SELECT QUALIFIED MONITORS AND TRAIN THEM. THEY MAY HAVE AN IN-HOUSE, THEY MAY CORRECT ME IF I'M WRONG WITH THE CR OH. IF YOU'RE AN INVESTIGATOR, YOU MAY NEED TO DO SOME TYPE OF AUDITING, THAT IS, IF YOU'RE A SPONSOR INVESTIGATOR, YOU ALSO NEED TO DO SOME OF THOSE THINGS AS WELL, TO MAKE SURE THAT YOUR SITE IS FOLLOWING ALL THOSE VARIOUS TYPES OF REQUIREMENTS. SO WHAT HAPPENS WITH SAFETY. THERE ARE REGULATION THAT IS COVER THIS, AND THERE ARE ALSO GUIDANCES SO IT REALLY DEPENDS UPON WHAT TYPE OF SAFETY OR POTENTIAL ADVERSE EVENTS ARE SEEN, AND WHEN THE INDIVIDUAL VS. TO NOTIFY THAT. WITHIN 15 DAYS, YOU HAVE TO MODIFY US IN WRITING OF A SERIOUS OR UNEXPECTED ADVERSE REACTION, FINDING SOME OTHER STUDIES, SUCH AS ANIMAL STUDY THAT IS MAY SUGGEST SOME PROBLEM. INCREASED RATE OF SERIOUS SUSPENDED ADVERSE REACTIONS, BEYOND WHAT YOU'RE SEEING IN THE PROTOCOLS AND IF THERE'S A SUSPECTED ADVERSE REACTION, YOU HAVE TO NOTIFY US BY 7 DAYS BY TELEPHONE OR FAX. WE STILL HAVE FAX MACHINES, AND WHAT DOES IT MEAN TO BE SUSPECTED? THERE'S A WHOLE GUIDANCE THAT TALKS ABOUT THAT. A SUSPECTED ADVERSE REACTION. ANY ADVERSE FOR WHICH A REASONABLE POSSIBILITY THE DRUG MAY HAVE CAUSED ADVERSE EFFECT. IT MAY NOT HAVE. MANY ARE VERY SICK AND HAVE MULTIPLE COMPLICATIONS BUT IF THERE IS A REASONABLE SUSPICION THAT IT HAPPENED, YOU NEED TO REALLY REPORT THOSE KINDS OF REACTIONS AND THERE'S A GUIDANCE THAT TALKS ABOUT THAT, GIVES THEM A BETTER UNDERSTANDING TO THE INDIVIDUAL INVESTIGATORS OF WHAT THAT MEANS. AGAIN, THINK ABOUT IN THE END, THIS PRODUCT IS GOING TO MARKETING. AND EVEN DURING THE INVESTIGATIONAL STUDY, THERE'S A RISK BENEFIT RATIO, IF YOU WILL, A RISK BENEFIT THAT INDIVIDUAL VS. TO CONSIDER. THERE ARE ANNUAL REPORT THAT IS HAVE TO BE SUBMITTED TO SAFETY AND THEY CONTAIN ALL THE INFORMATION SHOWN HERE, SO BASICALLY, THEY TALK ABOUT WHERE YOU ARE IN THE VARIOUS STUDIES, HOW MANY YOU HAVE. WHAT THINGS YOU'RE SEEING, THIS IS IN ADDITION TO THAT 7 AND 15 DAY RULE. SO THESE WILL SORT OF SUMMARIZE THOSE IN ADDITION TO OTHER THINGS THAT DON'T MEET THOSE LINES. IS THERE SOMETHING COMING UP IN THE FREE CLINICAL STUDY THAT, ITCH GUESS YOU A CONCERN FOR SAFETY. DO YOU NEED TO, IF THERE'S A MANUFACTURING CHANGE. THIS IS ESPECIALLY IMPORTANT FOR BIOLOGICS. SOME OF THOSE MINOR CHANGES CAN HAVE PROFOUND EFFECTS AND IT'S VERY OFTEN, HARD TO PROTECT SOME OF THOSE EFFECTS. WHAT ARE YOU DOING IN THE FUTURE YEAR. IN THE UPCOMING YEAR, IF YOU REVISE THINGS, BASED ON ALL THIS INFORMATION, HERE'S WHAT'S HAPPENING. IS THERE ANYTHING ELSE GOING IN EUROPE ARE YOU RUNNING A TRIAL IN YOU'RE AT THE SAME TIME? IF SO ACCIDENT YOU ARE OBLIGATED TO ITS WHAT'S GOING ON THERE IF YOU'RE PART OF THAT STUDY AND SO ON THERE'S A GUIDANCE THAT RELATES TO EX–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— IT'S EXTREMELY IMPORTANT WE HAVE A WHOLE GROUP OF INDIVIDUAL THAT IS GO OUT AND LOOK AT THE VARIOUS TYPES OF STUDIES TO VERIFY THE DATA SUBMIT TO THE FDA AND SO THEY MAKE SURE, IN ADDITION TO AUDITORS, WE HAVE INVESTIGATORS WHO WILL PERIODICALLY GO AROUND AND LOOK AT VARIOUS TYPES OF CLINICAL STUDIES. IT GETS A THOROUGH, EVERY BLA THAT COMES IN FOR MARKETING, GETS A BIORESEARCH MONITORING REVIEW. HOW YOU COLLECT THE PATIENT REPORT FORMS, ALL THE INFORMATION THAT YOU HAVE IS BASICALLY, THE UNDERPINNINGS OF THE DATA THAT YOU'RE SUBMITTING TO US, TOO SAY THIS PRODUCT IS BOTH SAFE AND EVOLUTIONARY CARIBBEANS. FDA WAS NOT NECESSARILY MAKING IT AS EASY AS THEY COULD BE. FOR INDIVIDUAL CLINICIANS TO USE PRODUCTS AND IIN, D IN EMERGENCY SITUATIONS. IF YOU LOOK AT THE PUBLIC AVAILABLE DATA, WE APPROVE 99% OF ALL REQUESTS FOR BOTH DRUGS AND BIOLOGICS. BUT IT WASN'T NECESSARILY, THE MOST FACT FIELD CLINICIAN WHO WASN'T FAMILIAR WITH HIS APPROACH. SO WE HAVE OVERHAUL THAD SYSTEM. HAD A REALLY QUICK AND EASY ENTRY PORTAL FOR CLINICIANS. MOST OF THE APPROVALS, ONCE THE INFORMATION IS COLLECTED, IT'S BY PHONE. THAT'S HOW FAST AND CRITICAL THEY ARE. THEY ARE DONE WITHIN HOURS, UNLESS THERE'S A REASON NOT TO. WE HAVE FACILITATED THE PAPER PROCESS TO MAKE IT EASIER FOR CLINICIANS TO USE THIS EXPANDED ACCESS. AGAIN, IT'S GOING TO BE IN A SITUATION WHERE THEY'RE USUALLY IND'S THAT ARE OUT THERE ON FILES. WE KNOW AND UNDERSTAND SOME OF THE SAFETY AND THE RISKS OF IT, IT'S GOING TO BE IN A SERIOUS, LIFE THREATENING CONSCIENCE. THE BENEFITS OUT JUSTIFY THE RISKS. IT'S NOT REALLY GOING TO INTERFERE WITH ON GOING TRIALS. THESE ARE INDIVIDUAL PATIENTS, AND IN SOME CASES, WE HAVE OTHER WAYS WHERE THEY MAY BE SET UP ON A RECURRING BASE FOR LARGE, MID-SIZED POPULATIONS WHERE YOU'RE GOING TO DO THIS FOR A LARGE NUMBER OF PATIENTS, PERHAPS, WHILE THE DRUG IS UNDER GOING ITS MARKETING REVIEW. AND FOR SOME PRODUCTS, AND — SORRY. FOR SOME TYPES OF PRODUCTS AND INVESTIGATION, CAN YOU NOW FILE FOR COST RECOVERY. IN OTHER WORDS, THE MANUFACTURE, IF YOU WILL, CAN RECOVER THE COST OF ACTUALLY MANUFACTURING THE PRODUCT AND THERE'S A WHOLE PROCESS FOR OBTAINING COST RECOVERY FOR THESE TYPES OF PRODUCTS. THIS IS ANOTHER WAY OF LOOKING AT THE DRUG AND BIOLOGICAL PRODUCT LIFE CYCLE. IT'S A TEXT BOOK, OUT OF YOUR TEXT BOOK. IT'S A CABLE OR A CHART NEAR THE TEXT BOOK. SO THIS LOOKS AT THE VARIOUS PHASES. HERE'S AGAIN, THE DISCOVERY PRECLINICAL ASSESSMENT. HERE'S THE CLINICAL RESEARCH AND DEVELOPMENT PHASES. HE WAS YOUR MARKETING, YOUR APPLICATIONS, BLA AND POST MARKETING, AND THIS SHOWS IN HERE, SOME OF THE AVAILABLE MEETINGS AND OTHER TYPES OF OPPORTUNITY THAT IS YOU CAN USE TO DEVELOP YOUR PRODUCT. I'LL COVER THESE IN A MINUTE. THESE ARE THINGS THAT HAVE COME UP IN THE LAST 15, 10, EVEN FIVE YEARS, ONE IS EVEN NOT ON HERE. OPPORTUNITIES CAN YOU USE THAT CAN HELP YOU ACCELERATE THE PRODUCT DEVELOPMENT AND APPROVE A. A WHOLE SERIES OF MEETINGS THAT GO ON. THE PREIND MEETINGS. END OF FADES TWO WHICH IS CRITICAL. MAYBE END OF PHASE 1 AS WELL. YOU HAVE A MEETING BEFORE YOU'RE GOING TO SUBMIT YOUR BLA TO RESOLVE CERTAIN ISSUES. SO THERE ARE 4 EXPEDITED PROGRAMS, AND THESE ARE COVERED NICELY IN OUR GUIDANCE, KNOWN AS FAST TRACK DESIGNATION, BREAK THROUGH THERAPY DESIGNATION, ACCELERATED APPROVAL. AND PRIORITY REGISTRATION. THESE ARE THINGS IN WHICH YOU — WELL, YOU HIT VARIOUS PHASES, EITHER DURING I.N.D. DEVELOPMENT OR BLA FOR PRODUCT THAT IS MEET THE DEFINITION WE MOVE OR ACCELERATOR USE DIFFERENT MECHANISMS IN VEHICLES TO TRY TO,A PROVE OR TO INCREASE THE ATTENTION WE PROVIDE AND DECREASE THE DEVELOPMENT TIME OR THE APPROVAL TIME. BREAK THROUGH THERAPY DESIGNATION IS THE MOST RECENT ONE AND IS REALLY, APPROPRIATE MOSTLY WHEN YOU'RE IN YOUR I.N.D. PHASE AND WE'LL COVER THAT IN A SECOND. ACCELERATED APPROVAL WE TYPICALLY DO OR CAN DO IF YOUR PRODUCT MEETS THE DEFINITION DURING THE B.L.A. OR MARKETING PHASE AS THIS PRIORITY REVIEW DESIGNATION. AND FAST TRACK ALSO, SO THESE FIRST TWO CAN BE USED MOSTLY DURING THE IND PHASE AND THESE LAST TWO REALLY RELATE TO WHEN YOU'RE IN THE MARKETING APPLICATION. ARENA. SO FAST TRACK. WHAT DOES THAT MEAN? YOU APPLY FOR THESE, THROUGH THE FDA AND WE SAY YES OR NO. AND YOU HAVE RIGHTS TO APPEAL ANY OF THESE DECISION THAT IS WE MAKE. IF YOUR PRODUCT HAS A SERIOUS CONDITION AND NONCLINICAL DATA DEMONSTRATES THE POTENTIAL TO ADDRESS AN UNMET MEDICAL NEED, IT GIVES US ABILITIES AND NEW ABILITIES TO EXPEDITE THE DEVELOPMENT AND REVIEW. IT ALLOWS YOU WHEN YOU GET TO MARKETING IN FEES 3 STUDIES TO SMALL ALL THE INFORMATION YOU HAVE, FOR THAT MARKETING APPLICATION IN A ROLLING REVIEW. SO YOU MAY SUBMITS TO, YOU KNOW, A CHUNK OF CLINICAL DATA, A BIG PART OF YOUR MANUFACTURING DATA AND THINGS, IF WE HAVE THE RESOURCES, AND THE ABILITY TO LOOK AT, BEFORE YOU ACTUALLY FORMALLY FILE YOUR B.L.A. IT CAN GIVE US A HEADS UP ON TRYING TO GIVE US THAT DATA IN ADVANCE. THAT'S FASTTRACK DESIGNATION. YOU APPLY DURING AN I.N.D. AND YOU'RE EITHER GRANTED OR NOT. YOU HAVE TO BE BOTH IN SERIOUS CONDITION AND UNNA CLINICAL TO DEMONSTRATE THE POTENTIAL. YES. INFORMATION DEPENDS OUTAGE OF DEVELOPMENT, WHICH FAST ATTACK IS REQUESTED. BABY, HOW MUCH DATA DO YOU REALLY HAVE TO DEMONSTRATE THE ADDRESS FOR THE MEDICAL NEED. YOU MAY NOT HAVE A WHOLE A LOT IN PHASE 1. YOU HAVE A LOT IN PHASE WOMP AGAIN T GIVES YOU THOSE THINGS THAT WE HAVE TALKED ABOUT. BREAKTHROUGH THERAPY. THIS IS PROBABLY THE HARDEST DESIGNATION TO GET IF YOU WILL. NOT ONLY DO YOU HAVE TO HAVE A SERIOUS CONDITION, BUT YOU ACTUALLY HAVE TO HAVE CLINICAL EVIDENCE IN THE CASE THE DRUG MAY DEMONSTRATE SUBSTANTIAL IMPROVEMENT OVER AVAILABLE THERAPY OR ONE OF THE SIGNIFICANT ENDPOINTS. SO IN HAS BEEN THE MOST RECENT ONE. IT'S BEEN DESCRIBED AS AN ALL HANDS ON DECK APPROACH TO DEVELOPING PRODUCT. THERE ARE SEVERAL PRODUCT THAT IS OF COURSE APPROVED IN BREAKTHROUGH THERAPY. THE HARDEST THING IS THAT YOU ACTUALLY HAVE TO HAVE THAT CLINICAL EVIDENCE, AS OPPOSED TO FAST TRACK WHERE YOU MAY BE ABLE TO RELY ON PRECLINICAL DATA IN CERTAIN MODELS TO GET FAST TRACK. IT HAS TO BE WITH THAT PARTICULAR BIOLOGIC OR DRUG, AND HAS TO BE A SUBSTANTIAL IMPROVEMENT OR THERAPY. IF YOUR PRODUCT DOESN'T LOOK LIKE IT'S GOING TO GETS ANY INCREASE, BUT YOU PROBABLY WON'T GET A BREAKTHROUGH THERAPY. YOU BASICALLY GET ALL THE FEATURES OF FASTTRACK. YOU GET MORE OF AN INTENSIVE GUIDE AND DEVELOPMENT, AND MORE INTERACTION BESIDES THE STANDARD REGULATORY MEETINGS. YOU GET THE COMMITMENT FROM THE ORGANIZATION AND IT'LL GET A HIGHER TENACIN THAT DIRECTORS WILL BE MORE INVOLVED IN YOUR THING, AND IT CAN ALLOW YOU TO BET MORE OF A PRIORITY REVIEW. CAN YOU REVIEW IT IN THE ACCELERATED MANNER DURING ITS MARKETING OPERATION PHASE. ACCELERATED APPROVAL HAS BEEN AROUND FOR A WHILE. WHERE WE APPROVE A PRODUCT BASED ON A SURROGATE. THAT CAN BE AN EXAMPLE OF TUMOR ELIMINATION THAT IS LIKELY TO — LIKELY TO PROTECT SOME BENEFITS. IF YOU HAVE A BY OR MARKER THAT'S BEEN RELATED TO A CLINICAL STUDY. THAT MAY BE ANOTHER EXAMPLE OF AN ACCELERATED APPROVE A. WE WILL REVIEW YOUR APPLICATION THAT HAS NOW CHANGED TO 8 MONTHS, BUT MANY OF THESE PRIORITY REVIEW APPLICATIONS GET REVIEWED MUCH FASTER. AGAIN, THIS IS ONLY AT MARKETING PHASE OF THAT. AGAIN, IT HAS TO MEET THE REQUIREMENT THAT THERE'S A SIGNIFICANT IMPROVEMENT IN THE SAFETY AND EFFECTIVENESS AND PREN OF TREATMENT, LIFE THREATENING ILLNESS. IF YOU DON'T GET A PRIORITY REVIEW, YOU'LL GET A STANDARD REVIEW, WHICH MEANS AT THE END OF 12 MONTHS, WE HAVE TO TELL YOU OUR CONCERNS WITH YOUR — ALL OF OUR OCCURRENCE WITH YOUR LICENSE APPLICATION IN ALL THE AREAS AND DISCIPLINES. — REFLECT THE RISKS, RELATED TO THIS PARTICULAR ADVERSE EVENT, AND SO ON AND SO FORTH. ORPHAN DRUGS ARE IN OTHER AREAS. BIOLOGIC THAT IS HAVE HAD ORPHAN DRUGS FOR MANY YEARS, AND HAVE BOOMED AND EXPANDED OVER THE LAST SEVEN, EIGHT YEARS. AN ORPHAN DRUG IS NO THERAPY EXISTS OR PRODUCT WILL SIGNIFICANTLY IMPROVE THE CURRENT THERAPY IS HOWAN ORPHAN DRUG IS DEFIND. YOUR IND PHASE, YOU GET AN ORPHAN DESIGNATION WHICH MEANS, THERE'S AN OFFICE OF ORPHAN DRUG PRODUCTS, WHO HAS CLINICIANS AND LAWYERS, AND THEY LOOK AT YOUR PARTICULAR PRODUCT IN CONSULTATION WITH THE REVIEWERS IN THE VARIOUS CENTERS TO DETERMINE WHETHER YOUR PRODUCT OR NOT, DETERMINES ORPHAN DESIGNATION. AND SEVERAL PRODUCTS DURING THE IIN, D PHASE CAN GET ORPHAN DESIGNATION. SO WHAT DOES THAT MEAN? IT'S INTENDED FOR THE SAFE AND EFFECTIVE DIG NOSE OR EFFECTS MORE AND IS NOT EXPECTED TO RECOVER THE COST OF DEVELOPING MARKET AND YOU CAN DID. A LITTLE CONFUSION, BUT IT'S A STATUTORYTORY DEFINITION. SO IT HAS TO BE SET UP IN SUCH A WAY, IT'S A VERY SMALL POPULATION OF INDIVIDUALS AND MEETS THE SEVERAL PRODUCTS. THAT MAY BE COMPETING IN THE MARKETPLACE, MAY RECEIVE ORPHAN DESIGNATION. HOWEVER, ONCE THEY ARE APPROVED, THE FIRST PRODUCT THAT IS THERE, IS KNOWN AS ORPHAN EXCLUSIVITY. AND THIS IS REGARDLESS WHETHER IT'S A BIOLOGIC OR A DRUG. THEY HAVE AN ADDITIONAL SEVEN YEARS IN WHICH THEIR PRODUCT IS GIVEN MARKET EXCLUSIVITY. AND NO ONE CAN LICENSE A PRODUCT ON THE MARKET. S IN AGAIN, THEY FAIL TO MEET A SUPPLY OR SOME OTHER PRODUCT COMES ALONG AND SHARES A BENEFIT IN TERMS OF SAFETY OR EFFICACY OVER THAT EXCLUSIVITY THAT PRODUCT HAS RECEIVED EXCLUSIVITY. THERE ARE GRANT THAT IS CAN BE APPLIED. THEY DON'T PUT ANY FEES AND SO FORTH. WHAT DO WE LOOK FOR AT THE LICENSES PRODUCT. IT'S SORT OF A REFLECTION ON WHAT WE HAVE LOOKED AT IN THE IND PHASE. AND IMPORTANT, WHETHER IT'S A DRUG OR BIOLOGICS, IT'S ESPECIALLY IMPORTANT FOR BIOLOGICS, AND HOW THE BIOLOGICS IS MADE BECAUSE THERE'S INHERENT VARIATION IN T. IT'S VERY IMPORTANT THAT YOU HAVE DEMONSTRATED TO US, BY THE TIME YOU REACH YOUR MARKETING APPLICATION, CAN YOU CONSISTENTLY MANUFACTURE THIS PRODUCT. OVER THE 20 YEARS, THAT HAS WOULD TREMENDOUS FOR CERTAIN CLASSES OF PRODUCT LIKE THE REDOMINANT BIOTECHNOLOGY PRODUCT. IT'S STILL RATHER CHALLENGING, FOR THE MORE COMPLEX BIOLOGICS, WHERE THERE'S NOT THE ABILITY TO, THEY'RE NOT AS PURE IF YOU WILL. AND NOT ABLE TO DEFINE THE CHARACTERISTIC UNLESS THE PRODUCT THAT, MAY PARTICULARLY EFFECT ITS OVER ALL PRODUCT QUALITY IN ANY ONE OF THESE CHARACTERISTICS. YOU HAVE TO HAVE ASTABLE LEVEL OF GM P COMPLIANCE. YOUR PRODUCT HAS BEEN APPROVED AND YOU HAVE TO FOLLOW APPROVE — THERE IS ENFORCEMENT, PERIODIC INSPECTIONS AND EDUCATION. I DON'T HAVE SLIDES IN HERE ACCIDENT BUT INSTEAD OF RELYING AM THE MANUFACTURERS TO REPORT OR THE CLINICIANS OR NURSE PRACTITIONERS OR OTHER NURSE PRACTITIONERS THAT RESPECT. IF YOU'RE INTERESTED, IT'S ACTUALLY VERY USEFUL. WE HAVE ADMINISTERED IN VACCINE AND WE'RE SEEING THIS SAFETY SIGNAL IN VARIOUS POPULATIONS. AND THEY MONITOR A WIDE VARIETY OF GROUPS OUT THERE. SO CERTAIN HEALTH, CERTAIN ININSURERS PROVIDE THEIR RECORDS TO US, THAT ARE MASKED. CERTAIN ARMED FORCES PROVIDE THE RECORD. CERTAIN HEALTH AGENCIES. SO USING THE WHOLE SENTINEL APPROACH HAS BEEN REF LUGARY, IN IDENTIFYING POTENTIAL SIGNAL THAT IS COME UP. AND REQUIRE FURTHER ATTENTION OR EVALUATION ADAPTIVE CLINICAL TRIAL DESIGN IS REALLY OF INTEREST NOW THE LAST COUPLE OF YEARS. THEY ARE INCREDIBLY LABOR INTENSIVE. IT MEANS HAVE THE FLEXIBILITY IN HOW YOU DESIGN YOUR TRIAL, BASED UPON WHAT VARIOUS FACTORS AND RESPONSES YOU SEE. INCLUDES THINGS LIKE BASIAN STATISTICS AS WELL. THEY'RE VERY COMPLEXED AND REQUIRES A LOT OF TIME AND INTERACTIONS WITH THE SPONSORS TO FIGURE OUT WHAT ARE THE POTENTIAL PERMUTATIONS AND THINGS THAT HAVE NATURE. A LOT HAS BEEN GOING ON WITH BIOMARKERS AND ALL TYPES OF OMECS, IN TERMS OF BEING ABLE TO MONITOR, ARE THEY PREDICTIVE, DO THEY RELATE TO A DISEASE, CAN YOU IDENTIFY THAT YOU WILL, THAT THAT BIOIF YOU BIOMARKER, YOU'RE GOING TO GET AN OUTCOME. DEMOGRAPHIC SUBGROUPS, ALL OF OUR REVIEWS ARE WRITTEN BY REVIEWERS JUST TO HAVE A DEMOGRAPHICS SECTION AS WELL. BOTH IN OUR STATISTICS, AS WELL AS OUR CLINICAL REVIEWS. YOU'LL SEE A DISCUSSION OF DEMOGRAPHIC SUBGROUPS. BIG DATA IS BECOMING VERY, VERY IMPORTANT. STANDARDS ARE NOT JUST WE ARE MOVING, AS PART OF A GOVERNMENT INITIATIVE AND FDA INITIATIVE TO, GET ALL OF OUR INFORMATION IN ELECTRONICALLY. WE HAVE WORKED WITH VARIOUS STANDARDS AND ORGANIZATIONS TO ACTUALLY DETERMINE DATA THAT CONTAINS THE CONTENT OF WHAT YOU'LL BE SUBMITTING TO US, AS WELL AS THE MESSAGING AROUNDS AND THEY ALL WORK TO STANDARDS. SO WE HAVE UPCOMING DEADLINES SO THAT IF YOU ARE SUBMITTING A B.L.A. IT MUST BE AN ELECTRONIC FORMAT. FOLLOWING THE COMMON ELECTRICAL DOCUMENT BY DECEMBER 15, 2017. AND ALL IIN, D'S, THAT ARE COMMERCIALLY SPONSORED, NOT INDIVIDUAL INVESTIGATORS HAVE TO BE SUBMITTED ELECTRONICALLY, A YEAR LATER. WE GET A LOT OF OUR ADVERSE EVENT REPORTED, AND MAKING SURE THAT WILL BE ELECTRONIC IN THE FUTURE. THE OTHER THING IS AND HAVING ALL OF THE DATA THAT YOU PROVIDE TO US, THE CLINICAL DATA, AND NOW, EVEN THE QUALITY OR THE MANUFACTURING DATA, ELECTRONICALLY, ALLOWS US TO PUT THIS INTO DATABASES AND ALLOWSES TO GO AND LOOK AT VARIOUS TYPES OF DISEASES AND TREATMENT MODALITIES. WHEN YOU SUBMIT YOUR APPLICATION, IT HAS TO STAND ON ITS FACE. IN OTHER WORDS, HAVE YOU TO PROVIDE ALL THE INFORMATION YOU NEED FOR THE SAFETY PURITY POTENCY AND THE EFFICACY OF THAT DATA DO ALLOW US TO RELY ON SOME OF THAT INFORMATION IN THE INNOVATOR, BUT ONLY SOME OF IT TO A VERY LIMITED AMOUNT, THE LAST THING IS COMBINATION PRODUCT. THAT'S PROVIDING INCREDIBLE CHALLENGES, BOTH ON THE SCIENTIFIC LEVEL ON&ON A REGULATORY LEVEL. FOR EXAMPLE, IF I HAVE A DEVICE AND I HAVE A BIOLOGIC. I HAVE GOOD MANUFACTURING PRACTICES, THAT YOU HAVE TO FOLLOW FOR THE PARTICULAR BIOLOGIC. IF YOU HAVE THEM FOR THE DEVICE AND HAVE I DIFFERENT SET OF GM P'S I HAVE TO FOLLOW. SOMETIMES THEY ARE COMPLEMENTARY, SOMETIMES THEY'RE IDENTICAL AND SOMETIMES THEY'RE DIFFERENT. AS A MANUFACTURER, I NEED TO FIGURE OUT WHAT SERIES OF HOW CAN I FULFILL BOTH SETS OF REGULATIONS BY COMING UP WITH A SYSTEM THAT, WORKSHOPS FOR ME. VERY CHALLENGING ON THAT LEVEL AND THE SCIENTIFIC LEVEL. THE INTERACTIONS BETWEEN S CERTAIN TYPES OF CELLS AND MATRICES, IS VERY AM COPLEX. AND WE THEREFORE, A LOT OF REVIEWS WITH THE SISTER CENTER, THE SISTER FOR DEVICES AS WELL. DATA TAPLATION MODEL. STANDARDIZED STANDARDS FOR EXCHANGE OF NONCLINICAL DATA, AND THESE ARE BEING USED FOR PRECLINICAL WORK AS WELL. COMING IN. ALL THE VARIOUS ANIMAL STUDIES OR CELLULAR-BASED STUDIES. OUR ADVERSE EVENT REPORTING IS COMING. SO EVEN TARGETING AT THE BEGINNING, ALL THE WAY THROUGH, YOU HAVE TO THINK ABOUT WHAT'S GOING TO BE HAPPENING IN A COUPLE OF YEARS, HOW CYCLECTOMY CLINICAL DATA SO IT'S GOING TO BE COMPLYING WITH THE UPCOMING REGULATIONS. THESE ARE WIDELY KNOWN MODELS. THEY'RE USED ACROSS THE 43, IN MANY CASES, THEY'RE INTERNATIONAL. HOPEFULLY, THEY'LL BE LIMITED
LIMITED AND IF YOU CAN AGREE, WE'RE ALL USING THESE TYPES OF STANDARDS THAT CAN HELP FACILITATE, THE BIOLOGICAL DRUG AND DEVELOPMENT. HOW YOU CAN SUBMIT ALL THIS INFORMATION ELECTRONICALLY. IT'S JUST A HIGHLIGHTED EXAMPLE. THERE'S ALL KINDS OF SUBMISSIONS, THEY HAVE TO GO AND UNDERSTAND IF YOU'RE ON THE GEEK SIDE OF THE HOUSE, HOW TO STRUCTURE YOUR DATA, COLLECT IT AND PUT IT INTO THE FORMATS TO PULL THE DATA OUT, AS WE LOOK AT THIS AND ARCHIVE AND SO ON. THERE'S MORE THAN ENOUGH INFORMATION. THANK YOU FOR RUNNING OVER AND ALLOWING ME TO RUN OVER AND BE LATE. THERE'S A TON OF STUFF OUT THERE. JUST GOING TO THE FDA AND START LOOKING FOR IT. I DON'T HAVE MY CONTACT INFORMATION UP HERE. BUT THE BOTTOM LINE IS, YOU'RE BETTER OFF GOING TO THE DIVISION OR THE GROUP WHO'S GOING TO REVIEW YOUR IND, IF YOU HAVE, YOU KNOW, A SPECIFIC CLINICAL QUESTION. AND THERE ARE FOLKS IN EACH CENTER, CALLED M BUDSMAN WHERE YOU CAN CLEARLY CALL TO SAY, I'VE GOT, YOU KNOW, THIS PARTICULAR MOLECULE. WHO'S GOING TO REVIEW MY MOLECULE AND THEY WILL PRETTY MUCH, MOST LIKELY, BE ABLE TO TELL, YOU'RE PROBABLY GOING TO GO TO THIS GROUP. YOU MAY GO TO THE CENTER FOR DRUGS. YOU MAY GO TO THE CENTER OF BIOLOGIC. MIMES IT'S CLEAR, SOMETIMES IT'S CONFUSING. THE M BUDSMAN PERSONS, CAN HELP YOU DIRECT TO WHERE YOU HAVE TO GO. AND THE BEST THING THEN IS TO FIND OUT, YOU KNOW, THAT REVIEW GROUP, USUALLY REVIEWED DIVISION OR BRANCH AND TO REALLY START YOUR DISCUSSIONS WITH THEM, BECAUSE FRANKLY, THEY ARE THE ONCE WHAT ARE MOST LIKELY GOING TO BE LOOKING AT MATERIAL. THE GUIDANCE YOU GET, THE UNDERSTANDING OF YOUR MOLECULE IS REALLY IMPORTANT TO START FROM THE BEGINNING FORWARD. OKAY. THAT'S IT. THANKS. YOU'VE BEEN VERY PATIENT.
01:12:29.667,00:00:00.000
HAVE A GOOD SAFE, DRIVE HOME.

2 Comments

  1. good lecture

  2. Don't forget insider trading of the drugs you approve. Don't leave out the recalls you called safe under the guise of "pseudoscience". How good is the science on recalled product? And what the hell are we paying you for?

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