WELCOME TO SESSION FIVE. IT'S HARD TO BELIEVE THAT WE'RE ALREADY AT NUMBER FIVE. SO THANK YOU FOR TUNING IN TODAY. AND A COUPLE REALLY QUICK ANNOUNCEMEN ANNOUNCEMENTS, FIRST OF WORD OF THE DAY IS PLACEBO AND I WILL REPEAT THAT AGAIN LATER. YOU SHOULD HAVE ALL GOTTEN EITHER AN ANNOUNCEMENT AND OR AN E-MAIL THAT WE'RE GOING TO USE SLIDO TOTED FOR BOTH DR. TRUOG AND DR. KIM'S PRESENTATION. I'M DPIETD ABOUT THAT. AND ONE MORE THING I GOT MY FLU VACCINE TODAY. PLEASE GO OUT AND GET YOUR FLU VACCINE THIS YEAR. WITHOUT FURTHER ADO I'M GOING TO INTRODUCE OUR FIRST SPEAKER, BOB TRUOG IS THE FRANCIS GLASS ANYWHERE LEAD PROFESSOR OF ANESTHESIOLOGIST AND PEDIATRICS AND CENTER FOR BIO ETHICS AT HARVARD MEDICAL SCHOOL. HE ALSO IS AN ACTIVE PRACTITIONERS IN THE PEDIATRIC INTENSIVE CARE WHERE HE SERVED FOR MORE THAN 30 YEARS INCLUDING DIVISION OF CRITICAL CARE MEDICINE. HE HAS MANY, MANY ACCOMPLISHMENTS. I'VE POSTED HIS FULL BIO IN THE SESSION IN CANVAS, SO PLEASE TAKE A LOOK AT THAT, DR. TRUOG HAS BEEN A MEMBER OF OUR COURSE FACULTY FOR 22 YEARS, LAST YEAR WAS 21, AND IT'S WITH GREAT PLEASURE THAT I HAND THE MIC OVER TO HIM AND YOU'LL HEAR FROM ME AS WE START THE POLLING ONCE DR. TRUOG GETS STARTED. >> DR. ROBERT TRUOG: WELL, GREAT, GOOD MORNING, EVERYONE. AND THANK YOU FOR THE NICE INTRODUCTION. YOU CAN HEAR ME, IS THAT TRUE. >> YES, I CAN HEAR YOU AND I GUESS WE'RE GOING TO GET YOUR SLIDES. OH, THERE YOU ARE, HI. >> DR. ROBERT TRUOG: YEAH I'LL SHARE MY SCREEN HERE. >> YOU'RE GOING TO BE IN CHARGE OF YOUR SLIDES. >> DR. ROBERT TRUOG: THAT'S RIGHT SO LET ME SHARE MY SCREEN AND LET ME KNOW -- YOU SHOULD BE SEEING THE SLIDE THERE, LET ME KNOW IF THAT'S NOT TRUE. YEAH SO I HAVE DONE THIS TALK FOR A VERY LONG TIME, I GUESS THIS IS THE 22ND YEAR, AND IT'S -- IT'S DISCUSSING A CASE THAT I WAS INVOLVED WITH WHEN I WAS A FELLOW AT BOSTON CHILDREN'S HOSPITAL. SO THE CASE IS OLD BUT IT MAKES I THINK A NUMBER OF VERY GOOD POINTS ABOUT HOW WE THINK ABOUT ETHICAL TILES THAT ARE JUST AS RELEVANT TODAY AS THEY WERE BACK THEN. FOR DISCLOSURE, I DO SERVE AS A PAID MEMBER OF SEVERAL DATA SAFETY MONITORING BOARDS, NONE OF THESE DO I THINK HAVE ANY IMPACT ON WHAT WE'LL BE DISCUSSING TODAY. THE PARTICULAR STUDY WE'RE GOING TO LOOK AT WAS PUBLISHED IN PEDIATRICS, AS YOU CAN SEE HERE. EXTRA MEMBRANE OXYGENATION AND CONVENTIONAL THERAPY IN NEONATES PULMONARY HIGH POTENTIAL OF THE NEWBORN A PROSPECTIVE RANDOMIZED STUDY. NOW I KNOW MANY OF YOU ARE PROBABLY FAMILIAR WITH ECMO IT'S BECOME A MUCH MORE COMMON THERAPY THESE DAYS BUT FOR THOSE OF YOU WHO AREN'T LET ME GIVE YOU A LITTLE BIT OF BACKGROUND. SO ECMO IS A FORM OF CARDIOPULMONARY BYPASS AND USED FOR PATIENTS WITH LIFE THREATENING PULMONARY OR CARDIAC FAILURE. AND THE WAY WE DO IT, AT LEAST IN BABIES, AND STILL THE WAY WE DO IT OVER THE LAST 20 YEARS OR SO, IS THAT WHEN WE INITIATE ECMO AN INCISION IS MADE HERE IN THE PATIENT'S NECK AND TWO CANULA ARE PASSED DOWN INTO THE HEART ONE INTO THE RIGHT ATRIUM AND THE OTHER INTO THE AORTIC ARCH AND WE DRAIN VENOUS BLOOD OUT OF THE RIGHT ATRIUM DOWN HERE TO A RESERVOIR WHERE MEDICATIONS ARE ADDED AND IN PARTICULAR HEPARIN IS THE KEY MEDICATION HERE, BECAUSE WE NEED OBVIOUSLY FOR THE BLOOD NOT TO CLOT BUT THAT ALSO CREATES THE POTENTIAL COMPLICATION OF HEMORRHAGE AND IN NEWBORN BABIES THE PLACE THAT WE OTHER ABOUT THE MOST IS HEMORRHAGING TO THE BRAIN. THE BLOOD THEN GOES THROUGH THE ARTIFICIAL HEART, WHICH IS A PUMP, AND THEN UP INTO THE ARTIFICIAL LUNG, WHICH IS A MEMBRANE OXYGENATOR AND TO SORT OF GIVE YOU THE IDEA OF HOW THIS WORKS, IF YOU IMAGINED A LARGE SILICON ENVELOPE THAT IS ROLLED UP INTO A CYLINDER AND BLOOD IS PUMPED IN ONE DIRECTION THROUGH THE INSIDE OF THE ENVELOPE FRESH GAS IS PASSED IN THE OPPOSITE DIRECTION THROUGH THE OUTSIDE OF THE ENVELOPE, YOU GET GAS EXCHANGE OCCURRING ACROSS THE SILICONE MEMBRANE. SO OXYGEN GOING INTO THE BLOOD CARBON DIOXIDE COMING OUT, SO THAT'S HOW THE ARTIFICIAL LUNG WORKS. THEN THE BLOOD GOES THROUGH A HEAT EXCHANGER TO HEAT IT BACK UP TO BODY TEMPERATURE AND THEN BACK INTO THE AORTIC ARCH WHERE IT PROFUSES THE SYSTEMIC SIDE OF THE CIRCULATION. NOW, WHEN WE DO ECMO THESE PATIENTS ARE TOO SICK TO GO DOWN TO THE OPERATING ROOM IN ORDER TO HAVE THE CANULA PLACED, SO WE BASICALLY BRING THE OPERATING ROOM UP TO THE ICU WE CREATE A STERILE ENVIRONMENT AND HERE YOU CAN SEE TWO OF OUR SURGEONS PLACING THE CANULA. AND ONCE THE BABY IS ON ECMO THIS IS SORT OF WHAT THE BED SPACE LOOKS LIKE, HERE EIGHT'S THE BABY OF COURSE WE HAVE A NURSE WHO TAKES CARE OF THE PATIENT 24/7 AND AN ECMO TECHNOLOGIES WHO IS TAKING CARE OF THE ECMO CIRCUIT AND HERE YOU CAN SEE THE BLOOD COMING DOWN TO THE RESERVOIR WHERE MEDICATIONS ARE ADD THEN UP TO THE ARTIFICIAL HEART THE PUMP WHICH PUMPS THE BLOOD UP THROUGH THIS WHITE CYLINDER HERE WHICH IS THE ARTIFICIAL LUNG, AND THEN IT GOES INTO THIS -- MAYBE YOU CAN SEE VERTICAL SILVER CYLINDER HERE WHERE THIS IS THE HEAT EXCHANGER WHERE WE WARM THE BLOOD BACK UP AND THEN BACK INTO THE BABY. AND THIS IS WHAT TYPICALLY LOOKS LIKE FOR A -- A BABY ON ECMO, IF WE -- IF WE WERE IN PERSON I WOULD ASK YOU WHAT YOU MIGHT NOTICE AS ODD ABOUT THIS, FOR THOSE OF YOU WHO HAVE WORKED IN INTENSIVE CARE UNITS, SINCE I CAN'T DO THAT I'LL POINT IT OUT FOR YOU IS HERE'S THE ENDOTRACHEAL TUBE THE BREATHING TUBE THAT GOES DOWN INTO THE BABY'S LUNGS WITHOUT ECMO THIS HAS TO BE CONNECTED TO A VENTILATE TORE TO BREATHE FOR A PATIENT BUT WHEN ON ECPO THE BRAY BEES DON'T NEED TO BREATHE SO IT DRAMATICALLY MAKES THAT POINT BUT IN A SOMEWHAT DISHONEST WAY BECAUSE THIS WAS JUST DONE FOR THE PHOTOGRAPH. WE DO ACTUALLY KEEP THE ENDOTRACHEAL TUBE CONNECTED TO A VENTILATOR NOT SO MUCH TO BREATHE FOR THE PATIENT BECAUSE OFTEN WE DON'T BUT RATHER TO PROVIDE POSITIVE PRESSURE HERE TO HELP KEEP THE LUNGS EXPANDED AND HEAL MORE RAPIDLY. HERE'S THE CANULA YOU CAN SEE AND IF YOU USE YOUR IMAGINATION YOU MIGHT CONVINCE YOURSELF THAT THE BLOOD IN THE CANULA DOWN HERE IS A LITTLE DARKER THAN THE BLOOD UP HERE, SO THIS IS THE VENOUS BLOOD THAT IS COMING OUT OF THE PATIENT AND THIS IS THE ARTERIAL BLOOD GOING BACK IN. THAT'S THE TECHNOLOGY, LET ME GIVE YOU BACKGROUND TO THE TRIAL AND WHAT LED UP TO IT. IN THE 1970S A MULTI CENTER RANDOMIZED CONTROL TRIAL HAD SHOWN THAT ECMO WAS NOT EFFECTIVE FOR TREATING ACUTE RESPIRATORY DISTRESS SYNDROME IN ADULTS. ONE OF THE PARTICIPANTS IN THAT 1970S TRIAL WAS ROBERT BARTLET, BOB BART LET WHO WAS THEN A SURGEON AT MASS GENERAL HOSPITAL, WHO WAS ONE OF THE PARTICIPATING HOSPITALS. HE LEFT MASS GENERAL TO GO TO MICHIGAN AND HE BEGAN TO USE ECMO TO TREAT BABIES WITH A CONDITION CALLED P PH N OR PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN. AND HIS IDEA, AT THAT POINT, WAS THAT THE REASON ECMO HADN'T WORKED IN THE ADULT STUDY WAS BECAUSE THE PATIENTS PROBABLY ALREADY HAD I REMEMBER VERY FAR VERSIBLE LUNG DISEASE SO SUPPORTING THEM WITH ECMO WASN'T GOING TO CHANGE THE SITUATION, BUT P PH N WAS UNIQUE BECAUSE IT'S A DISEASE WHERE THE BABIES HAVE TEMPORARY SPASM OF THE PULMONARY ARTERY SO BLOOD CAN'T GET TO THE LUNGS BUT THAT IS SUPPORTED FOR A FEW DAYS TO A WEEK THAT SPASM RELAXES BLOOD FLOW RETURNS TO THE LUNG AND SO THEY CAN BE TAKEN OFF OF ECMO, AND THIS WAS HIS IDEA AND INDEED HIS RESULTS WERE VERY, VERY IMPRESSIVE. YOU KNOW, TO EVERYBODY AT MICHIGAN IT LOOKED LIKE THIS WAS SAVING LIVES. AND SO IT BECAME SORT OF THE STANDARD OF CARE AT HIS HOSPITAL. THE PROBLEM WAS, IS THAT HE WASN'T ABLE TO CONVINCE OTHER PEOPLE AROUND THE COUNTRY. THEY WERE LOOKING AT WHAT HE WAS DOING, THEY GO WELL YOU KNOW THAT'S INTERESTING, BUT YOU KNOW WE'VE SEEN -- WE'VE SEEN INTERESTING THINGS BEFORE THAT DIDN'T ACTUALLY PAN OUT, AND SO YOU KNOW UNLESS THERE IS A STUDY, A RANDOMIZED CONTROL TRIAL THAT SHOWS THAT ECMO IS SUPERIOR TO CONVENTIONAL VENTILATION YOU KNOW WE'RE NOT GOING TO DO IT. AND SO HERE HE IS, HE'S IN THIS SITUATION WHERE HE THINKS HE HAS AN ABSOLUTELY GAME-CHANGING THERAPY THAT IS SAVING LIVES HE'S USING IT, IT LOOKS REALLY, REALLY SUCCESSFUL TO HIM BUT NOBODY IS BUYING IT. AND SO THIS BRINGS US TO THE FIRST QUESTION, WHICH AGAIN IF WE WERE IN PERSON I'D BE ASKING YOU IN THE AUDIENCE, BUT I CAN'T DO THAT BUT WE DID COME UP WITH AN ALTERNATIVE PLAN HERE, SO I WANT TO YOU IMAGINE THAT YOU'RE BOB BARTLET YOU'RE THE SURGEON AND WOULD YOU HAVE SOUGHT TO PERFORM A RANDOMIZED CONTROL TRIAL IN MICHIGAN TO DEMONSTRATE THE SUPERIORITY OF ECMO TO CONVENTIONAL MEDICAL THERAPY? WOULD YOU HAVE SAID I NEED TO DO AN RCT IN ORDER TO CONVINCE THE REST OF THE COUNTRY THE REST OF THE WORLD MY COLLEAGUES OR WOULD YOU HAVE SAID NO FOR ONE REASON OR ANOTHER, THAT WE'LL GET TO, I'M NOT GOING TO DO THAT. WE'RE GOING TO USE A POLL WE WOULD LIKE TO YOU VOTE YES OR NO, YES I WOULD USE AN RCT TO PROVE THE SUPERIORITY OF ECMO THERAPY OR NO IT WOULD NOT BE ETHICAL FOR ME TO RANDOMIZE PATIENTS TO A CONTROL GROUP GIVEN MY EXPERIENCE WITH ECMO. GO, ARE YOU THERE, ARE WE GOING TO VOTE? >> THE VOTES ARE COMING IN. SORRY, LOOK AT THAT. AND I'M GOING TO GIVE THE STUDENTS A CHANCE TO LOG IN, SO FOR THOSE OF YOU WHO ARE OUT THERE LOOKS LIKE A NUMBER OF YOU HAVE STARTED VOTING, SO THAT'S TERRIFIC AND WE'LL GIVE THEM MAYBE ANOTHER MINUTE AND A HALF OR SO OKAY GREAT THANK YOU AGAIN FOR ALL OF YOU WHO HAVE VOTED. AND BOB RIGHT NOW WE HAVE 75 PERCENT OF THE GROUP ENDORSES DOING THE RCT TO PROVE THE SUPERIORITY. >> DR. ROBERT TRUOG: ALL RIGHT. THAT'S FASCINATING. SO SINCE WE CAN'T ACTUALLY HAVE A CONVERSATION ABOUT IT, BUT SINCE I'VE HAD THIS CONVERSATION MANY TIMES IN THE PAST, ME SORT OF SHARE WITH YOU WHAT I IMAGINE SOME OF YOU WERE THINKING. SO ASK YOURSELF, IN TERMS OF HOW YOU VOTED, WHICH OF THESE REASONS MOST RESONATED WITH YOU, SO FOR THE 75 PERCENT OF YOU WHO SAID YES I WOULD DO AN RCT, I IMAGINE THAT MANY OF YOU THOUGHT, WITHOUT A CONTROL GROUP, WE COULD NEVER BE SURE IF THE NEW THERAPY IS BETTER, RIGHT? HE DOESN'T HAVE ANY CONTROL PATIENTS. RCTS ARE THE GOLD STANDARD FOR CONVINCING PHYSICIANS TO CHANGE THEIR PRACTICE AND SO THAT SIMPLY NEEDS TO HAPPEN. OR BY PROVING THE SUPERIORITY OF ECMO I CAN SAVE THE LIVES OF MANY MORE BABIES, THEREFORE I HAVE AN ETHICAL OBLIGATION TO DO THE STUDIES. >> IF HE DOES THIS THROUGH HIS WHOLE CAREER MAYBE HE'LL SAVE THE LIVES OF 100 PEOPLE BUT IF HE CHANGES PRACTICE AROUND THE WORLD HE WOULD SAVE MORE. FOR THE 25 PERCENT OF YOU WHO SAID NO I WILL NOT DO AN RCT ONE OF THE REASONS YOU MIGHT GIVE IS IT WAS UNETHICAL TO RANDOMIZE PATIENTS WHEN I'M CONVINCED THAT ONE THERAPY IS BETTER THAN THE OTHER OR THAT IT WOULD BE UNETHICAL FOR DOCTORS AND NURSES TO LET A PATIENT DIE WHEN THEY THINK THAT THE PATIENT COULD BE SAVED, OKAY? SO HOW DID BARTLET RESPOND TO THIS? SO HE -- HE SAID, WELL, OKAY, IF YOU WANT A RANDOMIZED CONTROL TRIAL I'LL GIVE YOU A RANDOMIZED CONTROL TRIAL. AND SO HE PUBLISHES THIS PAPER, EXTRA CIRCULATION IMMUNO RESPIRATORY FAILURE A PROSPECTIVE RANDOMIZED STUDY, RIGHT, SO IT LOOKS LIKE HE'S DELIVERING, BUT YOU HAVE TO LOOK AT HOW HE DID IT, BECAUSE IT WAS NOT IN THE CONVENTIONAL WAY THAT YOU MIGHT HAVE THOUGHT. HE USED A RANDOMIZATION STRATEGY CALLED THE PLAY THE WINNER DESIGN. AND I'M GOING TO TELL YOU ABOUT IT IN WORDS, FIRST, AND THEN I'M GOING TO SHOW YOU HOW IT PLAYED OUT. SO WE'RE GOING TO GO THROUGH IT KIND OF TWICE BECAUSE IT'S A LITTLE BIT COMPLICATED. SO LET ME EXPLAIN IT TO YOU IN WORDS. THE WAY THE DESIGN WORKS IS YOU START WITH A BUCKET, IF YOU WILL, AND A BUCKET HAS TWO MARBLES IN IT, ONE IS YELLOW, WE'LL SAY THAT'S FOR ECMO ONE IS BLACK WE'LL SAY THAT'S CONVENTIONAL MEDICAL THERAPY. FOR THE FIRST PATIENT YOU ENROLL YOU REACH INTO THE BUCKET AND PULL OUT A MARBLE AND THAT DETERMINES WHAT THERAPY THE PATIENT GETS. NOW HERE'S THE HARD PART, IF THAT PATIENT SURVIVES FOR THE NEXT DRIVE YOU PUT ANOTHER MARBLE OF THE SAME COLOR IN THE BUCKET. IF THAT PATIENT DYES FOR THE NEXT DRAW YOU PUT A MARBLE OF THE OPPOSITE COLOR IN THE BUCKET. SO IT WILL BE MORE CLEAR NOW IF I EXPLAIN TO YOU HOW IT WORKS. THIS IS WHAT ACTUALLY HAPPENED IN BARTLET'S STUDY THE FIRST DREW THE YELLOW MARBLE AND SURVIVED SO THE RULE IS ANOTHER MARBLE OF THE SAME COLOR YELLOW WOULD GO INTO THE BUCKET FOR THE NEXT DRAW, OKAY? THEN THE SECOND PATIENT WAS ENROLLED, THAT PATIENT GOT THE BLACK MARBLE AND DIED. SO THEN FOR THE NEXT DRAW ANOTHER MARBLE OF THE OPPOSITE COLOR NOW YELLOW, WOULD GO INTO THE BUCKET. OKAY? AND THAT CONTINUED, AND THERE WERE 11 PATIENTS ENROLLED, 10 OF THEM GOT ECMO, ALL OF THEM SURVIVED, AND THE ONE WHO DIED WAS THIS ONE HERE, AND HERE YOU'RE GOING TO HAVE TO TRUST ME I'LL SAY A LITTLE BIT MORE ABOUT THIS AM A MOMENT, BUT YOU'LL HAVE TO TRUST ME THAT WHEN THE STATISTICIANS LOOK AT THIS THE P IS LESS THAN .05 HERE THAT ECMO IS STATISTICALLY AND CLEARLY THE SUPERIOR THERAPY. ALL RIGHT? SO -- AND YOU CAN SEE HOW THIS IS WORKING, IS THAT FOR EACH DRAW THE RANDOMIZATION STARTS TO SHIFT TOWARDS THE MORE SUCCESSFUL TREATMENT. SO BY THE TIME THIS 11TH PATIENT WAS DRAWN AT THAT POINT THERE WERE NINE YELLOW MARBLES IN THE BUCKET AND ONE BLACK MARBLE SO YOU CAN SEE IT WAS HEAVILY WEIGHTED TOWARDS THE MORE SUCCESSFUL THERAPY. I ALSO WANT TO JUST POINT OUT, THAT THE ETHICAL IMPLICATIONS HERE WERE REAL. SO LET ME TELL YOU A LITTLE BIT ABOUT THIS -- THIS PATIENT WHO DIED. THIS WAS A CONVERSATION I HAD WITH BOB BARTLET AT ONE OF THE ECMO CONFERENCES YEARS AGO. SO BOB BARTLET WAS IN ANN ARBOR AND GOT A CALL FROM IN MICHIGAN THESE ARE NORMALLY COMPETE FOR PATIENTS DON'T TRANSFER PATIENTS BACK AND FORTH BUT THE CALL DR. BARTLET LET ME TELL YOU WE'VE GOT A BABY HERE WITH VERY SEVERE P PH N THIS IS A WOMAN WHO IS IN HER 40S, SHE HAS HAD MANY TRIALS OF INFERTILITY TREATMENTS, THE BIRTH WAS VERY COMPLICATED SHE ACTUALLY HAD TO HAVE A HYSTERECTOMY AT THE TIME OF BIRTH BECAUSE OF BLEEDING, SO THIS IS HER ONLY OPPORTUNITY TO BE PREGNANT, AND I HEARD YOU'RE DOING ECMO IN ANN ARBOR AND I WANT TO TRANSFER THIS PATIENT AND I WANT THIS PATIENT TO GET ECMO. AND SO DR. BARTLET RESPONDS YES WE ARE DOING ECMO BUT I HAVE TO TELL YOU WE JUST STARTED THIS STUDY AND SO THE PATIENT IS GOING TO HAVE TO BE ENROLLED IN THE STUDY AND THE CHANCE THE PATIENT CANNOT GET ECMO THE GUY IS LIKE NO THIS CAN'T BE BUT IT IS, THEY TRANSFER THE PATIENT TO ANN ARBOR AND LOW AND BEHOLD THIS IS THE ONE PATIENT THAT GETS THE BLACK MARBLE, IT WAS EMOTIONALLY WRENCHING INITIALLY THIS BABY STARTED TO DO BETTER FOR 48/72 HOURS BUT THEN THINGS WENT DOWN THE TUBES AND THE BABY ENDED UP DYING. AND HE SAID IT WAS HORRIBLE FOR EVERYBODY THAT WAS THERE TO SEE THIS HAPPEN. HE ALSO TOLD ME THAT LATER ON IN THE STUDY HIS NIECE IN INDIANA WAS ALSO BORN WITH P PH N, AND TRANSFERRED UP TO ANN ARBOR AND HE SAID YOU KNOW SHE NEVER -- SHE NEVER NEEDED ECMO SHE NEVER QUALIFIED FOR ECMO BUT IF SHE DID I WOULD HAVE ENROLLED HER IN THE TRIAL AS WELL. SO THESE KIND OF ETHICAL AND EMOTIONAL CONCERNS ARE NOT JUST THEORETICAL THEY'RE VERY, VERY REAL. SO LET'S GO ON TO QUESTION NO. 2. SO IMAGINE THAT YOU WERE A NEONATOLOGIST IN BOSTON, AND YOU READ THIS ARTICLE FROM BOB BARTLETT BOSTON OR ANYWHERE, I MEAN I'M IN BOSTON SO IMAGINE WHEREVER YOU'RE AT YOU'RE A NEONATOLOGIST, WHEN YOU READ THIS ARTICLE WOULD YOU HAVE TOLD YOUR HOSPITAL ADMINISTRATOR THAT YOU NEEDED NOW TO START AN ECMO PROGRAM BECAUSE THERE'S A PROSPECTIVE RANDOMIZED TRIAL THAT NOW SHOWS THAT E CM O IS SUPERIOR, SO WHY OR WHY NOT? SO WE'RE GOING TO DO THE POLL AGAIN YES YOU WOULD SAY THIS IS A STATISTICALLY SIGNIFICANT RANDOMIZED CONTROL TRIAL I SHOULD CHANGE MY PRACTICE AND CREATE A PROGRAM AT MY HOSPITAL OR NO REGARDLESS OF WHAT THE STATISTICS SHOW THIS TRIAL DOES NOT CONVINCE ME THAT ECMO IS A SUPERIOR THERAPY. SO FOR THOSE OF YOU WHO SAID YES I WOULD CHANGE MY PRACTICE, YOU MIGHT HAVE THOUGHT WE NEED TO TRUST STATISTICS. IF THIS TRIAL IS RESULT IS STATISTICALLY SIGNIFICANT, WHICH I TOLD YOU IT WAS AND IT IS, WE SHOULD CHANGE OUR PRACTICE. OR SOME OF YOU MIGHT HAVE THOUGHT NO I WOULD NOT CHANGE MY PRACTICE, BECAUSE THE RESULT IS CONTINGENT ON THE OUTCOME OF ONLY ONE PATIENT. IF THAT PATIENT HAD SURVIVED THE TRIAL MIGHT HAVE GONE VERY DIFFERENTLY OR YOU MIGHT THINK THAT RCTS MUST HAVE BALANCED RANDOMIZATION 50/50 OR THEY ARE NOT VALID OR THAT THE TRIAL SHOULD HAVE BEEN DONE AT ANOTHER CENTER WITH UNBIASED PHYSICIANS. SO THESE ARE SOME OF THE WAYS THAT YOU MIGHT HAVE THOUGHT ABOUT IT. SO LET ME TELL YOU HOW THIS ACTUALLY DID DEVELOP. SO THERE WAS AN EDITORIAL THAT ACCOMPANIED THE BARTLETT PAPER AND IT WAS PUBLISHED BY JIM WEAR WHO IS A STATISTICIAN AT THE HARVARD SCHOOL OF PUBLIC HEALTH AND MICHAEL EPSTEIN WHO IS CHIEF AT BOSTON HOSPITAL. THEY WROTE THE CLINICAL INDICATIONS FOR THIS NEW AND COMPLEX TREATMENT REMAIN UNDEFINED FURTHER RANDOMIZED CONTROLLED TRIALS WILL BE DIFFICULT BUT NEVERTHELESS REMAIN NECESSARY. SO THEY WERE NOT CONVINCED BY THIS. AND IN THE -- YOU KNOW, TYPICAL ENTREPRENEURIAL FASHION OF RESEARCHERS THEY SAID OKAY IF THAT TRIAL WASN'T GOOD WE'RE GOING TO DO OUR OWN. SO THIS WAS THE TRIAL THAT THEY FOLLOWED UP WITH, AND THE ONE THAT WE'RE GOING TO TALK NOW ABOUT MORE, AGAIN, THIS -- I WAS A FELLOW IN -- IN ANESTHESIA AND CRITICAL CARE MEDICINE AT THE TIME THAT THIS WAS DONE SO I WAS NOT A PART OF THE DECISION MAKING PROCESS, I DIDN'T HAVE ANY INSIDE ACCESS TO WHAT WAS GOING ON, BUT I DID HAVE A FRONT ROW SEAT TO THE WAY THIS PLAYED OUT. LET ME TELL YOU A LITTLE BIT ABOUT THE TRIAL. FIRST OF ALL DECISION WAS MADE TO SEPARATE THE PATIENT LOCATIONS. SO FOR THOSE WHO WERE GOING TO RECEIVE CONVENTIONAL THERAPY CONVENTIONAL MEDICAL THERAPY, THEY WERE GOING TO BE CARED FOR ON THE 7TH FLOOR IN THE NEONATAL ICU, WHERE THERE WERE NEONATOLOGISTS, AND AN IMPORTANT POINT HERE WAS THAT NO PATIENTS HAD EVER BEEN OFFERED ECMO AT BOSTON'S CHILDREN'S HOSPITAL FOR THE DISEASE OF P PH N, OKAY? AND THAT'S IMPORTANT, BECAUSE IT WASN'T LIKE IF YOU GOT TO BOSTON YOU KNOW BEFORE WE STARTED THE TRIAL YOU WOULD HAVE GOTTEN ECMO BUT NOW THAT A TRIAL WAS RUNNING YOU MIGHT NOT GET IT. THAT WAS THE PROBLEM THAT BOB BARTLETT HAD HE HAD BEEN OFFERING THIS TO ANYBODY NOW HE STARTS A TRIAL AND IT'S NOT OPEN TO EVERYBODY. WE DIDN'T HAVE THAT PROBLEM WE HAD NEVER OFFERED IT FOR P PH N IT WASN'T AVAILABLE BEFORE AND NOW BEING TAKEN OFF OF THE TABLE BECAUSE A TRIAL WAS RUNNING. ALSO THE GENERAL ATTITUDE AMONG OUR NEONATOLOGISTS AND INDEED AROUND THE COUNTRY WAS ANTI ECMO, A SURGICAL APPROACH TO WHAT WAS THOUGHT TO BE A MEDICAL DISEASE. AND YOU KNOW, I DIDN'T MENTION IT, BUT ONE OF THE THINGS THAT HAPPENS WITH ECMO IS YOU GET LIGATION OF THE CAROTID ARTERY. WHEN THE CATHETER COMES OUT OF THE ARTERY WE TIE OFF THE VESSEL SO THE BABIES BECOME DEPENDENT UPON THEIR CIRCLE OF WILLIS IN ORDER TO GET BLOOD FLOW TO THEIR BRAIN FOR THE REST OF THEIR LIVES, THIS IS A PRETTY RADICAL THERAPY. ON THE OTHER HAND, PATIENTS WHO GOT ECMO WERE CARED FOR IN A PEDIATRIC ICI WHERE I WAS WORKING ON THE 5TH FLOOR OF THE HOSPITAL SO PHYSICALLY SEPARATED. THE STAFFING HERE WAS DIFFERENT, THIS WAS PRIMARILY STAFFED BY ANESTHESIOLOGISTS AND SURGEONS. MUCH AND ONE OF THE UNIQUE FEATURES IS THAT THE PEOPLE ON THE 5TH FLOOR HAD BEEN USING ECMO BUT FOR BABIES WITH A DIFFERENT DISEASE, CONGENITAL DIAPHRAGMATIC HERNIA WHERE THE DIAPHRAGM DOES NOT FORM ON ONE SIDE OF THE BODY AND IT KEPT THESE BABIES ALIVE UNTIL THE WHOLE NEW DIAPHRAGM COULD BE SURGICALLY REPAIRED. THE ADVANTAGE OF THIS WAS THAT, YOU KNOW, ECMO IS A VERY COMPLICATED MECHANICAL THING AND WHEN YOU FIRST START DOING IT, NO MATTER WHO YOU ARE, TYPICALLY THE FIRST PATIENTS MAYBE DON'T DO QUITE SO WELL AS THEY WOULD HAVE IN EXPERIENCED HANDS. SO WE WERE ALREADY BEYOND THAT STEEP PART OF THE LEARNING CURVE, WE WERE PRETTY GOOD AT DOING ECMO BUT AGAIN FOR BABIES WITH A DIFFERENT DISEASE AND ALSO YOU KNOW SORT OF THE SURGICAL ETHIC OF A CHANCE TO CUT IS A CHANCE TO HEAL. THERE'S THIS SURGICAL IDEAL THAT -- AND MAKING US MORE PROBABLY PRO ECMO THAN OUR COLLEAGUES ON THE 7TH FLOOR. AND SO THIS WAS THE LAYOUT AND IT DID KIND OF SET UP A HEALTHY COMPETITION, RIGHT? YOU GOT PEOPLE WHO ARE PRO-ECMO DOING THE ECMO PEOPLE WHO ARE ANTI ECMO WHO ARE NOW GOING TO BE PRETTY COMMITTED TO THE TREATMENT THAT THEY DO OFFER. SO -- SO THAT WAS -- THAT WAS PART OF THE STUDY DESIGN. THE OTHER PART THAT I WANT TO TELL YOU ABOUT IS ELIGIBLE ECMO, ELIGIBLE NEWBORNS HAD THE DISEASE PPHN AND PREDICTED MORTALITY OF 85 PERCENT BASED ON RETROSPECTIVE DATA FROM OUR INSTITUTION AND THE MOST RECENT DATA WE COULD GET, OKAY? SO WE LOOKED BACK OVER TWO YEARS, WE PICKED OUT THE BABIES WITH PPHN AND GOT CRITERIA FOR ENROLLMENT THAT WOULD HAVE PRE DIKTSD PREDICTED 85 PERCENT MORTALITY. THE ONLY ONE WHO KNEW WAS JIM WARE THE STATISTICIAN, NONE PHYSICIANS KNEW THIS THE STRATEGY WAS BABIES WOULD BE RANDOMIZED 5 50/50 BETWEEN THE TWO TREATMENTS, THIS WOULD CONTINUE UNTIL THERE WERE FOUR DEATHS IN ONE ARM OR THE OTHER, WITH THAT FOURTH DEATH THE STUDY WOULD ENTER PHASE TWO WHERE ALL OF THE PATIENTS WOULD BE ASSIGNED TO THE MORE SUCCESSFUL THERAPY, UNTIL THERE WERE FOUR DEATHS IN THAT ARM OR UNTIL STATISTICAL SIGNIFICANCE WAS ACHIEVED. AND THEN LAST PART WAS THAT CONSENT WAS OBTAINED ONLY FROM THE PATIENTS OF THOSE BABIES WHO WERE RANDOMIZED TO THE EXPERIMENTAL THERAPY. NOW I'M GOING TO COME BACK TO THAT LAST POINTS ABOUT CONSENT LATER ON IN THE TALK. RIGHT NOW I JUST WANT TO 123 FOE /* TO FOCUS ON THIS NUMBER FOUR, I WAS SURPRISED WHERE THIS NUMBER CAME FROM DID THEY MAKE IT UP OR WHAT S ? I DIDN'T HAVE THE ANSWER TO THAT UNTIL A NUMBER OF YEARS LATER WHEN I BEGAN TO TEACH THIS CASE WITH JIM WARE THE STATISTICIAN I WAS JIM WHERE DID THIS NUMBER COME FROM. HE WOULD POINT TO THIS PAPER THAT HE HAD PUBLISHED ON -- ON THE STUDY, AND I MEAN NO KIDDING HE WOULD ACTUALLY SHOW THESE -- THESE FORMULAS TO THE ROOM AND IN A VERY CALM AND CONFIDENT WAY SAY YOU KNOW THIS IS OBVIOUSLY VERY CLEAR TO ME BUT I CAN SEE THERE WAS A NUMBER FOUR HERE AND NUMBER FOUR HERE BUT BEYOND THAT I HAVE NO IDEA AND I STILL DON'T KNOW WHERE THAT NUMBER FOUR CAME FROM AND WE WOULD HAVE A LOT OF FUN TEACHING IT TOGETHER. SADLY HE PASSED AWAY A COUPLE YEARS AGO, BUT KIND OF KIDDING EACH OTHER BECAUSE FOR HIM THIS WAS SECOND NATURE THE STUFF HE HAD FOR BREAKFAST FOR ME IT WAS ALWAYS A MYSTERY. BUT I THINK IT ALSO SHOWS THE FACT THAT THESE KINDS OF ADAPTIVE SCHEMES ARE COMPLICATED. THEY'RE MATHEMATICALLY VERY COMPLICATED. SO HOW DID IT ALL TURN OUT? SO HERE'S WHAT HAPPENED: SO DURING PHASE ONE OF THE TRIAL NINE PATIENTS WERE RANDOMIZED TO ECMO ALL NINE SURVIVED. 10 PATIENTS WERE RANDOMIZED TO CONVENTIONAL THERAPY SIX SURVIVED AND FOUR DIED. SO PER THE PLAN, WHEN THIS FOURTH DEATH HAPPENED, THE STUDY ENTERED PHASE TWO WHERE ALL OF THE PATIENTS WERE ASSIGNED TO THE MORE SUCCESSFUL THERAPY WHICH IN THAT CASE WAS ECMO 19 OF THESE PATIENTS SURVIVED, ONE DIED, AND AT THAT POINT THE STUDY WAS DETERMINED TO HAVE STATISTICAL SIGNIFICANCE AND IT WAS STOPPED WITH ECMO BEING DECLARED THE WINNER. SO LET ME POINT OUT A COUPLE OF THINGS HERE: FIRST OF ALL, GOING BACK TO THE STUDY ENROLLMENT, YOU REMEMBER THAT THE ELIGIBILITY CRITERIA WERE BASED ON A MORTALITY OF 85%, BUT WHAT P DID WE ACTUALLY SEE IN BABIES WHO DIDN'T GET ECMO? NOTHING LIKE 85% MORTALITY, WE SAW 40% MORTALITY. AND YOU KNOW WHY WAS THIS? WELL YOU KNOW THERE'S A FEW ANSWERS TO THIS, NONE OF THEM MAYBE SATISFYING, ONE IS THAT THE NUMBER ARE SMALL MAYBE IF WE WOULD HAVE SEEN THE PREDICTIVE MORTALITY, OR IS THE HOSPITAL IN EFFECT GOING ON THE HOSPITAL EFFECT WHEN YOU START A STUDY THOSE WHO ARE SORT OF PARTS OF THE STUDY MAYBE WORK A LITTLE HARDER THAN THEY WOULD HAVE OTHERWISE, THEY KNOW THEY'RE UNDER A MICROSCOPE THEY'RE BEING WATCHED, DID THE NEONATOLOGISTS PERFORM BETTER BECAUSE A STUDY WAS GOING ON. I DON'T KNOW, MAYBE THERE WERE OTHER REASONS. BUT IT DOES POINT OUT ONE OF THE ADVANTAGES OF RANDOMIZED TRIALS OVER OBSERVENAL STUDIES BECAUSE YOU DON'T OFTEN -- IT'S NOT NECESSARILY THE CASE THAT WHAT YOU SEE GOING FORWARD IS THE SAME AS WHAT YOU SAW IN THE PAST. THE OTHER LITTLE POINT I WOULD MAKE HERE IS EVEN IN THIS ONE DEATH WAS AN ANOMALY THIS BABY DIED DURING ECMO CANNULATION WHEN THE CANULA PERFORATED THE RIGHT ATRIA. THE BABY DIED WITHIN MOMENTS. THIS IS A PROBLEM WITH ECMO BUT ON THE OTHER HAND IN THOSE CANNULATE WITH ECMO WE SAW 100 PERCENT SURVIVAL. SO THAT'S THE TRIAL. NOW I WANT TO TALK SOME ABOUT THE ETHICS. AND IF THERE'S ONE THING I'D LIKE YOU TO TAKE AWAY FROM THIS TALK IS THAT THERE IS A FUNDAMENTAL CONFLICT WHEN WE TALK ABOUT CARE THAT CAN NEVER BE RESOLVED. THE TWO DIFFERENT ROLES HERE ON THE ONE HAND BEING A HEALER BEING A SCLIN ANYTHINGS, ON THE OTHER HAND BEING A SCIENTIST BEING AN INVESTIGATOR, I WOULD LIKE TO SUBMIT TO YOU THAT THERE'S A CONFLICT HERE THAT CAN NEVER BE ELIMINATED. SO IT'S BEEN WRITTEN ABOUT IN THE FOLLOWING WAY THIS FUNDAMENTAL DILEMMA, THIS JAY KATZ WROTE I'VE A DILEMMA IN FRONT OF PHYSICIANS AND INVESTIGATORS AS PHYSICIANS THEY'RE DEDICATED FOR CARING FOR THEIR PATIENTS AS INVESTIGATORS THEY ARE DEDICATED TO CARING FOR THEIR RESEARCH, THESE TWO COMMITMENTS CONFLICT. WHENEVER AN INDIVIDUAL PHYSICIAN/INVESTIGATORS COMES FACE-TO-FACE WITH AN INDIVIDUAL PATIENT/SUBJECT. AND YOU KNOW I THINK IT'S WELL CAPTURED IN THIS CARTOON FROM THE NEW YORKER A NUMBER OF YEARS AGO HERE'S THE TOMBSTONE MEMBER PLACEBO GROUP. THE PUBLIC IS AWARE OF THIS, THERE'S SOME DISTRUST AROUND THE RESEARCH ENTERPRISE. SO HOW DO WE FIX THIS PROBLEM? LET ME SUGGEST A COUPLE OF WAYS: SO ONE POSSIBLE SOLUTION IS TO CREATE A FULL SEPARATION OF THE ROLES SO YOU NEVER HAVE THE SAME PERSON OR PEOPLE ACTING IN THE ROLE OF CLINICIANS VERSUS RESEARCHERS. SO REBECCA DRESSER ANOTHER BIO ET THINKS WROTE ABOUT THIS IN A HARSH WAY YOU HAVE TO HAVE SEPARATION OF ROLES IT NEEDS TO BE VERY TRANSPARENT RESEARCHERS MUST GIVE PATIENTS STARK BOLD DRAT MAT PARTICULAR SIGNS THAT RESEARCH IS DIFFERENT FROM CLINICAL CARE INSTEAD OF WHITE COATS ASSOCIATED WITH MEDICAL CARE INVESTIGATORS COULD WEAR RED ONES. THERE WOULD BE NO DOUBT WHEN SOMEBODY WALKS IN YOUR ROOM IF IF THEY HAVE A RED COAT ON THEY'RE THERE TO DO RESEARCH IF THEY HAVE A WHITE COAT ON THEY'RE THERE TO TAKE CARE OF YOU. A PROBLEM WITH THIS IS THAT -- WELL FIRST OF ALL LET ME SAY WHENEVER IT CAN BE DONE IN A REASONABLE WAY IT SHOULD BE DONE. I THINK THIS IS OFTEN DONE, AND IT IS A GOOD SOLUTION THIS SEPARATION OF ROLES. BUT IT'S NOT ALWAYS PRACTICAL. SO IF YOU THINK ABOUT WHERE YOU GUYS ARE ALL AT AT THE NIH, IF SOMEBODY IS OUT THERE WITH A VERY RARE FORM OF CANCER, LET'S SAY, AND THEY COME TO THE NIH, IT'S QUITE LIKELY THAT THERE IS GOING TO BE A PERSON THERE WHO IS LIKE THE WORLD EXPERT ON TAKING CARE OF PATIENTS WITH CANCER AND NO SURPRISE IT'S ALSO THE PERSON WHO IS DOING THE RESEARCH. SO FOR YOU AS A PROSPECTIVE PERSON COMEING IN YOU ACTUALLY DON'T WANT FULL SEPARATION OF THE ROLES RIGHT? YOU REALIZE THAT BY COMING TO THE NIH YOU'RE GOING TO BE A PART OF RESEARCH TRIALS BUT YOU ALSO WANT THAT PERSON TO BE TAKING CARE OF YOU. SO IN THOSE KIND OF SITUATIONS, IT'S DIFFICULT, OR IMAGINE THE BARTLETT THING YOU KNOW IF YOU'RE COMEING IN AND YOU'RE GOING TO BE PUT ON ECMO DO YOU WANT THE SURGEON WHO HAS PUT HUNDREDS OF BABIES PUT ON ECMO TO BE THE ONE CAN KNEW LATING YOUR BABY OR TO SEPARATE THE ROLES DO YOU WANT A SURGEON WHO HAS NEVER DONE THIS BEFORE TO BE TASKED WITH THIS RATHER CHALLENGING SITUATION? SO IT'S NOT ALWAYS A BEST OR PRACTICAL SOLUTION. POSSIBLE SOLUTION NUMBER TWO IS PERSONAL ECMO EMPLOYEES. THE IDEA HERE IS IF YOU'RE GOING TO BE THE IN THE ROLES AS BOTH CLINICIAN AND INVESTIGATOR YOU MUST BE PERSONALLY UNBIASED BETWEEN THE TWO TREATMENT ARMS. YOU MUST BE PERSONALLY BALANCED ON THE EDGE OF THE SWORD IF YOU WILL. YOU MUST BE ABLE TO LOOK THAT PATIENT/SUBJECT IN THE EYE AND SAY I JUST HONESTLY DON'T KNOW WHICH ONE IS BETTER. AND I SUSPECT THAT FOR MANY OF YOU, WHO THOUGHT THAT THANK BART SHOULDN'T BE DOING THE TRIAL THIS IS IN YOUR MIND IF HE IS CONVINCED THAT HE HAS A LIECH LIFE SAVINGS THERAPY HE SHOULDN'T BE DOING THE TRIAL. MAYBE SOMEBODY ELSE SHOULD DO IT BUT VIOLATING AN ETHICAL COMMITMENT NOT TO BE SAVING LIVES WHEN HE THOUGHT HE COULD SAVE ONE. THE PROBLEM WITH PERSONAL ETHICAL POISE THE ENGAGED IN CLINICAL RESEARCH AND YOU PROBABLY DWOEEVOTED AN ENORMOUS AMOUNT OF EFFORT TO A PARTICULAR DRUG OR TREATMENT. I DOUBT YOU WOULD HAVE DONE THAT IF YOU DIDN'T THINK YOU HAD A TREATMENT THAT WAS GOING TO BE SUCCESSFUL. AND SO THAT'S WHAT DRIVES US TO DO CLINICAL RESEARCH. I DON'T THINK WE SHOULD THINK IT'S UNUSUAL IF SOMEBODY'S BELIEVING IN THE TREATMENT THAT THEY ARE STUDYING AND THAT THEY ARE NOT IN PERSONAL ECHO POISE. AND THE PROBLEM WITH DEMANDING PERSONAL ECHO POISE OFTEN IT LEAVES INVESTIGATORS FEELING EITHER QUILT TEE OR CYNICAL, QUILT TEE LIKE WOW I PROBABLY SHOULDN'T BE ENROLLING PATIENTS BECAUSE I'M NOT IN PERSONAL EQUIPOISE OR CYNICAL NO THERE'S NOTHING WRONG WITH ME ENROLLING HES PATIENTS IF ETHICS SAYS THERE'S SOMETHING WRONG WITH IT THERE'S SOMETHING WRONG WITH ETHICS. THIS WAS WHAT DROVE BENJAMIN FREEDMAN WHO PASSED AWAY A NUMBER OF YEARS AGO CANADIAN BIO ETHICIST WHO DEVELOPED THIS CONCEPT OF CLINICAL EQUIPOISE AND IT IS A STATE OF UNCERTAINTY WITHIN THE MEDICAL COMMUNITY AS A WHOLE, NOT NECESSARILY A PARTICULAR INVESTIGATOR PERSON, BUT THE MEDICAL COMMUNITY AS A WHOLE. AND IT'S KIND OF LIKE THIS: IMAGINE YOU'RE STUDYING A DRUG FOR HYPERTENSION, AND THE PERSON HAS COME INTO THE CLINIC AND YOU SIT DOWN AND SAY YOU KNOW I HAPPEN TO BELIEVE THAT THIS DRUG A IS BETTER FOR HYPERTENSION BUT IF YOUR APPOINTMENT HAD BHN WITH MY COLLEAGUE DOWN THE HALL I KNOW SHE WOULD HAVE RECOMMENDED B I RESPECT HER VIEWS, I HAVE MY OWN, BUT BECAUSE OF THIS CLINICAL EQUIPOISE THIS UNCERTAINTY WITHIN THE COMMUNITY WOULD YOU AGREE TO HAVE YOUR TREATMENT DETERMINED BY A COIN FLIP SO WE CAN LEARN FROM THIS EXPERIENCE? THAT'S THE GENERAL IDEA AROUND CLINICAL EQUIPOISE IT DOES NOT REQUIRE PERSONAL UNCERTAINTY. I THINK I THINK THE HARVARD ECMO TRIAL IS A GOOD EXAMPLE IT'S LIKELY THERE WAS NO SINGLE INVESTIGATOR THAT WAS IN A STATE OF CLINICAL EQUIPOISE THE COLLECTIVE UNCERTAINTY IN BOSTON HOSPITAL AND AROUND THE COUNTRY IT MET WITH THE CLINICAL EQUIPOISE AND THAT'S WHAT MADE IT ABLE TO ENROLL THE PATIENTS IN THE TRIAL. ADAPTIVE RANDOMIZATION, AND THIS IS I'LL TELL YOU WHAT D IS, BUT THE GOAL HERE IS TO BALANCE THESE CONFLICTING OBLIGATIONS, THESE ROLES OF CLINICIAN VERSUS INVESTIGATOR. THE DEFINITION OF ADAPTIVE RANDOMZATION IS DEVIATEING FROM BALANCE OR 50/50 RANDOMIZATION WITH MORE PATIENTS ASSIGNED TO THE THERAPY THAT IS LEADING DURING THE TRIAL. ESSENTIALLY YOU CAN SAY IT'S LIKE BETTING ON THE HORSE WHO IS OUT IN FRONT BEFORE WE KNOW HOW THE RACE WILL END, THAT'S CONCEPTUAL. IT MINIMIZES THE NUMBER OF PATIENTS ASSIGNED TO THE THERAPY THEREFORE ATTEMPT TO MINIMIZE THIS CONFLICT BETWEEN HEALER AND INVESTIGATOR WHERE YOU'RE GOING TO SAY I'M GOING TO BALANCE THESE OBLIGATIONS, I WANT TO DO GOOD SCIENCE BUT I WANT TO BE THE BEST DOCTOR I CAN AND MAKE SURE I SAVE THE MOST LIVES I CAN. NOW IT'S INTERESTING THAT THE BARTLETT TRIAL 50/50 RANDOMIZATION WAS GUARANTEED ONLY FOR THE FIRST PATIENT, RIGHT? WE STARTED OUT WITH BAU BUCKET THAT JUST HAD TWO MARBLES IN IT WHEN THE HARVARD INVESTIGATORS CRITICIZED THE BARTLETT TRIAL SAYING IT WASN'T GOOD THEY WERE CRITICIZING ADAPTIVE RANDOM SFLAGS BUT WHEN FACED WITH THAT SAME ETHICAL CONCEPT THEMSELVES THEY ALSO ADOPTED AN ADAPTIVE STRATEGY. THEIRS DIFFERED FROM BARTLETT ONLY IN THE SENSE THAT 50/50 RANDOMIZATION WAS GUARANTEED UNTIL THERE WAS A 4TH DEATH IN ONE ARM. THERE'S DISADVANTAGES, ONLY ONE PRIMARY OUTCOME OF INTEREST BECAUSE YOU WILL ADJUST THE STRATEGY ON THAT OUTCOME IN THE ECMO IT WAS MORTALITY AND THE OUTCOME MUST BE APPARENT IN A SHORT PERIOD OF TIME BECAUSE YOU HAVE TO FEED IT IN THE RANDOMIZATION SCHEME. IN ECMO WE KNEW WHETHER THE PATIENT SURVIVED OR DIED VERY QUICKLY. ONE ASPECTS OF THIS WHEN YOU THINK ABOUT IT MORE BROADLY IS THIS STRATEGY MAY SUFFER FROM ACCRUAL BIAS BECAUSE VOLUNTEERS MAY WANT TO BE RECRUITED INTO THE TRIAL LATER. AGAIN THIS WASN'T A DECISION FOR THE ECMO BECAUSE A DECISION NEEDED TO BE MADE IMMEDIATELY AND I PROBABLY SHOULD HAVE MENTIONED THIS BEFORE AND BOSTON WAS REALLY THE ONLY OPTION FOR THEM THESE BABIES WERE TOO SICK TO BE TRANSPORTED TO THE NEAREST OTHER CENTER THAT COULD HAVE OFFERED ECMO WHICH WAS IN PHILADELPHIA. SO THEY COULDN'T DEFER ENROLLMENT, IF YOU WILL, A DECISION HAD TO BE MADE IMMEDIATELY. THE BOSTON TRIAL WAS CRITICIZED FROM BOTH DIRECTIONS, THERE WERE THOSE THAT SAID NONE OF THE PATIENTS SHOULD HAVE BEEN ASSIGNED TO CONVENTIONAL THERAPY. SO I'M QUOTING HERE FROM AN ISSUE OF THE JOURNAL STATISTICS IN MEDICINE THAT DEVOTED AN ENTIRE ISSUE TO TALKING ABOUT THIS TRIAL THESE CAME FROM COMMENTARIES. DAWN BETTER STATISTICIAN SAID NO PATIENTS SHOULD HAVE BEEN ASSIGNED ON CONVENTIONAL THERAPY WAS HAVING AN EXCESS NUMBER OF DEATHS BALANCED BY THE WORTH OF INFORMATION GAINED? MY ANSWER A RESOUNDING NO. AT THAT POINT BASED ON THE BARTLETT TRIAL ALL OF THE PATIENTS SHOULD HAVE GOTTEN ECMO. OTHERS SAID NOT ENOUGH PATIENTS WERE ASSIGNED TO CONVENTIONAL THERAPY. ONE WROTE THE RESEARCHERS WERE SO PREOCCUPIED WITH ETHICAL PROBLEMS THEY STOPPED CONVENTIONAL THERAPY TOO SOON. THERE IS A SLIGHTLY HYSTERICAL VIEW THAT WE NEED TO STOP A STUDY AS SOON AS WE HAVE AN IDEA ABOUT WHICH TREATMENT MIGHT BE BETTER. YOU CAN ARGUE LOOKING AT ALL OF THIS THAT PERHAPS THE APPROACH THEY TOOK WAS A GOOD BALANCE THIS NUMBER FOUR THIS IDEA THAT WE WOULD OFFER THE MORE SUCCESSFUL THERAPY TO ALL PATIENTS ONCE WE HAD A FOURTH DEATH MAY HAVE BEEN GOOD BALANCE. IN FACT, FOR THOSE OF YOU WHO MIGHT BE INTERESTED IN THE SOCIOLOGY OF THIS, AS PATIENTS WERE DYING IN THE NEONATAL ICU ON THE 7TH FLOOR THE NURSES WHO WE OFTEN THINK OF AS THE CANNEARY IN THE COAL MINE THE NURSES BEGAN TO BE MORE RESISTIVE ABOUT KEEPING PATIENTS IN THE ICU AND NOT OFFERING ECMO AND BY THE TIME THERE WAS A FOURTH DEATH IN THE NEONATAL ICU AND ALL BABIES GETTING ECMO TWO FLOORS DOWN WERE SURVIVING THEY SAID WE'RE NOT GOING TO DO THIS ANYMORE AND AT THAT POINT THE FOURTH DEATH ALL BABIES WOULD RECEIVE ECMO THAT RESOLVED THAT ETHICAL TENSION. NUMBER FOUR MAY HAVE PLAYED AN ACTUAL PIVOTAL ROLE IN ALLOWING THE STUDY TO BE DONE. I WANT TO SAY THAT ADAPTIVE DESIGN COULD BECOME MUCH MORE ACCEPTED IN THE LAST FEW YEARS AND IN FACT THE FOUNDATIONAL BASIS FOR WHAT WE NOW CALL PLATFORM TRIALS WHICH ARE BECOMING VERY POPULAR. AND SO YOU KNOW IN A PLATFORM TRIAL YOU MIGHT START HERE FOR EXAMPLE WITH THREE POSSIBILITIES STANDARD OF CARE AND A COUPLE OF INTERVENTIONS, AND THEN AS YOU MOVE INTO THE TRIAL BEFORE STATISTICAL SIGNIFICANCE IS ACHIEVED FOR ANYTHING, YOU MAY ADOPT THIS SORT OF PLAY THE WINNER STRATEGY. THIS GROUP ISN'T LOOKING SO GOOD IN THE EARLY NUMBERS SO WE'RE GOING TO DROP THEM, ADD ANOTHER INTERVENTION WE GET A LITTLE FURTHER ALONG WE'RE GOING TO ADD ANOTHER INTERVENTION SO YOU END UP TESTING MULTIPLE THERAPIES AT ONCE NONE OF THEM GOING TO THE POINT OF STATISTICAL SIGNIFICANCE UNTIL YOU GET TO A VERY FINELY HONED UNDERSTANDING OF WHICH TREATMENTS ARE WORKING AND WHICH AREN'T BEFORE YOU GO INTO A RANDOMIZED PART OF THE TRIAL. AND THE MOST FAMOUS OF THESE IS THE I SPY TRIAL WHICH HAS GONE THROUGH MANY ITERATIONS, HERE YOU GET YOU SEE DR. BERRY WHO HAD COMMENTED ON THE ECMO TRIAL AS ONE OF THE BIG PRO MOAN NENTS OF THESE. IT IS WORTH US TALKING ABOUT ADAPTIVE DESIGNS BECAUSE THEY ARE VERY COMMON NOW. AND JUST LIKE I SHOWED YOU WITH THAT PAGE OF STATISTICAL STATISTICS FROM TIM WARE THE MATH IS COMPLICATED. THESE REALLY REQUIRE A VERY HIGH LEVEL OF COMPUTATIONAL SOPHISTICATION IN ORDER TO RUN AND THEY ARE NOT VERY INTUITIVE. SO THAT'S ADAPTIVE RANDOMIZATION. LET'S GO ON TO THE VERY LAST TOPIC THAT WE'LL TALK ABOUT, WHICH IS RANDOMIZED CONSENT. YOU REMEMBER I TOLD YOU THAT ONLY THE BABIES WHO WERE RANDOMIZED ECMO ONLY THEIR PATIENTS WERE APPROACHED FOR INFORMED CONSENT. FOR THE BABIES RANDOMIZED TO CONVENTIONAL THERAPY CONSENT WAS NOT OBTAINED. I WANT TO EXPLAIN HOW THIS WORKS. WHEN YOU THINK ABOUT A CONVENTIONAL RCT WITHOUT INFORMED CONSENT YOU WILL DETERMINE A PATIENT IS ELIGIBLE FOR TREATMENT AND THEY'LL BE RANDOMIZED TO A OR B. THIS IS STRAIGHT FORWARD RANDOMZATION. HOPEFULLY THIS DOESN'T EVER HAPPEN OUTSIDE OF THE LABORATORIES AT NIH WITH MICE, BECAUSE WHAT'S MISSING HERE IS INFORMED CONSENT. AND SO IN THE TRADITIONAL ROLE THAT WE DO, FIRST IF WE DETERMINE A PATIENT IS ELIGIBLE WE SEEK THEIR INFORMED CONSENT IF THEY SAY YES THEY GET RANDOMIZED IF THEY SAY NO THEY'RE DROPPED. NOW ALREADY WE HAVE A POTENTIAL PROBLEM HERE IN THAT THIS REQUIRES US TO KNOW THAT PATIENTS WHO HAVE RANDOMIZED DO NOT DIFFER IN SIGNIFICANT WAYS TO THOSE WHO ARE DROPPED. WE'VE ALREADY INTRODUCED COMPLICATIONCOMPLICATIONS, THIS IS PROPOSED BY A STATISTICIAN AT THE SCHOOL FOR PUBLIC HEALTH LET ME SHOW YOU WHAT HE PROPOSED ONCE A PATIENT IS DETERMINED TO BE ELIGIBLE FOR THIS STUDY INSTEAD OF FIRSEEKING THEIR INFORMED CONSENT THEY ARE RANDOMIZED IF THEY SAY YES THEY GET IT IF THEY SAY NO THEY GET CONVENTIONAL THERAPY. BUT IF RANDOMIZED TO CONVENTIONAL THERAPY WE DON'T ASK FOR THEIR CONSENT BECAUSE THEY'RE NOT A PART OF THE STUDY, THEY'RE GETTING CONVENTIONAL THERAPY. AND SO YOU KNOW THIS IS THE ARGUMENT THAT WAS MADE IN THE ECMO TRIALS, IF PATIENTS WERE RANDOMIZED TO CONVENTIONAL THERAPY THAT'S WHAT THEY GOT. ONLY IF THEY WERE RANDOMIZED TO ECMO DID THEY GET THE -- WERE THEY APPROACHED FOR CONSENT. IT DID TURN OUT IN FACT, THAT ALL 29 PATIENTS WHO WERE RANDOMIZED TO ECMO DID CONSENT. NOBODY REFUSED AND YOU CAN IMAGINE WHY, THEY WERE APPROACHED SAYING, YOU KNOW, WE DO HAVE THIS NEW TREATMENT, THERE'S -- YOUR CHILD HAS AN 85 PERCENT PREDICTIVE MORTALITY, WE DO HAVE THIS NEW TREATMENT, WE ALREADY KNOW YOU CAN HAVE IT IF YOU WANT IT ALL YOU NEED TO DO IS SAY YES, NOT SURPRISING THAT EVERYBODY DID SAY YES. SO WE'RE LOOKING AT THE TIME AND WE'RE GOING TO FINISH ON TIME FOR SURE, BUT I'D LIKE TO GO TO OUR SECOND TO LAST QUESTION, IMAGINE THAT YOU WERE ON THE IRB AT BOSTON CHILDREN'S HOSPITAL WHEN THIS STUDY WAS PROPOSED, WOULD YOU HAVE APPROVED THIS ZELEN RANDOMIZATION SCHEME, WHY OR WHY NOT, YES, I WOULD HAVE VOTED TO APPROVE THE ZELEN RANDOMIZATION SCHEME OR NO I WOULD HAVE NOT VOTED TO APPROVE THE ZELEN SCHEME AND I'M GOING TO PAUSE MUTE MY SELF AND WE'LL VOTE ON THIS ONE. >> THE VOTES ARE COMING IN, AND WE WERE GOING TO ACTUALLY STOP AT 9:15 FOR QUESTIONS AND ANSWERS, BUT WHAT -- WHAT I'D LIKE TO DO IS FOR YOU TO FINISH, BOB, THAT WE CAN GO UNTIL 9:30, AND WHAT WE USUALLY DO IS HAVE FOLKS POST QUESTIONS EITHER BY E-MAIL AND/OR THE DISCUSSION BOARD, AND I CAN MODERATE THOSE AND IF SOMEONE TRIES TO STUMP ME OR DOES STUMP ME I MIGHT REACH OUT TO YOU FOR AN ANSWER, IF THAT'S OKAY. >> DR. ROBERT TRUOG: OF COURSE THAT WOULD BE OKAY. >> TERRIFIC. >> DR. ROBERT TRUOG: THANK YOU. >> WE'LL GIVE FOLKS ANOTHER MINUTE, THE POLLING TAKES A LITTLE BIT OF TIME. OKAY IT LOOKS LIKE 2/3 OF THE GROUP WOULD HAVE APPROVED THE ZELEN RANDOMIZATION SCHEME. >> DR. ROBERT TRUOG: OKAY. SO FOR THOSE OF YOU WHO SAID YES, MIGHT HAVE BEEN THINKING THE CONTROL BABIES WERE NOT REALLY RESEARCH SUBJECTS THEIR CARE WAS UNCHANGED TO WHAT IT WOULD HAVE BEEN HAD THE STUDY NEVER BEEN ERFORMED YOU MIGHT HAVE THOUGHT IT WAS CRUEL TO TELL A PERSON THAT A TREATMENT THAT MIGHT HAVE SAVED THEIR BABY'S LIVES WERE AVAILABLE BUT THEY COULDN'T HAVE IT, SOME BABIES GET IT BUT YOU'RE NOT GOING TO GET IT OR YOU MIELT NOT HAVE APPROVED THE SCHEME BECAUSE IT IS UNETHICAL TO TREAT PATIENTS WITHOUT INFORMED CONSENT OR WRONG TO TREAT THE PATIENT WITHOUT THE PATIENT'S KNOWLEDGE OR INTENTIONALLY WITHHOLDING INFORMATION FROM PATIENTS IS DECEPTION AND DECEPTION IS ALWAYS WRONG. INDEED WHEN THIS WAS PUBLISHED HERE'S THE ARTICLE THAT APREERD PEERED THE DAY AFTER IN THE BOSTON GLOBE, BY RICHARD NOX A REPORTER FROM NCR, SOMEBODY ACTUALLY CLIPPED THIS OUT OF THE GLOBE AND SENT IT TO THE NIH. AND THEY -- THE NIH GOT BACK TO CHILDREN'S AND THEY SAID WAIT A MINUTE, YOU GOT TO SAY WHY YOU DID THIS. SO THE CHILDREN'S IRB MADE THE FOLLOWING ARGUMENTS, THAT THE CONTROL PATIENTS WERE REALLY NOT RESEARCH SUBJECTS BECAUSE THEY WERE GETTING EXACTLY THE SAME CARE, EXACTLY THE SAME CARE, THAT THEY WOULD HAVE RECEIVED HAD THERE NOT BEEN A STUDY. AND THEY WERE ALSO NOT REALLY BEING OFFERED A CHOICE, YOU KNOW, SO AGAIN, WOULD YOU HAVE GONE TO THEM AND SAID WE'RE DOING THIS STUDY, YOU'RE TELLING US HAS ALREADY BEEN RANDOMIZED TO CONVENTIONAL TREATMENT YOU HAPPENED TO GET ECMO BUT WE SOMEHOW FEEL OBLIGATED TO TELL YOU AND THE TWO LEAD AUTHORS THE STUDY SAID MIKE EPSTEIN THE NIGH O NEONATOLOGIST SAID THE DECISION WAS CONTROVERSIAL WE HAD SEVERAL WEEKS OF DISCUSSION OVER AUTONOMY VERSUS PATERNAL LICHL, JIM WARE SAID I PREFER TO CALL IT OPENNESS VERSUS COMPASSION. THEY SAID FAILURE TO CROSSOVER WOULD HAVE BEEN UNBEARABLE. SO THE RESPONSE FROM THE NIH WAS TO REPRIMAND THE HOSPITAL. THE OFFICE OF RESEARCH PROTECTION SAID THE HOSPITAL IRB MADE DECISIONS THAT RIGHTFULLY BELONGED TO THE PATIENTS THEY BLEW IT. GEORGE ANNAS SAID WE WERE DOING EXACTLY WHAT PHYSICIANS DID BEFORE WE HAD A DOCTRINE OF INFORMED CONSENT MAKING DECISIONS FOR PARENTS. I DON'T THINK EITHER OF THESE ARE PARTICULARLY RELEVANT BUT I THINK OPENNESS AND TRANSPARENCY OVERALL IS PROBABLY THE STRONGEST CRITICISM. WHICH BRINGS ME TO THE VERY END, ARE RCTS THE ONLY WAY TO LEARN? AND YOU KNOW THERE'S THIS REAL PRESSURE AROUND ECMO TO SAY THAT UNLESS YOU HAD AN RCT THE EVIDENCE WASN'T GOING TO BE CONVINCING, AND I'D LIKE TO POINT OUT THAT YOU KNOW I THINK THERE'S A LOT OF WAYS THAT WE LEARN IN MEDICINE, NOT JUST RCTS AND HERE'S THE LIST WE START WITH THINGS THAT ARE VERY UNRELIABLE ANECDOTAL CASE REPORTS, RCTS ARE NOT AT THE TOP OF THE LIST, METAANALYSES WE SAY ARE EVEN BETTER. BUT THE IDEA IS THAT THERE'S A LOT OF WAYS WE CAN LEARN, THE ONLY DIFFERENCE IS HOW MUCH CONFIDENCE WE HAVE IN THAT. STATISTICIANS THEMSELVES HAVE CRITICIZED OUR RELIANCE ON THE RCT THE BRILLIANT SUCCESS OF THE RCT HAS BECOME A FORM OF IRNT ELECT SHUL TYRANNY WE SHOULD NOT PROCEED ON WHERE THERE IS NO RANDOMIZATION THERE IS NO TRUTH. ARTICLES HAVE SAID WE FOUND LITTLE EVIDENCE THAT EVIDENCE OF TREATMENT EFFECTS ON OBSERVATIONAL STUDIES REPORTED AFTER 1984 ARE EITHER CONSISTENTLY LARGER THAN OR QUALITATIVELY DIFFERENT FROM THOSE OBTAINED IN RANDOMIZED CONTROLLED TRIALS. I'M GOING TO PASS THIS SO WE CAN HAVE TIME FOR THE LAST QUESTION, GIVEN ALL THAT YOU'VE SEEN ARE YOU NOW CONVINCED THAT ECMO IS SUPERIOR TO CONVENTIONAL THERAPY YES BASED ON THE DATA FOR THE TWO TRIALS I AM CONVINCED THAT ECMO IS SUPERIOR OR NO I AM NOT CONVINCED. I WILL MUTE MYSELF. >> GREAT THE VOTES ARE COMING IN, AND I DO HAVE ONE QUESTION FROM THE GROUP, AND YOU JUST TOUCHED ON IT A SECOND AGO ABOUT WHETHER CONDUCTING A CASE CONTROL TRIAL WOULD HAVE ADDRESSED SOME OF THE SORT OF ETHICAL CONFLICT BETWEEN THE PHYSICIAN VERSUS INVESTIGATOR, DO YOU WANT TO SHARE ANY THOUGHTS ON THAT. >> DR. ROBERT TRUOG: YEAH, SURE. I MEAN I THINK THAT WOULD BE A VERY VIABLE OPTION. ON THAT LIST OF THINGS THAT YOU KNOW NOT AS HIGH DEGREE OF CONFIDENCE AS WITH AN RCT WE DID SEE THE MORTALITY IN THE CONTROL BABIES SHIFTED DRAMATICALLY WHEN AN RCT WAS STARTED, BUT YES, THEY COULD HAVE ABSOLUTELY BEEN AN ALTERNATIVE TO A RANDOMIZED CONTROL TRIAL. >> GREAT. SO WE'LL GIVE FOLKS ANOTHER COUPLE SECONDS HERE. SO WE'VE GOT 87% OF THE FOLKS CONVINCED THAT ECMO IS BETTER THAN THE TRADITIONAL THERAPY. YOU DID A GOOD JOB OF CONVINCING THEM. >> DR. ROBERT TRUOG: WELL I'D ALSO BE VERY INTERESTED IN HEARING FROM THE 13% AS TO WHAT THEY FIND NOT CONVINCING. >> EXACTLY. >> DR. ROBERT TRUOG: THEY'RE IN GOOD COMPANY, I THINK, BECAUSE MY LAST POINT I WANT TO MAKE SHE HERE IS THAT WHEN THE UK WAS CONSIDERING ADOPTING ECMO THEY WERE SKEPTICAL OF THE DATA THEY SAID THE EXISTING RCTS OF NEONATAL ECMO SUGGESTED REDUCTIONS IN MORTALITY BUT WERE NOT CONCLUSIVE BECAUSE THEY USED ADAPTIVE DESIGNS WHICH MAY HAVE INTRODUCED BIAS, SO IN THE UK THEY DID THEIR OWN RANDOMIZED TRIALS, FROM 93 TO 95, 108 WERE RANDOMIZED STRAIGHT UP 50/50 RANDOMIZATION, TRIAL WAS STOPPED EARLIER WHEN 50 PERCENT OF THE ECMO PATIENTS SURVIVED ONLY 41% FOR THOSE IN CONVENTIONAL THERAPY A STRONG P VALUE MY COLLEAGUE WROTE IN THE LANCET THAT THIS TRIAL WAS UNETHICAL THAT THERE WAS ALREADY SUFFICIENT EVIDENCE THAT ECMO WAS SUPERIOR AND 22 BABIES THE NUMBER OF LIVES THAT WOULD HAVE BEEN SAVED HAD THE TRIAL NOT BEEN DONE 22 BABIES WERE UNNECESSARILY SACRIFICED. REALLY TO SATISFY OUR WORSHIP IF YOU WILL OF THE RANDOMIZED CONTROL TRIAL. MY LAST SLIDE HERE IS I DON'T WANT YOU TO THINK I'M OPPOSED TO RCTS I AM NOT, THEY'RE USUALLY THE BEST APPROACH, BY IT'S CONFLICT BETWEEN PHYSICIAN AND INVESTIGATES TORE IS PROFOUND, IT CAN NEVER BE ENTIRELY ELIMINATED. ADAPTIVE RANDOMIZATION IS ONE WAY TO BALANCE THIS, AND IS INCREASE WILLINGLY BEING USED. ZELEN RANDOMIZATION REDUCES THE PSYCHOLOGICAL BURDENS OF INVESTIGATORS BUT BASED ON THE RESPONSE I THINK IT'S PROBABLY AN UNACCEPTABLE APPROACH. I REALIZE I WENT LONG I KNOW YOU'RE GOING TO HAVE A CHANCE TO ENGAGE IN DISCUSSION, AND PLEASE FEEL FREE TO E-MAIL ME AS WELL AND I'LL DO MY BEST TO RESPOND. THANKS VERY MUCH TO THE OPPORTUNITY TO CONTRIBUTES. >> YES THANK YOU SO MUCH FOR JOINING US TODAY AND THERE'S A WILD ROUND OF APPLAUSE HERE IN LIPCET AUDITORIUM. THANK YOU AGAIN I'M SURE WE'LL SEE YOU NEXT YEAR PERHAPS IN PERSON OR PERHAPS VIA ZOOM AGAIN. THANKS AGAIN, AND HAVE A LOVELY REST OF YOUR DAY. >> DR. ROBERT TRUOG: OKAY THANK YOU SO MUCH BYE BYE. >> THANK YOU. OKAY FOLKS, SO WE ARE NOW GOING TO TRANSITION TO SCOTT KIM WHO'S GOING TO TALK WITH US ABOUT THE ETHICS OF PRAGMATIC TRIALS. I WILL REMIND YOU THAT THE WORD OF THE DAY IS PLACEBO, WE ARE RUNNING ABOUT FIVE MINUTES LATE, WHICH IS -- IS TOTALLY FINE, SCOTT'S GOING TO START AT 9:30. WE'LL HAVE 10 MINUTES FOR QUESTIONS AND ANSWERS, A REMINDER YOU CAN POST THOSE ON THE DISCUSSION BOARD OR SEND E-MAILS IF YOU HAVE QUESTIONS ABOUT DR. TRUOG'S LECTURE SEND THOSE AND WE CAN TAKE CARE OF THEM. EITHER I CAN ADDRESS THEM OR WE'LL SEND THEM ONTO HIM. THANK YOU AND I WILL REINTRODUCE SCOTT. WE MET HIM A COUPLE OF WEEKS AGO, HE IS A FACULTY MEMBER HERE IN THE DEPARTMENT OF BIO ETHICS AT THE CLINICAL CENTER BOTH A PHILOSOPHER IS A PSYCHIATRIST AND IS GOING TO TALK ABOUT ETHICAL ISSUES IN PRAGMATIC RANDOMIZED CONTROL TRIALS THANKS SCOTT. >> DR. SCOTT KIM: GREAT HOLLY CAN YOU SEE MY SCREEN? >> I SURE CAN DO YOU WANT TO PUT IT ON PRESENTATION MODE. >> DR. SCOTT KIM: YES I'M GOING TO DO THAT NOW. >> TERRIFIC. WE SEE IT. >> DR. SCOTT KIM: GREAT. ARE TERRIFIC. YOU KNOW THERE'S AN ECHO, OKAY IT'S GONE NOW. GREAT. THANK YOU HOLLY. GOOD MORNING, EVERYBODY. EVEN THOUGH I CAN'T SEE YOU. I NOTICED THAT BOB HAD MOUNTAINS IN THE BACKGROUND SO I PUT MY RIVER SCENE JUST TO GIVE YOU A LITTLE CHANGE OF PACE. I'M GOING TO TALK ABOUT ETHICAL ISSUES THAT ARE PRAGMATIC RCTS, AND THE WAY I'M GOING TO DO IT IS FIRST BRIEFLY DESCRIBE WHAT THESE TRIALS ARE, AND I WILL FOCUS ON THE KIND OF TRIAL WHERE PEOPLE ATTEMPT TO COMPARE TWO ALREADY IN USE INTERVENTIONS, SO WE'LL TALK ABOUT THAT. AND DESCRIBE WHAT SOME OF THEEST CAL ISSUES ARE, I WANT TO SPEND SOME INTERACTIVE TIME EXPLORING SEVERAL EXAMPLES OF THESE TYPES OF PRAGMATIC TRIALS AND DISCUSS THEM TOGETHER, JUST GET YOUR INTUITIONS FLOWING. AND IT WILL BE IMPORTANT TO DO THIS, BECAUSE IT WILL TEST SOME OF THE PRINCIPLES THAT WE WILL HAVE REVIEWED UP TO THAT POINT, AND THEN I WILL CONCLUDE WITH TWO SETS OF REMARKS, ONE IS JUST A VERY BRIEF FRAMEWORK FOR HOW TO EVALUATE THESE KIND OF TRIALS, BUT ALSO I WANT TO -- I ADD TWO OR THREE SLIDES IN WHICH HOW THINGS COULD BE IMPROVED IF WE COULD TWEAK THE REGULATIONS A BIT. SO THAT'S MORE OF THE -- MY OWN OPINIONS ABOUT THAT. OKAY. SO IMPORTANCE OF THESE PCTS, YOU MIGHT THINK THERE IS A KIND OF PRAGMATIC IDEAL THAT'S ONE OF THE MOST POPULAR TOPICS IN MEDICINE AT MEDICAL RESEARCH THESE DAYS BECAUSE ESPECIALLY DURING AND AFTER THE OBAMA CARE DEBATE, PEOPLE REALIZED THAT IF YOU COULD DO CERTAIN TYPES OF TRIALS IT COULD REALLY MAKE THINGS BETTER AND SAVE MONEY, AND THIS IS I'M GOING TO EXPLAIN THAT IN A SEC. SO BY PRAGMATIC IT MEANS INFORMATION THAT HAS REAL-WORLD EFFECTIVENESS, THAT PHRASE IS USED QUITE OFTEN. AND WHAT YOU DO IS YOU ACCRUE SUBJECTS IN SETTINGS AND METHODS THAT MIMIC THE REAL WORLD USE OF DIMENSIONS RATHER THAN A HIGHLY SELECTIVE GROUP OF PEOPLE. YOU HAVE HEARD IN THE NEWS THESE DAYS ABOUT HOW SOME VACCINE TRIALS ARE ONLY TESTED ON YOUNG HEALTHY PEOPLE HOW DO THEY GENERALIZE THAT TO A WIDER POPULATION? THAT'S THE SAME IDEA. THESE TRIALS WOULD USE INTERVENTIONS THAT ARE ALREADY WIDELY USED, USING OUTCOMES THAT CLINICALLY RUNNY VENT. TYPICALLY WHAT PEOPLE LIKE TO DO WITH THESE TRIALS ARE USE ELECTRONIC HEALTH RECORDS ALREADY EXIST WHERE DOCTORS OBVIOUSLY DOCUMENT WHETHER A PATIENT HAS IMPROVED OR NOT AND THOSE ARE KIND OF RELEVANT AREAS THAT PEOPLE ARE INTERESTED IN. SO ROUGHLY THE IDEA IS TO MIMIC THE USUAL CLINICAL OPERATIONS IN THE RESEARCH PROCEDURES. SO THE KIND -- THE TYPE OF TRIALS THAT I WANT TO MOSTLY FOCUS ON LET'S SAY IS WHERE THEY COMPARE TWO MORE INTERVENTIONS COULD BE DRUGS, PROCEDURES, POLICIES, YOU KNOW, IT COULD BE COMPUTER PROMPTS TO DOCTORS AS THEY'RE EVALUATING A PATIENT OR SOMETHING THAT SAYS HAVE YOU THOUGHT OF THIS, THAT KIND OF STUFF THERE ARE OFTEN STANDARDS OF CARE ARE USUAL OR ACCEPTABLE PRACTICES, THERE'S NO STANDARD TERM FOR THIS. AND FOR EXAMPLE, THIS COULD BE VERY USEFUL WHEN SUPPOSE YOU HAVE TWO -- LET'S SAY INTERVENTIONS, A AND B, AND B IS NEW AND IT'S 100 TIMES MORE EXPENSIVE, THAT SOUNDS OUTRAGEOUS BUT YOU ALL KNOW THIS IS TRUE, IN FACT YOU MIGHT EVEN HAVE CASES WHERE IT'S MORE THAN 100 TIMES EXPENSIVE OR B IT'S MORE BURDEN SOME TO USE BECAUSE THERE'S SOME LIMITED DATA TO BE MORE EFFECTIVE SO THERE'S A LITTLE BALANCES BUT THERE'S SUFFICIENT DATA. OR ONE OF THE TWO OFTEN USED INVENTIONS HAS MUCH MORE RIGOROUS DATA SUPPORTING ITS USE BUT A WHICH IS VERY SIMILAR DOMINATES THE MARKET INSTEAD, THIS SOMETIMES HAPPENS IN SOME TYPES OF DIURETICS. A AND B ARE COMMONLY USED PROCEDURES, AND HERE THEY'RE NOT REGULATED BECAUSE IF IT'S JUST A PROCEDURE OF WHAT TO DO THEN OFTEN THERE AREN'T AS MUCH RESEARCH DATA SIMPLY BECAUSE THAT'S NOT SOMETHING THAT BROADENS THE MARKET THAT REQUIRES CLINICAL TRIAL. A AND B WITH ARE TWO HEALTH SYSTEM LEVEL POLICIES OR PRACTICES FOR INSTANCE. COULD BE STAFFING LEVEL CHANGES AND THINGS LIKE THAT. OR B HAS EVOLVED AT THE STANDARD BASED ON ONE STUDY OR ON THEORETICAL GROUNDS OVER THE DECADES BUT IT'S NEVER BEEN TESTED AGAINST ALTERNATIVE A, LET'S SAY. SO THESE ARE -- SHOULD BE FAMILIAR TO MOST CLINICIANS. SO WHEN A AND B ARE COMPARED IN THE PRAGMATIC RCT THE QUESTION IS FOR INSTANCE WHAT IS THE RESEARCH TO THE SUBJECT. WELL CONSIDERED THAT THESE TRIALS USE LITTLE OR NO RESEARCH SPECIFIC MEASURES, FOR INSTANCE, YOU KNOW, EXTRA LUMBAR PUNCTURES OR EXTRA INTERVIEWS, EVEN, SOMETIMES IT COULD SIMPLY BE WHAT'S RECORDED IN THE ELECTRONIC RECORD, SO THERE'S VERY -- THERE'S VIRTUALLY NONE EXTRA BURDEN. SOMETIMES THE ONLY RESEARCH PROCEDURE COULD BE JUST A RANDOMIZATION, WHICH THE PATIENTS ARE -- MAY NOT BE AWARE OF. SO THE ONLY SOURCE OF RESEARCH A RISK WOULD BE IF ANY THERAPEUTIC INTERVENTIONS ARE BEING TESTED ON THE DIFFERENCES. SO -- AND EVERY SUBJECT RECEIVES ACCEPTED LEVEL OF TREATMENT. AS I MENTIONED THESE ARE WITHIN THE STANDARD OF CARE KIND OF INTERVENTIONS. SO IF YOU PUT ALL THAT TOGETHER YOU MIGHT SAY WELL WHAT'S THE PROBLEM? IT SEEMS LIKE IT'S PRETTY BENIGN, IT COULD BE USEFUL. SO HERE'S -- THIS IS WHY THERE HAVE BEEN DISCUSSIONS, ETHICAL DISCUSSIONS AND WHY YOU'RE HEARING A LECTURE ABOUT IT TODAY IS THAT THE PRAGMATIC IMPERATIVE TO MIMIC REAL WORLD PRACTICE SEEMS SOMEWHAT INCOMPATIBLE WITH THE KINDS OF ETHICS OVERSIGHT MODEL THAT WE USE THAT ASSUMES THAT PRAGMATIC TRIALS HAVE SIGNIFICANT RESEARCH RISK ORE COULD HAVE SIGNIFICANT RESEARCH RISKS. BY THAT I MEAN YOU HAVE TO USE THE SAME KIND OF REGULATORY PROCEDURES FOR THESE. SO IF YOU IMAGINE THE WORLD AS THE ION OR NOT NATIONAL ACADEMIES IMAGINE BACK IN 2007 WHERE YOU HAVE A SYSTEM WHERE RESEARCH AND CLINICAL CARE ARE VERY CLOSELY INTEGRATED IN THE SYSTEM THROUGH THE ELECTRONIC RECORDS SO THAT YOU COULD INTEGRATE THE LEARNING OF WHICH INTERVENTION IS BETTER AS PART OF DOING THE CLINICAL CARE. SO YOU COULD SORT OF IMAGINE A CONTINUOUS SYSTEM OF INTEGRATING THE TWO TYPES OF OPERATIONS DOING THESE VERY CLOSELY CLINICALLY MIMICKING RCTS WITH USUAL CLINICAL OPERATION. ON THE OTHER HAND IF YOU HAVE TO INSERT A TRADITIONAL INFORMED CONSENT FOR A RANDOMIZED CLINICAL TRIAL TO EVERY PATIENT, SUBJECT AND -- OR CLINICIAN PATIENT ENCOUNTER, IT DOESN'T SEEM QUITE REALISTIC THAT THAT COULD BE DONE, SO YOU COULDN'T REALLY DO A PRAGMATIC TRIAL. SO THAT'S IN A NUTSHELL IS SOMEWHAT OF AN ISSUE. SO SEEING THIS, SOME PEOPLE HAVE PROPOSED THAT YOU JUST NEED AN ENTIRELY NEW ETHICS FRAMEWORK. SO ONE QUOTE HERE SAYS THAT THE FRAMEWORK WE PROPOSED REJECTS THE ASSUMPTION THAT CLINICAL RESEARCH AND CLINICAL PRACTICE ARE FROM AN ETHICS POINT OF VIEW FUNDAMENTALLY DIFFERENT ENTERPRISES, OR DRAWING A SHARP DISTINCTION BETWEEN RESEARCH AND THERAPY CAN BE APPEALING BUT A GROWING NUMBER OF PRODUCTIVITIES IN HEALTH CARE CANNOT BE COMFORTABLY CLASS FIEDZ AS EITHER RESEARCH OR THERAPY, THE ONE EXCLUDING THE OTHER. SO SOME PEOPLE THINK, WELL, LOOK, YOU CAN'T TELL IF THIS IS RESEARCH OR CLINICAL CARE SO THE DISTINCTION WE USUALLY USE NEEDS TO BE JETTISONED, THAT'S ONE APPROACH. SO SOME ARGUE THAT BASED ON THIS LINE OF REASONING THAT PCTS ARE INDEED ETHICALLY SPECIAL. SO THAT YOU COULD FOREGO INFORMED CONSE CONSENT. SO OBTAINING -- THESE ARE SOME OF THE QUOTES I WON'TS READ EACH ONE BUT THEY ALL BASICALLY SAY THAT, LOOK, WE NEED TO CREATE WAYS OF WEIGHTING OR MAKING THIS NOT REQUIRED TO DO THESE STUDIES. SO CONNECTED WITH THIS IS THE FOLLOWING: CURRENTLY WE DO NOT ALLOW WAIVERS OF CONSENT FOR CHANGES FROM THE USUAL TRADITIONAL CONSENT UNLESS THE STUDY CAN BE CATEGORIZED AS NO OR MINIMAL RISK, IF YOU THINK ABOUT IT, YOU RESEARCH WITH PEOPLE WITHOUT THEIR KNOWING ABOUT IT, IF THERE WAS RISK, REAL RISK INVOLVED, SO IF THERE EVER WERE RESEARCH STUDIES THAT YOU COULD ALLOW WITHOUT CONSENT THEY SHOULD BE MINIMAL RISK. SO SOME HAVE ARGUED THERE IS A FAMOUS CONTROVERSIAL TRIAL SUPPORT TRIAL IN NEONATAL INTENSIVE CARE UNIT WHERE ONE OF THE THINGS THEY DID WAS MANIPULATE THE OXYGENATION MONITORS SO THAT IT WOULD ALTER THE TARGET OXYGENATION LEVELS WITHIN WHAT THEY FELT WERE PREVAILING STANDARDS OF CARE AND THEY FELT FOR EXAMPLE SOME RESEARCH -- SOME -- I SHOULD SAY BIO WEAPONS WOULD NOT BE INCREASED IN RISK. SO THERE HAVE EVEN BEEN PROPOSALS AND THIS ACTUALLY PROPOSAL CAME BEFORE THE REGULATORY CHANGES, BUT WITH THE NEW LAW, NOW I'M TRYING TO -- OH, THE CURES ACT, 21ST CENTURY CURES ACT, THE FDA HAS CHANGED ITS REGULATIONS SUCH THAT IT CAN NOW ALLOW WAIVERS OR ALTERATIONS OF CONSENT. THIS USED TO NOT BE POSSIBLE UNDER THE FDA REGULATIONS, UNDER THE COMMON RULE, AS I'LL EXPLAIN LATER, THAT WAS POSSIBLE. BUT UNDER THE FDA'S VERSION YOU COULD NOT, BUT THAT'S CHANGED. AND PRECEDING THIS SOME PEOPLE SUGGESTED THAT YOU COULD ACTUALLY CATEGORIZE EVEN FDA REGULATED PRODUCTS BEING COMPARED IN AN RCT TO BE SEEN AS MINIMAL RISK, FOR INSTANCE, THIS IS THE PROPOSAL FROM ONE OF THE ARTICLES, IT SAYS THAT THE FOLLOWING TWO CATEGORIES ARE TO BE DEEMED MINIMAL RISK, CATEGORIES OF RCTS, SO THAT THEY ARE ELIGIBLE FOR AYE ALTERATION OR WAIVER OF CONSENT. SO IF THEY ARE TESTING NUMBER ONE, ONE OR MORE REGULATED PRODUCTS, SO IF THE -- LET'S SAY A AND B HAVE BEEN APPROVED FOR THE INDICATION THEY WILL BE TESTING IN THE TRIAL, THAT THEY'RE SAYING AUTOMATICALLY THAT SHOULD BE DEEMED A MINIMAL RISK, AND TWO, ONE OR MORE REGULATORY PRODUCTS ARE NOT USED ACCORDING TO LABEL IN THE STUDY, BUT IT'S -- BUT THAT IS, IN FACT, HOW FROM AN EXPERT OR STANDARD OF CARE PERSPECTIVE THAT'S HOW IT IS BEING USED. SO EVEN IF A AND B DON'T HAVE FDA APPROVAL FOR THAT INDICATION IF THAT'S A WIDELY ACCEPTED USE THEN IT SHOULD BE MINIMAL RISK, AS LONG AS A AND B ARE BOTH ON THE MARKET AND USED. SO THIS PRETTY SWEEPING KIND OF SUGGESTION, AND IT -- IT DOES HAVE SOME INTUITIVE APPEAL. SO WHAT THEY'RE SAYING IS IF -- COMPARING STANDARDS OF CARE THEN IT IS MINIMAL RISK. AND THEREFORE IT MAKES IT ELIGIBLE FOR ALTERATION OR WAIVERS OF CONSENT. OKAY, SO THAT'S THE BACKGROUND. SO THAT'S A SUGGESTION, AND I THOUGHT WHAT WE COULD DO IS GO THROUGH SOME EXAMPLES. SO THAT I BELIEVE WE'RE GOING TO HAVE SOME INTERACTIVE STUFF SO HOLLY WILL PROBABLY GUIDE ME THROUGH THIS AS I GO THROUGH SOME OF THIS MATERIAL. SO -- >> SCOTT, JUST TO LET YOU KNOW WHAT WILL HAPPEN IS WHEN YOU ASK YOUR QUESTION, SORRY, WHEN YOU ASK YOUR QUESTION I WILL OPEN THE POLL, FOLKS WILL HAVE A CHANCE TO VOTE AND THEN I WILL LET YOU KNOW WHAT THE RESULTS ARE AND THEN WE'LL GO ON TO THE SECOND QUESTION FOR THAT SAME. >> DR. SCOTT KIM: OKAY WE DON'T HAVE TO WAIT MORE THAN FIVE OR TEN SECONDS OR WHATEVER YOU -- >> LET'S WAIT ABOUT 30 IF THAT'S OKAY. >> DR. SCOTT KIM: YEAH IF WE DO THAT IT WILL BE FIVE MINUTES JUST FOR THE THING, OKAY LET'S KEEP GOING AND WE'LL SEE HOW IT WORKS OUT. GREAT I TRUST YOU SINCE YOU'RE THE EXPERT ON DOING THIS INTERACTIVE STUFF. THIS IS A TRIAL THAT WAS PUBLISHED IN THE NEW ENGLAND JOURNAL AND THE QUESTION THEY ASKED WAS ELIMINATING COPAYMENTS FOR PRESCRIPTION DRUGS IMPROVE MEDICATION ADHERENCE AS WELL AS OUTCOMES IN PEOPLE WHO HAVE HAD RECENT HEART ATTACKS. IF YOU HAVE RECENT HEART ATTACKS FOR THOSE PEOPLE YOU RANDOMIZE SUCH THAT SOME PEOPLE DON'T HAVE TO PAY ANY COPAY FOR THEIR HEART DRUGS WHEREAS OTHER PEOPLE PAY THE TRADITIONAL COPAY, THAT WAS IT AND THEY RANDOMIZED BY CLUSTER BY INSURANCE PLAN SPONSOR IN OTHER WORDS BY EMPLOYER, SO YOU KNOW PEOPLE WHO WORKED FOR MAYBE NIH WOULD GET FULL COVERAGE AND NO COPAYMENT BUT IF THEY WORKED FOR LET'S SAY SOME OTHER ENTITY THEY WOULD. THE PRIMARY OUTCOME WAS COMPOSITE OF READMITS AND REVASCULARIZATION, SO THIS -- IS THIS STUDY MINIMAL RISK? SO THE RANDOMIZATION PROCEDURE TWO YOU GET THE BONUS OF NO COPAYMENT OR GO TO THE USUAL COPAYMENT HOW MANY PEOPLE THINK THIS IS MINIMAL RISK. >> YEAH SO THE FIRST QUESTION IS NOW OPEN AND THE OPTION IS TO EITHER LET US KNOW YOU THINK IT'S MINIMAL RISK OR MORE THAN MINIMAL RISK. >> DR. SCOTT KIM: WILL I SIGH A GRAPH. >> NO I WILL REPORT IT TO YOU. >> DR. SCOTT KIM: BY PERCENTAGE. >> YES AND I'M GIVING FOLKS 15 SECONDS. >> DR. SCOTT KIM: OKAY, TERRIFIC. >> DR. SCOTT KIM: IT'S A GUT REACTION. >> HERE IT IS 80% SAY IT'S MINIMAL RISK. >> DR. SCOTT KIM: OKAY 80% IS INFORMED CONCEPT NEEDED FOR THIS TRIAL. >> SO THAT'S THE SECOND QUESTION, EVERYONE, GIVEN WHAT SCOTT'S SHARED DO WE NEED TO GET INFORMED CONSENT FROM FOLKS? >> DR. SCOTT KIM: THIS ONE WE -- OKAY I'M GOING TO WAIT. >> OKAY, 87% SAY YES WE NEED TO GET INFORMED CONSENT. >> DR. SCOTT KIM: OH, SO HERE IS -- LET ME JUST -- OKAY. NO MORE -- OKAY, GOOD. SO HERE IS MY ANALYSIS, THE INTERVENTION HAD NO BURDENS ON SUBJECTS, I FELT THAT THERE WAS NO RISK, NO ADDITIONAL RISK, RESEARCH RISK, BECAUSE THE COPAY GROUP THERE'S NO DIFFERENCE BETWEEN WHAT THEY USUALLY DO OR BEING INCLUDED IN THE RESEARCH, AND NO COPAY GROUP IT'S HARD TO IMAGINE WHY NOT PAYING THE COPAY, WHICH IS SOMETIMES HAPPENS IN SOME INSURANCE PLANS COULD RESULT IN WHAT LOSS OF WELFARE. SO THAT SEEMS KIND OF UNREASONABLE TO ASSUME THAT. SO I WOULD AGREE THAT THIS IS NO OR MINIMAL RESEARCH RISK. THIS WAS A CLUSTER RANDOMIZED TRIAL, SO IT WAS -- THEY COULD HAVE I SUPPOSE SENT INDIVIDUAL E-MAILS, BUT -- OR INFORMED CONSENT FORMS, BUT THIS WAS DONE WITHOUT INFORMED CONSENT. OKAY LET'S LOOK AT THE HYPOTHETICAL STUDY THAT WAS PROPOSED IN A VERY INTERESTING COMMENTARY BY DAVID ASCH FROM PENN. HE SAID IMAGINE CURE TO SEE IF TWO INVENTIONS WILL INCREASE ADHERENCE TO KOL O LON OS COLON OSCOPIES THEY WANT TO DO WITH THREE ARMS ONE A KWHIM SICK CAL CARD COLONOSCOPY SCREENING, B A CARD WITH APPOINTMENT BORING LOOK WE MADE AN APPOINTMENT FOR YOU CAN YOU PLEASE SHOW UP IF YOU CAN'T LET US KNOW. AND C, USUAL BORING FORM LETTER WHATEVER THEY END UP DOING OR NOT DOING. OKAY. SO PRIMARY IS HOW MANY PEOPLE -- WHAT PERCENTAGE OF THE PEOPLE WOULD GET SCREENED GET THE COLONOSCOPY? WHAT IS THE RESEARCH RISK OF THIS STUDY? >> OKAY FOLKS THE POLL IS OPEN WHAT IS THE LEVEL OF RISK OF THIS RESEARCH STUDY AND I'M SORRY FOLKS ARE STILL HAVING TROUBLE WITH THE VOTING CLEARLY SOME OF YOU ARE HAVING NO TROUBLE, I CAN'T SEE THE COMMENTS ON MY SCREEN, SO I APPRECIATE THAT FOLKS ARE ADDING THOSE, BUT I CAN'T SEE THOSE AND ADD THEM UP, THAT'S AN OPERATOR ERROR PROBLEM. SO SCOTT HERE'S YOUR ANSWER, 81% OF THE GROUP THINKS THAT IT'S MINIMAL RISK. >> DR. SCOTT KIM: OKAY. I'M GOING TO SKIP THE NEXT QUESTION AND GO TO JUST MY COMMENT WHICH IS THAT I TEND TO AGREE WITH FOLKS THAT THIS IS A MINIMAL RISK. THERE'S AN ECHO. HOLLY? OKAY THANK YOU. AND I DON'T THINK THAT INFORMED CONSENT IS NECESSARY FROM ALL THREE ARMS, I THINK BY VIRTUE OF GETTING THIS THEY HAVE A CHOICE TO DO IT OR NOT DO IT, AND WHETHER THEY GET SCREENED I DON'T THINK THERE'S ANY SPECIFIC MADE FOR -- I THINK I GUESS WHAT I'M SAYING IS IT COULD PROBABLY GO THROUGH THE CRITERIA FOR SOME TYPE OF WAIVER AND IT PROBABLY COULD WORK, BUT YOU KNOW, I GUESS SOME IRBS MIGHT DISAGREE. SO LET'S TALK ABOUT THIS ONE, THIS IS ANOTHER -- I'M NOT FAVORING HE NEW ENGLAND JOURNAL THE REASON I'M DOING IT IS TO SHOW YOU WITHIN ONE PROMINENT JOURNAL THERE ARE STUDIES THAT HAVE THESE KIND OF DESIGNS. SO HEADPOST STUDY WAS PUBLISHED IN 2017, IT ASKED THE FOLLOWING QUESTION DOES LYING FLAT ON YOUR BACK AFTER ACUTE ISCHEMIC STROKE IMPROVE OUTCOMES? THEY ASKED THIS QUESTION BECAUSE A METAANALYSIS HAD SHOWN THAT THERE WAS BETTER BLOOD FLOW TO THE AFFECTED HEMISPHERE WITH THAT POSITION. HOWEVER, BOTH JUST REGULAR SITTING UP IN THE HOSPITAL BED OR LYING FLAT WERE -- ARE USED DEPENDING ON WHICH DOCTOR, WHICH HOSPITAL, IT VARIED. SO THEY DID A CLUSTER RANDOMIZED TRIAL BY HOSPITAL, BUT OBVIOUSLY INTERVENTION IS INDIVIDUAL. AND IT WAS BETWEEN EITHER BEING SUPINE OR SITTING UP FOR -- AT 30 DEGREES, FOR 24 HOURS AFTER COMING INTO THE HOSPITAL, I BELIEVE, AND THEY WERE ASKED TO MAINTAIN THIS POSITION FOR EATING, DRINKING, AND TOILETING. SO IT'S -- YOU KNOW, NOT CHALLENGED THAT COULD BE CHALLENGING, ESPECIALLY FOR SUPINE FOLKS. PRIMARY OUTCOME VARIABLE WAS THEY CHECKED AT 90-DAYS OUT, WHICH GROUP HAD GREATER AMOUNT, IF ANY, COMPARED TO TWO GROUPS IN TERMS OF DISABILITY. SO HOW MANY PEOPLE THINK THAT THIS STUDY IS MINIMAL RISK? >> OKAY THE POLL IS OPEN AND YOU GOT A LITTLE BIT OF FEEDBACK SCOTT WHEN THE MICROPHONE IS HOTTED HERE AT LIPSIT SO IT SHOULD ALWAYS RESOLVE AS SOON AS I MOVE AWAY FROM THE MIC. >> DR. SCOTT KIM: YES I FIGURED THAT THANK YOU. >> WE'LL GIVE FOLKS A COUPLE MORE SECONDS. >> DR. SCOTT KIM: CONTRARY TO WHAT PEOPLE THINK PEOPLE DON'T WANT TO HEAR THEIR OWN VOICE. >> OKAY WE'VE GOT 2/3 OF THE GROUP SAYING IT'S MORE THAN MINIMAL RISK. >> DR. SCOTT KIM: OKAY. SO THAT'S QUITE A DIFFERENCE FROM THE PREVIOUS ONE. I WILL POINT OUT THAT THE KIND OF REASONING THAT WAS PROPOSED IN THE FIRST HALF OF MY TALK, WHICH IF YOU USE THAT REASONING TECHNICALLY ALL THESE STUDIES SHOULD BE CONSIDERED MINIMAL RISK. SO MY POINTS HERE IS EVEN THOUGH THE THEORETICAL JUSTIFICATIONS FOR A PRACTICING MINIMAL RISK IT SOUNDS REASONABLE IN THE ABSTRACT BUT YOU REALLY NEED TO GET INTO THE NITTY GRITTIES OF INDIVIDUAL STUDIES TO SEE IF YOU FEEL LOOKING AT IT THAT IT IS MINIMAL RISK. AND WHAT I HOPE TO DO IS BRIEFLY TALK ABOUT WAYS OF ANALYZING ITSELF IN A LITTLE MORE DETAIL SO THAT WE DO HAVE THAT. OKAY, IS A WAIVER OF CONSENT OKAY? IN OTHER WORDS IS IT ETHICAL TO HAVE DONE THIS STUDY WITHOUT THE PATIENTS NOT KNOWING SO IN OTHER WORDS GOING THROUGH THE ENTIRE INTERVENTION NOT KNOWING THAT THEY WERE IN A RESEARCH STUDY? HOW MANY PEOPLE THINK IT WAS OKAY, IT WOULD BE OKA OKAY,. >> GIVE FOLKS A COUPLE MORE SECONDS. SO WE'VE GOT 85% THINK THAT A WAIVER OF CONSENT IS NOT OKAY. >> DR. SCOTT KIM: YEAH THAT MEANS 15% THINK IT IS OKAY. I WOULD LIKE TO TALK TO THOSE FOLKS. I HOPE SOME OF THEM WILL COMMENT OR ASK QUESTIONS AT THE END, WHEN WE HAVE A DISCUSSION PART, BECAUSE I THINK THIS IS THAT PEOPLE DO HAVE DIFFERENT INTUITIONS AND I WOULD LIKE TO TALK ABOUT IT. OKAY. SO LET ME GO AHEAD WITH THIS AND I'M JUST GOING TO DESCRIBE HOW THEY DID STUDY THIS STUDY. IN THE PAPER THEY SAY THAT CRITICAL WAS APPROVED BY ALL REGULATORY AUTHORITIES AND ETHICS COMMITTEE AT THE PARTICIPATING CENTERS, QUOTE, THIS IS ALL QUOTES, A SENIOR EXECUTIVE OFFICER AT EACH HOSPITAL ACTED AS, QUOTE, A GUARDIAN AS PART OF THE CLUSTER RANDOMIZED TRIAL DIVIDED AND ADDED CONSENT AT AN INSTITUTIONAL LEVEL TO HEAD POSITION TO BE IMPLEMENTED AS A LOW-RISK INTERVENTION TO CLUSTERS OF PATIENTS AS PART OF THEIR ROUTINE CARE. I WANT YOU TO NOTICE THE LANGUAGE USED HERE, BECAUSE WHAT THEY ARE ASSERTING IS THAT, LOOK, WE -- WE DIDN'T GET CONSENT FROM INDIVIDUALS BECAUSE THIS WAS DONE AS PART OF ROUTINE CARE. SO IT IS USING THE VERY LARGE SOME GROUPS OF BIO ETHICISTS HAVE FELT WAS JUSTIFIED TO THINK THIS WAY. OKAY. WRITTEN INFORMED CONCEPT WAS SUBSEQUENTLY OBTAINED FROM THE PATIENTS AND THEIR APPROVED SURROGATES BUT THIS WAS ONLY CONSENT TO USE THE DATA AND FOR FOLLOW UP ASSESSMENTS. SO THERE IS SOME TROUBLE MAKERS WHO WROTE A LETTER TO THE EDITOR, INCLUDING ME, WHO QUESTIONED WHETHER OR NOT A WAIVER OF CONSENT WAS OKAY AND WHETHER THIS WAS TRULY LOW RISK STUDY. AND THIS WAS THE RESPONSE TO THAT LETTER BY THE INVESTIGATORS, THEY SAID IT'S INSUFFICIENT AMOUNT OF LEVEL 1 EVIDENCE SPECIFYING THE BENEFITS AND HARMS OF HEAD POSITIONING FOR PATIENTS WITH ACUTE STROKE THE FACT THAT PEOPLE CHANGED THEIR HEAD POSITIONS WITHIN ROUTINE HOSPITAL SXAR IN DAILY LIFE, AS THEY SHIFT FROM ACTIVITY DURING THE DAY, IN OTHER WORDS WHAT THEY'RE SAYING IN THE SECOND BULLET IS LOOK BEFORE LYING ON THE BACK, THEY SIT UP, THAT'S A MINIMAL RISK THING. ALTHOUGH, IT IS -- IT SEEMS TO US IT'S A LITTLE BIT DIFFERENT FROM DOING IT WHEN YOU HAVE A STROKE, BUT -- AND THE VIEW THAT PATIENT CARE WOULD NOT BE COMPROMISED BY EITHER OF THE INTERVENTIONS, I THINK MEANING THAT THEY'RE BOTH DONE, SO YOU CAN'T SAY ONE IS GREATER THAN THE OTHER. SO THE FIRST POINT HERE IS THAT THERE'S ESSENTIALLY SAYING THAT THERE WAS EQUIPOISE, I'M GOING TO -- I HOPE I WILL ADDRESS SOME OF THESE POINTS LATER AND YOU CAN SEE THAT, BUT MY PERSONAL VIEW IS THAT THESE -- THESE ARE SOMEWHAT MISGUIDED RESPONSES TO THEIR JUSTIFICATION, AS A JUSTIFICATION, SORRY. OKAY LET'S DO ANOTHER ONE, THIS WAS PUBLISHED IN 2013 IN CET AND THE QUESTION THEY ASKED WHICH IS BETTER IN ACUTE HEART ATTACKS, HEPARIN OR THIS NEW DRUG AT THE TIME WHAT WAS CALLED BIVALIRUDIN, IT WAS VERY EXPENSIVE AND IT WAS USED IN THE EMERGENCY ROOM. SO THEY COMPARED IN THE EMERGENCY ROOM IN THE SETTING OF AN ACUTE MI AND THE PRIMARY OUTCOME WAS SEVERAL FACTORS INCLUDING MORTALITY AND ALSO THEY KEPT CLOSE TRACK AS A PRIMARY SAFETY END POINT LEADING BECAUSE OBVIOUSLY THAT'S A COMPLICATION. THIS IS HOW THEY DID CONSENT FULL ETHICAL APPROVAL WAS GRANTED FOR WHAT THEY CALL DELAY CONSENT, AND ESSENTIALLY IT'S THE SAME THING WITH THE HEAD PEOPLE DID THEY DID INTERVENTION WITHOUT GETTING CONSENT AND AFTERWARDS THEY SOUGHT CONSENT TO USE THE DATA. SO THIS IS WHAT THEY'RE SAYING, AND THERE WAS ACTUALLY ETHICS EDITORIAL ACCOMPANY IT PRAISING HOW ETHICAL THE STUDY WAS, AND THIS WAS THE ET THINKS IN LANCET SAID FAR FROM BEING UNETHICAL THE STUDY SETS A HIGH STANDARD EVER CONSENT SOME DEBATE SURROUNDS WHETHER PATIENTS SHOULD BE SOUGHT CONSENT IS PRESENT REGARDING EQUIPOISE THOSE SHOULD BE FAMILIAR TO YOU AND RANDOMIZATION DOES NOT POSE ANY ADDED RISKS. PRESUMABLY WHAT THEY MEAN HERE, RANDOMIZATION MEANING DEPENDS -- WHICHEVER ONE YOU GET YOU CAN -- THERE'S NO ADDED RISK BY RANDOMIZATION. I WOULD CALL ATTENTION -- I'M NOT GOING TO ANALYZE THIS PARTICULAR COMMENTARY AT THIS POINT, BUT I WANTED TO POINT OUT THIS ALTERNATIVE ARTICLE, ON THE VERY SAME STUDY BY NEIL DICKERT A CARDIOLOGIST AND FRANK MILLER FROM BMJ2015 THAT GIVES A CONTRARY POINT OF VIEW. I THINK WE CAN DO THIS ONE, TOO. OKAY. SO THIS IS AN OLDER STUDY, AND THE -- IT'S A QUESTION OF THE DELIVERY ROOM MANAGEMENT IS APPARENTLY VIGOROUS MECONIUM-STAINED NEONATE THE QUESTION THEY ASKED IS THAT BETTER THAT SUPPORTIVE CARE IN REDUCING MECONIUM ASPIRATION SYNDROME SOME BABIES WHEN THEY'RE BORN WHILE IN THE WOMB THEY COULD HAVE A DISCHARGE OF MECONIUM WHICH IS TOXIC SO THEIR QUESTION IS THEY COME OUT THEY LOOK FINE, WHAT SHOULD WE DO? BECAUSE WE'RE WONDERING IF THEY BREATHE -- IF THEY SWALLOWED THIS INTO THEIR LUNGS IT COULD BE BAD. SO INTUBATION AND SUCTIONING VERSUS EXPECTED MANAGEMENT WAS THE RANDOMIZATION THE PRIMARY OUTCOME WAS WHETHER OR NOT THEY DEVELOPED THIS SYNDROME CALLED MECONIUM-ASPIRATION SYNDROME AND ANY COMPLICATIONS EITHER FROM MAS OR FROM THE PROCEDURES WHEN YOU DO INTUBATION SUCTIONING SOMETIMES YOU CAN HAVE AN ATTACK. SO WHAT IS THE RISKS OF THIS STUDY. >> SO THE POLL IS OPEN. WHAT'S THE LEVEL OF RISK OF THIS MW CONIUM WHAT'S THE RISK YOU EITHER HAVE MINIMAL RISK OR MORE THAN MINIMAL RISK. MW CONIECONIUM THE RESULTS ARE IN 94% BELIEVE IT'S MORE THAN MINIMAL RISK. >> DR. SCOTT KIM: OKAY. SO WAS INFORMED CONSENT REQUIRED FROM THE PARENTS FOR THIS STUDY? SHOULD IT HAVE BEEN REQUIRED? >> AND QUESTION, SHOULD PARENTS HAVE BEEN ASKED FOR THEIR INFORMED CONSENT? HE CAN K.I . SO WE'VE GOT 94% WHO SAY YES, PERHAPS THE SAME 94%. >> DR. SCOTT KIM: OKAY. >> WHO SAID YES TO THE PREVIOUS ONE. >> DR. SCOTT KIM: THIS STUDY WAS DONE WITHOUT INFORMED CONSENT AND I WILL EXPLAIN THEIR RATIONALE THIS WAS A NO INFORMED CONSENT FOR THE CALL 6789 THE RATIONALE INCLUDED WIDE ACCEPTANCE OF BOTH PROPOSED MANAGEMENT STRATEGIES, AGAIN THIS SHOULD BE A COMMON THEME FOR YOU, WE'RE TESTING TWO PRACTICES THAT YOU KNOW DEPENDING ON WHERE YOU ARE WE THINK IS WITHIN STANDARD OF CARE, SO PERHAPS THEY THOUGHT THIS IS NO DIFFERENT THAN JUST TREATING PEOPLE. MECONIUM-STAINED AMNIOTIC FLUID IS FREQUENTLY NOT NOTED UNTIL MOMENTS BEFORE DELIVERY, SO YOU KNOW YOU CAN'T DO COUNSELING AND INFORMED CONSENT, SO THAT WAS A POINT THEY MADE. I WOULD SAY AS AN ASIDE, I MENTIONED THIS SUPPORT STUDY EARLIER IN THIS TALK WHICH IS ANOTHER NICU STUDY, NOT ANOTHER IT WAS A NICU STUDY THAT ALSO REQUIRED A TIME SENSITIVE KIND OF PROCEDURES, SO WHAT THEY DID WAS THEY ACTUALLY OBTAINED CONSENT DURING PRENATAL VISITS. IF SOMETHING HAPPENS, IF WE NEED TO DO THIS, WOULD YOU BE WILLING TO BE ENROLLED AND THAT'S HOW THEY GOT CONSENT FOR THAT. THIS NUMBER TWO THERE WAS A WAY OF GETTING AROUND IT. THREE INHERENT DIFFICULTIES OF OBTAINING VALID -- SAME THING. WE ESTIMATED THAT IF WE WERE TO ATTEMPT TO OBTAIN INFORMED CONSENT EVEN DURING PRENATAL VISITS AT MOST WE WOULD ONLY BE ABLE TO ENROLL 70% OF ELIGIBLE INFANTS. SO THAT WAS SEEN AS A SCIENTIFICICALLY SUCH A LOSS THAT THIS WAS GIVEN AS A KIND OF PRACTICAL RATIONALE AND BASICALLY THE IDEA ANOTHER SCIENTIFIC RATIONALE. I WILL SAY THAT I'M VERY SYMPATHETIC TO THE SCIENTISTS HERE IN THE SENSE IT IS ABSOLUTELY TRUE IF YOU ENROLL EVERYBODY YOU GET SO MUCH BETTER DATA. THAT'S ONE OF THE BIG ATTRACTIONS OF DOING THESE KIND OF STUDIES WITH SOME ALT TRAGS OR WAIVER OF CONSENT. THE QUESTION IS THAT IS TRUE FOR ANY KIND OF STUDY THE QUESTION IS WHETHER OR NOT IT WAS APPROPRIATE IN THIS CASE. AND I DON'T KNOW IF SUCH A STUDY COULD BE CONDUCTED AGAIN, NOW, IN 2020. JUST A FEW YEARS AGO THERE WAS A DEBATE IN THE JOURNAL PEDIATRICS BEING DOING A KIND OF FOLLOW UP TO THIS KIND OF STUDY WITHOUT CONSENT. AND THERE WAS SOME DISAGREEMENT AMONG THE COMMENTATORS. OKAY. SO WHAT I'VE DONE SO FAR JUST TO REVIEW IS TO EXPLAIN WHAT PRAGMATIC TRIALS ARE, OR TO EXPLAIN WHAT THE ETHICAL ISSUES ARE, ON FIRST BLUSH IT SEEMED LIKE WHEN YOU'RE DOING JUST COMPARISON OF DRUGS -- DRUGS PROCEDURES ALREADY IN USE, WHERE A DOCTOR COULD GIVE YOU EITHER ONE OF THOSE AND IT WOULD BE PERFECTLY ACCEPTABLE IF YOU DO STUDIES COMPARING IT AT THAT POINT IT SEEMS LIKE IT WOULD BE KIND OF TRIVIAL OR NO RESERVE RISK. ON THE OTHER HAND, WHEN WE GO THROUGH SPECIFIC EXAMPLES OF THESE STUDIES OUR INTUITIONS ARE CHALLENGED SO IT DOESN'T SEEM THAT WAY. SO I'M GOING TO GO THROUGH SOME RECOMMENDATIONS SO PROCEDURES THAT WE MIGHT THINK ABOUT AS WE EVALUATE THESE KIND OF STUDIES, EITHER AS PEOPLE DESIGNING THE STUDIES, WRITING PROPOSALS FOR IRBS OR AS IRB MEMBERS. OKAY. THE FIRST QUESTION THAT SHOULD BE ASKED IS THAT THE PCT HAVE CLINICAL CAL /* EQUIPOISE IT SEEMS OBVIOUS BUT WHEN SOMETHING IS WIDELY USED IT SEEMS THIS IS WHAT WE DO BUT IF YOU HAVEN'T VERIFIED THAT THESE ARE WITHIN STANDARD OF CARE, YOU MAY ACTUALLY BE TESTING SOMETHING THAT'S KIND OF OUT OF THE ORDINARY AND EXPERIMENTAL. INDEED SOME PEOPLE HAVE ARGUED ESPECIALLY FOR NON REGULATED INTERVENTIONS LIKE ICU PROTOCOLS THAT THIS HAS HAPPENED. SO ONE PAPER THAT TRIES TO DOCUMENT AND ARGUE ABOUT -- ARGUE THAT THIS HAPPENS IS THE PAPER THAT YOU CAN -- I REFER YOU TO, ONE OF THE AUTHORS IS A DR. -- A SCIENTIST OF ETHICS AT THE NIH, DR. NATANSON, THE SECOND QUESTION IS TO ASK WHY IS IT THAT INITIALLY WHEN WE THINK ABOUT TWO STANDARDS OF CARE TREATMENTS BEING COMPARED AND THEY ARE BOOTH ACCEPTABLE IT SEEMS LIKE GOSH WHAT'S THE RISK? WHY DOES THAT INTUITION NOT GET BORNE OUT WHEN WE ACTUALLY LOOK AT SPECIFIC CASES? AND I'M GOING TO TRY TO EXPLAIN THAT ON THIS POINT AND WHY IT'S IMPORTANT NOT TO USE THIS GENERAL RULE LIKE THEY ARE BOTH APPROVED BY THE FDA AND IF YOU'RE GOING TO COMPARE IT YOU SHOULD ASSUME MINIMAL RISK. THE REASON I'M AGAINST THAT IT DOESN'T TAKE INTO ACCOUNT THE FOLLOWING KIND OF CONSIDERATIONS. NUMBER ONE, IT IS TRUE THAT THESE KIND OF SOC MEANING STANDARD OF CARE PCTS ARE SPECIAL AND THEY'RE DIFFERENT FROM RCTS OF NOVEL INTERVENTIONS IN THE FOLLOWING TWO WAYS, NUMBER ONE, WE CAN JUST ASSUME THERE IS CLINICAL EQUIPOISE BY DEFINITION YOU WOULD PROPOSE THESE STUDIES BECAUSE THERE'S A DIVISION OR DIFFERENCE WITHIN THAT SETTING. SO AS LONG AS YOU -- WHAT'S THE RIGHT WORD -- IF IT'S TRULY A STANDARD OF CARE SO YOU'VE DONE THE STEP THAT I MENTIONED IN STEP ONE OF CHECKING TO SEE THAT, THAT THESE ARE STANDARD OF CARES, THEN BY THAT FACTS, BY DEFINITION, IT IS IN CLINICAL EQUIPOISE, OKAY THAT'S ASSUMING OF COURSE THERE HASN'T ALREADY BEEN TRIAL COMPARING THEM IN WHICH CASE YOU WOULD KNOW IF THEY ARE SHALL PERFORM. SECOND AND I THINK THIS IS A RM IMPORTANT POINT WHEN DO YOU A NOVEL DRUG OR INTERVENTION RCT EVEN IF IT'S IN EQUIPOISE EVEN THOUGH IT'S A NOVEL DRUG IT MAY GENUINELY BE IN EQUIPOISE IN THE SENSE THAT YOU DON'T KNOW COMPARED AGAINST THE STANDARD OF DATA WHICH IS BETTER WHICH IS WHY YOU'RE GOING TO DO THE RCT. HOWEVER IN THESE KIND OF TRIALS, AND I'M SORRY I SKIPPED ONE STEP, WHICH IS THAT HOWEVER IN RCTS OF NOVEL AGENTS YOU HAVE TO ASK THE QUESTION, OKAY, IT IS TRUE THAT THERE IS EQUIPOISE IN THAT SENSE, YOU DON'T KNOW WHICH IS BETTER, BUT IT'S ALSO TRUE THERE COULD BE RISK INVOLVED WITH THE UNKNOWNS OF THIS NOVEL INTERVENTION SUCH THAT YOU HAVE TO ASK THE NEXT STEP, DO WE KNOW ENOUGH ABOUT THIS SO THAT IT'S SAFE ENOUGH TO TEST IT IN THIS RCT? THAT IS AN EXTRA STEP FOR A NOVEL INTERVENTION RCT. HOWEVER, IN THESE STANDARDS OF CARE PCTS WHERE YOU ESTABLISHED THAT THERE'S STANDARD EVER CARE YOU'VE ANSWERED THE QUESTION BECAUSE IT'S ALREADY WIDELY USED FOR THAT INDICATION. IT IS. I PERSONALLY THINK IT'S BECAUSE OF THESE INTUITIONS THAT PEOPLE CONFUSE IT WITH THE IDEA THAT THERE IS MINIMAL RISK. BUT THESE DON'T -- THESE CONSIDERATIONS BY THEMSELVES DON'T TELL YOU THAT ALL THESE STUDIES ARE MINIMAL RISKS, FOR THE FOLLOWING REASON: RESEARCH RISK SHOULD BE DEFINED AS THE INCREMENTAL RISK INCURRED BY A SUBJECT BY BEING IN THE STUDY VERSUS NOT BEING IN THE STUDY. SO IF I STEP INTO THE STUDY DO I INCUR SOME RISK I OTHERWISE HADN'T? WOULDN'T HAVE. NOW, IN ORDER FOR THESE STUDIES TO BE WORTH WHILE, IN OTHER WORDS IN ORDER FOR THEM TO BE NOT BE A COMPLETE WASTE OF TIME AND RESOURCES, SCIENTISTS HAVE TO REALLY BELIEVE THAT, YOU KNOW, IT'S WORTH DEVOTING THESE RESOURCES TO FIND OUT WHETHER THERE'S A DIFFERENCE. SO THERE HAS TO BE A REAL PROSPECT THAT ONE OR THE OTHER IT HAS TO BE BETTER DEPENDING UPON THE EVIDENCE. IT'S JUST THAT WE DON'T HAVE SUFFICIENT EVIDENCE TO SAY YOU SHOULD ALWAYS DO A FIRST OR B FIRST. OTHERWISE THERE WOULDN'T BE A NEED TO DO THE STUDY. THIS PROSPECT TRANSLATES INTO THE PROSPECT THAT SOMEONE RECEIVING D IN ORDINARY CARE COULD FACE A DIFFERENT WELFARE OUTCOME BY ENTERING THE STUDY SINCE SHE COULD RECEIVE A INSTEAD. AND SINCE PCT EVERY PCT WILL HAVE SUCH A PROSPECT EVERY PCT IF IT'S A WELL JUSTIFIED PCT, HAS SOME RISK OF DIFFERENT WELFARE OUTCOME FOR AN INDIVIDUAL, IT COULD BE BETTER T COULD BE WORSE, BUT IT IS DIFFERENT THAN IF YOU WENT WITH YOUR DESIGNATED USUAL CARE. SO AS A ROUGH GUIDE, I WOULD SUGGEST THAT YOU NEED TO DRILL DOWN INTO THE INDIVIDUAL STUDY AND ONE OF THE THINGS THAT I SUSPECT THAT CHANGED PEOPLE'S INTUITIONS ABOUT THE EXAMPLES I GAVE IS THAT THE MAIN OUTCOME VARIABLES IN THOSE STUDIES REALLY WERE QUITE DIFFERENT, AND THAT SHOULD HELP US TO THINK ABOUT WHETHER OR NOT THE RESEARCH STUDY IS MINIMAL RISK OR NOT AND THE THIRD POINT I'M JUST REPEATING THE REGULATORY -- PARTS OF THE REGULATIONS, WHICH IS THAT IN ORDER FOR SOMETHING TO BE CONSIDERED ELIGIBLE FOR MODIFICATION A WAIVER OF CONSENT, THERE ARE CERTAIN REGULATORY REQUIREMENTS AND I'M STATING THAT FOR YOU AS A REMINDER I BELIEVE YOU MAY HAVE A LECTURE ON THAT OR SOMETHING LIKE THIS LATER, THE BASIC IDEA IS IT SHOULD BE MINIMAL RISK AND YOU COULDN'T DO THE RESEARCH IS THEN PRACTICABLE WITHOUT THE WAIVER OR ALTERATION AND SO AVERAGE AFFECT ALREADY EXISTING THE WELFARE OF PARTICIPANTS AND THERE SHOULD BE DEBRIEFING, THIS IS ONE OF THE MOST COMMONPLACES YOU DO THIS IS ON DECEPTION STUDIES WHERE YOU SEE SOMEBODY YOU DON'T GET TO VERIFY THEY HAD IT. OKAY I'M GOING TO CLOSE WITH A COUPLE TWO OR THREE IT SLIDES ABOUT SOME CHANGES TO THE REGULATIONS THAT WOULD MAKE EVERYBODY'S LIFE A LITTLE BIT EASIER BUT I DON'T KNOW IF THIS WILL EVER HAPPEN BUT I JUST RAISE THIS AS A WAY OF THINKING ABOUT THE ETHICS, BECAUSE THE ETHICS AND REGULATIONS DON'T ALWAYS COINCIDE. OKAY. I BELIEVE THAT IN GENERAL NO INDIVIDUAL INTERVENTION PCT, IN OTHER WORDS, THERE ARE SOME CLUSTER/CLUSZ CENTER RANDOMIZED TRIALS IF IT'S A GOOD STUDY WELL DESIGNED AND SO FORTH AND MEETS OTHER CRITERIA THEN SINCE YOU CAN'T DO THE STUDY WITHOUT A WAIVER OF CONSENT, YOU MIGHT HAVE TO DO IT WITHOUT CONSENT. HOWEVER IF THE INTERVENTION ITSELF IS INDIVIDUAL, I DON'T THINK A COMPLETE WAIVER WOULD BE A GOOD IDEA. SO THAT BECAUSE IF WE'RE TRYING TO CONDUCT PCTS THAT CLOSELY MIMIC CLINICAL PRACTICE IT DOESN'T MAKE SENSE TO HIDE HOW WE CHOOSE BETWEEN INTERVENTIONS A AND B BECAUSE THAT'S PART OF HOW WE CONDUCT OUR BUSINESS WHEN WE TALK TO PATIENTS, WE OUGHT TO. SO THAT'S RELATED TO THE SECOND SUGGESTION, FOR STANDARD OF CARE PCTS AND POINT CONSENT PROCESS SHOULD MIMIC CLINICAL CONSENT AS MUCH AS POSSIBLE TO THE EXTENT THE KINDS OF THINGS YOU'RE DOING OVERLAP WITH THE CLINICAL PRACTICE BUT YOU WANT TO BE EXPLICIT ABOUT THE RESEARCH COMPONENT IN YOUR DISCUSSIONS. SO THE TRULY IMPORTANT QUOTE RESEARCH ELEMENT HAS TO DO WITH DISCUSSION OF HOW YOU CHOOSE BETWEEN IT'S TWO ALTERNATIVE TREATMENTS. AND THE LEVEL OF DETAIL THAT YOU TALK ABOUT IT WOULD, I THINK, SHOULD BE DETERMINED BY HOW YOU WOULD TALK ABOUT THAT IN A REGULAR CLINICAL SETTING. SO THAT IF IT'S -- IF FOR A -- WHAT WE CALL A PREFERENCE SENSITIVE DECISION, IN OTHER WORDS, YOU COULD DO AOB, YOU REALLY HAVE THIS PRACTICE OF SHARED DECISION MAKING, YOU GO THROUGH YOUR -- YOU CLINICAL GUIDELINES SAY YOU REALLY NEED TO DISCUSS THIS WITH THEM, IN THOSE KIND OF SITUATIONS IT COULD EASILY INSTEAD OF THAT DURING THAT SHARED DECISION MAKING CONVERSATION YOU SIMPLY ADD THIS RESEARCH COMPONENT DISCUSSION ABOUT RANDOMIZATION. AND THE OTHER REQUIRED ELEMENTS SHOULD BE DISCLOSED DURING WHO JUST VERY BRIEFLY OR I BELIEVE YOU COULD PROBABLY DROP THEM ALTOGETHER FOR SOME FOR INSTANCE, YOU KNOW, WHERE THEY CAN GO IF SOMETHING HAPPENS IN THE RESEARCH. SINCE THIS IS ALREADY OCCURRING IN DOCTOR'S OFFICES IT'S HE PRETTY OBVIOUSLY WHERE THEY SHOULD GO. THIS SHOULD TAKE ONLY A LITTLE MORE TIME THAN A REGULAR CLINICAL CONSENT, AND IT WOULD MIMIC CLINICAL PRACTICE. SUGGESTION THREE, I THINK THAT WE NEED TO REVISE THE REGULATIONS SO THAT THIS SHOULD BE DIFFERENT STANDARDS IF THEY INVESTIGATOR IS COMPOINPOSING A COMPLETE WAIVER VERSUS MODIFYING THE CONSENT. IF YOU'RE COMPLETELY TRANSPARENT THAT THERE'S A STUDY THAT WE'RE GOING TO DO THIS DIFFERENTLY AND SO FORTH AND YOU ONLY HIT THREE OR FOUR OF THE 11 OR HOW MANY REQUIRED ELEMENTS, THE SUBJECT KNOWS THE RESEARCH IT'S AN ALTERATION FROM THE TRADITIONAL CONSENT REQUIREMENT BUT THAT'S ARE ETHICALLY VERY DIFFERENT FROM COMPLETELY KEEPING THE PERSON IGNORANT. SO THAT'S ONE POINT. THE OTHER POINT IS THAT I THINK THAT FOR SOME EVER THESE PCTS WHERE YOU'RE COMPARING TWO THINGS THAT ARE STANDARDLY USED, EVEN IF OUR INTUITION IS THAT IT WOULD OVERALL RESEARCH GREATER THAN MINIMAL RISK, AS LONG AS THERE'S TRANSPARENCY YOU COULD USE A STREAMLINED ALTERNATIVE INCENT PROCEDURE THAT SHOULD BE ALLOWED, SO THAT SOME OF THESE STUDIES THAT WOULDN'T QUITE MEET MINIMAL RISK STANDARD BY OUR INTUITIONS THAT WE EXAMINED COULD STILL BE DONE WITH ALTERED CONSENT THAT WOULD ALLOW THESE PRAGMATIC TRIALS TO BE DONE. BUT WOULDN'T HAVE TO GO THROUGH THIS LONG, WRITTENED CONSENTED OF TRADITION FORM OR FORCE INVESTIGATORS TO ASK FOR A COMPLETE WAIVER, WHICH I THINK THAT'S A PROBLEM. OF COURSE THIS WOULD ALL REQUIRE REGULATORY CHANGE. SO IN SUMMARY THE FACT THAT A PCT IS COMPARING TWO STANDARD OF CARE INTERVENTIONS DOESN'T BY ITSELF CREATE A SPECIAL ETHICAL CATEGORY OF LOW RISK RESEARCH THAT MAY BE DONE WITHOUT CONSENT. IF THERE'S ANY ONE METHOD THAT YOU CAN TAKE AWAY FROM IT I THINK IF ANYBODY SAYS LOOK THEY'RE BOTH STANDARDS OF CARE THIS IS LIKE CLINICAL PRACTICE DON'T WORRY ABOUT IT, THIS IS NO DIFFERENT FROM CLINICAL PRACTICE, I THINK THE QUESTION YOU SHOULD ASK IS: OKAY, LET'S LOOK AT THE PROTOCOL, LET'S GO THROUGH EACH ELEMENT AND SEE WHAT IT'S LIKE, JUST LIKE WE DID. INSTEAD CAREFUL CASE-BY-CASE ANALYSIS REQUIRES SOME OF THESE STUDIES WILL BE MINIMUM RISK, AND SOME OR MANY WILL NOT BE. AND FINALLY, I THINK IT'S IMPORTANT TO RECOGNIZE THAT THESE PCTS ARE INDEED UNIQUE AND DIFFERENT FROM TRADITIONAL NOVEL COMPOUND OR PROCEDURE RCTS AND WE SHOULD TRY TO COME UP WITH FLEXIBLE CONSENT PROCEDURES SO THAT WE CAN COME CLOSER TO INTEGRATING CLINICAL AND RESEARCH PRACTICES ABOUT -- THAT -- THAT'S THE IDEA WHARF PEOPLE HAVE CALLED THEIR LEARNING HEALTH CARE SYSTEM. THANK YOU. >> THANK YOU SCOTT. BIG GIANT ROUND OF APPLAUSE HERE FROM LIPCET. SO LOOKS LIKE YOU'RE FISHING THERE ON THE POTOMAC. SO FOLKS REMEMBER YOU CAN SEND IN E-MAILS WITH QUESTIONS OR I HAVE A DISCUSSION BOARD SET UP SO WE HAVE ONE QUESTION THAT HAS A COUPLE OF PARTS WE'LL ASK THE FIRST PART. THIS IS FROM CAROL BASED ON PRINCIPALS OF PRAGMATIC TRIALS EVEN IF THE RISK IS DEEMED MINIMAL WHAT HAPPENS IF THE DETAILS ABOUT THE TRIAL IS DISCLOSED TO PATIENTS AND THEY WANT TO BE PROTECTED AGAINST ANY RISK, NO MATTER WHAT? >> DR. SCOTT KIM: I'M NOT SURE WHAT THAT MEANS. >> MAYBE I'LL SAY ANOTHER -- LET'S SAY -- >> DR. SCOTT KIM: YOU KNOW, IF THERE IS A TRANSPARENT -- LET'S SAY THERE'S A BRIEF ORAL CONSENT AS PART AOF PART OF A TRIAL LIKE THAT THE PATIENT COULD SAY NO I DON'T WANT TO BE IN IT DON'T USE MY DATA. PLEASE DO WHATEVER YOU'RE GOING TO DO I MIGHT BE MISS UND UNDERSTANDING YOU. THAT'S WHAT WOULD HAPPEN I BELIEVE. >> WHAT I'M THINKING ABOUT IT LET'S SAY WE DO A PRAGMATIC TRIAL YOU MENTIONED EARLIER THE IDEA OF MAYBE A CLUSTER RANDOMIZED TRIAL WHERE EVERYBODY THAT'S AT NIH GETS THE -- I CAN'T REMEMBER IF IT WAS A DISCOUNT ON MY DRUGS, IF I -- >> DR. SCOTT KIM: YEAH NO COPAY. >> NO COPAY AND EVERYONE IN KAISER DOESN'T GET THAT. >> DR. SCOTT KIM: MM-HMM. >> WHAT IF I AM AT THE NIH AND I DON'T WANT THAT? I DON'T WANT THAT TO BE SOMETHING THAT I GET, EVEN THOUGH EVERYONE MAY THINK THAT THAT'S A BENEFIT, MAYBE I HAVE A PARTICULAR FEELING ABOUT WHAT I SHOULD PAY IN TERMS OF MY FAIR SHARE. >> DR. SCOTT KIM: YEAH, WELL, SO MY ANSWER TO THAT IS THAT KIND OF THING HAPPENS ALL THE TIME NOW, ESPECIALLY IN REGARD TO ANY PRIVACY RISK THAT A PERSON MIGHT HAVE FOR USE OF RESEARCH DATA AND SO FORTH, THEY MIGHT HAVE GIVEN SOME VERY BROAD PERMISSION FOR SOME USE, OR THERE ARE CERTAIN PROCEDURES THAT WE HAVE THESE FEDERAL REGULATIONS THAT ALLOW RESEARCHERS TO DO RESEARCH WITHOUT EXPLICIT CONSENT WITHOUT TRANSPARENCY THE INDIVIDUAL TRANSPARENCY AND THAT IS A SOCIETY LEGAL DECISION THAT'S BEEN MADE TO SAY THAT THE OVERALL BENEFITS TO EVERYBODY OUT WEIGHS THE MINIMAL CONCERN THAT THERE MIGHT EXIST IN THAT SITUATION. SO THAT YOU COULD SAY THAT'S -- THAT IS THE SOCIETAL DETERMINATION AND THE INDIVIDUAL IN THAT CASE WOULD NOT HAVE ANY CHOICE. >> GREAT. >> AND THAT'S WHAT THE WAIVER MEANS. >> YEAH, RIGHT? >> DR. SCOTT KIM: I MIGHT HAVE MISUNDERSTOOD. >> NO I GET IT. I THINK BASICALLY I THINK THE -- I'LL INTUIT WHERE I THINK THIS PERSON IS COMING FROM: YOU KNOW, ONE POSSIBILITY IS THAT SO MANY OF YOU MAY KNOW THE GUYSINGER HEALTH CARE SYSTEM UP IN RURAL PENNSYLVANIA, THEY ARE REALLY KNOWN FOR INCORPORATE RATING PRAGMATIC TRIALS AND VARIATIONS OF PRAGMATIC TRIALS INTO THEIR STANDARD OF CARE, IT'S BASICALLY HOW THEY DO BUSINESS FOR LACK OF A BETTER TERM, AND SO IF YOU ARE ASSIGNED TO GUYSINGER HEALTH PLAN YOU ARE LIKELY TOLD AND MADE AWARE WHEN THESE TYPES OF THINGS ARE GOING ON, MAYBE WHEN YOU YOU KNOW, FIRST SIGN UP FOR YOUR HEALTH PLAN, TECHNICALLY IT SEEMS LIKE SOMEONE COULD SAY, I'M TOTALLY AGAINST THAT, I UNDERSTAND YOUR EXPLANATION, BUT I'M JUST TOTALLY AGAINST RESEARCH, THEY MAY SAY TO THE PERSON, YOU MIGHT HAVE TO SEEK CARE ELSEWHERE. I DON'T KNOW. >> DR. SCOTT KIM: I SUPPOSE THAT'S POSSIBLE. >> I MEAN I GUESS MAYBE ANOTHER WAY TO SAY THAT GUYSINGER HAS A FEW PEOPLE THAT DON'T WANT TO BE A PART OF IT, AND THEY'RE JUST NOT, IT'S SO FEW THAT IT'S RELATIVELY EASY TO MARK THEIR ELECTRONIC -- >> DR. SCOTT KIM: I THINK THIS QUESTION HAS TO BE A PRACTICAL ONE GIVEN THAT PROBABLY EXISTS WHAT DO YOU DO ABOUT IT? THE CHOICES ARE YOU DECIDE NOT TO SET UP THE EXTRA SOFTWARE PROGRAMMING IN YOUR SYSTEM THAT WOULD ALLOW THEM TO OPT OUT. IT SEEMS LIKE WITH MODERN TECHNOLOGY IT WOULD NOT BE DIFFICULT FOR THEM TO SAY, OH, PUSH THIS BUTTON AND THIS PERSON NAME NEVER COMES UP FOR THESE TRIALS. IF THEY'RE NOT WILLING TO DO THAT AND THE SYSTEM ALLOWS THEM TO DO IT AND IT'S LEGAL AND SO FORTH I MEAN WOULD YOU HAVE TO TALK TO A LAWYER ABOUT THAT PART THEN THEY WOULD HAVE TO GO FIND INSURANCE ELSEWHERE. I WOULD SUSPECT THOUGH THAT THIS COULD BE AN ISSUE IT SEEMS LIKE THAT'S A FAIRLY REASONABLE ACCOMMODATION. ON THE OTHER HAND, IF YOU'RE ONE OF 20 DIFFERENT -- IF YOU'RE A FEDERAL EMPLOYEE IT WOULD BE -- IT WOULD BE A HARDER CASE SINCE YOU HAVE LIKE 33 DIFFERENT OPTIONS THAT YOU COULD CHOOSE FROM, MAYBE? I DON'T KNOW. THAT WOULD BE A PRACTICAL WAY OF LOOKING AT IT. NEXT? >> SO THE RELATED QUESTION IS: I DON'T THINK WE TALKED MUCH ABOUT THIS WHETHER THIS IS A DOMESTIC OR INTERNATIONAL PHENOMENON. ARE PRAGMATIC TRIALS -- ARE THESE BEING ADOPTED WORLDWIDE. >> DR. SCOTT KIM: YES. I WOULD SAY THE FOLLOWING: I KEEP HEARING MYSELF SO I'VE GOT IT -- THE -- THE COMMONWEALTH COUNTRIES, SO BRITISH COMMONWEALTH COUNTRIES USED TO BE CALLED, THEY TEND TO BE A LITTLE BIT MORE IMPIRICIST AND LIKE THIS STUFF. SOME OF THESE STUDIES, THE PCTTI STUDY WAS DONE IN ENGLAND AND HEAD POST STUDY EVEN THOUGH SOME INVESTIGATORS IN US I DON'T BELIEVE ANY SUBJECT WAS RECRUITED IN THE US, THEY WERE RECRUITED FROM EUROPEAN COUNTRIES, UK, CANADA, MAYBE AUSTRALIA, I DON'T KNOW, BUT NOT US, WHICH IS KIND OF TELLING, BECAUSE I THINK HAVING LOOKED AT THE PROTOCOL I -- I DON'T KNOW THAT MANY USIRBS COULD HAVE AGREE WITH THAT. >> SO LET ME JUST CHECK, HERE, FOR ANY ADDITIONAL QUESTIONS. OKAY. SO ANOTHER QUESTION, COULD YOU EXPLAIN A LITTLE MORE ABOUT ALTERATION OF INFORMED CONSENT, WHAT DO YOU MEAN BY THAT ALTERATION? >> DR. SCOTT KIM: YES. SO IF YOU READ THE REGULATIONS IT SOUNDS MAINLY LIKE THE CONCERN THERE IS YOU KNOW AN INFORMED CONSENT REQUIREMENT I'M NOT TALKING ABOUT DOCUMENTATION OF CONSENT, THAT'S A SEPARATE SET OF CRITERIA ABOUT HOW YOU DOCUMENT THE CONSENT, I'M TALKING ABOUT HOW YOU DO THE INFORMED CONSENT, ALL THE ELEMENTS WHAT INFORMATION NEED TO BE INCLUDED, SO THE PRAGMATIC EXAMPLE ALTERATION MEANS YOU LEAVE OUT ONE OF THE 11 ELEMENTS. LIKE FOR EXAMPLE IF I HAD AN INFORMED CONSENT PROCESS IN WHICH I DIDN'T TELL PEOPLE SOMETHING LIKE OH, I CAN'T REMEMBER IF IT'S IN THE REQUIRED OR THE AS OF TIED TO LIST, BUT SOMETHING LIKE -- >> MAYBE ALTERNATIVES AS AN EXAMPLE. >> DR. SCOTT KIM: ALTERNATIVES, CONFIDENTIALITY OR THINGS LIKE THAT, OR WHERE THEY CAN GO TO GET MORE INFORMATION IF THEY HAVE CONCERNS ABOUT THE TRIAL, THINGS LIKE THIS, IF YOU LEAVE THAT OUT THAT WOULD BE CONSIDERED AN ALTERATION OF INFORMED CONSENT. AND THAT'S TREATED FROM A REGULATORY PERSPECTIVE THAT'S TREATED IDENTICALLY TO, BELIEVE IT OR NOT, IN TERMS OF THE BAR THAT YOU HAVE TO MEET, IF YOU COMPLETELY WAIVE CONSENT. SO IF YOU WANT TO LEAP OUT COUPLE ITEMS FROM THAT LIST OF 11 THINGS, YOU HAVE TO MOUNT THE SAME JUSTIFICATIONS THAT YOU WOULD IF YOU ARGUE THAT WE NEED A WAIVER OF CONSENT. >> GREAT. THANK YOU. AND I CAN -- I'LL POST ON THE -- THERE'S A PARTICULAR SECTION IN THE CODE THAT TALKS ABOUT IT, I'LL POST THAT IN RESPONSE TO THIS QUESTION. SO THAT'S ALL THE TIME WE HAVE FOR QUESTIONS. THANK YOU SO MUCH FOR JOINING US, SCOTT. AND THANKS AGAIN FOR PARTICIPATING IN THE CLASS. WE REALLY APPRECIATE IT. >> DR. SCOTT KIM: THANK YOU HOLLY. >> ANOTHER BIG ROUND OF APPLAUSE. OKAY FOLKS WE ARE JUST A COUPLE MINUTES BEHIND, AND SO WHAT I'M GOING TO DO, WE'RE GOING TO HAVE OUR BREAK FROM 10:30 TO 10:45, AT 10:45 S SARA HULL AND I ARE GOING TO ENGAGE IN QUASI DISCUSSION ABOUT INFORMATIONAL REVIE BOARDS, WE HAVE SOME TOPICS THAT WE WOULD WANT TO COVER AND WOULD LOVE TO HEAR FROM YOU ABOUT QUESTIONS YOU HAVE FOR INFORMATIONAL REVIEW BOARDS AND STUDIES, SO BE BACK TO YOU IN 15 MINUTES SOME OF ARE YOU COMING BACK AND GETTING SETTLED. I HAVE THE PLEASURE OF COHOSTING THIS SESSION WITH SARA HULL YOU MET SARA LAST WEEK IF NOT BEFORE WHEN WE SPOKE ABOUT INCLUSION WITH THE NATIVE POPULATIONS, AND WE WHERE GOING TO SPEND THE REST OF TODAY ON THE TOPIC OF INSTITUTIONAL REVIEW BOARDS. AS I MENTIONED, WE HAVE SOME PREPARED REMARKS, BASICALLY TO GET THE BALL ROLLING, WE WOULD LOVE TO HEAR FROM YOU AND ANSWER QUESTIONS THAT YOU HAVE, SO REMEMBER YOU CAN ALWAYS SEND QUESTIONS IN BY E-MAIL OR POST THEM IN THE DISCUSSION BOARD IDENTIFIED AS DISCUSSION BOARD FIVE. SO ARE YOU THERE, SARA? DR. SARA HULL: I AM HERE CAN YOU HEAR ME. >> DR. HOLLY TAYLOR: I CAN SO I'M GOING TO GO AHEAD AND GET STARTED. DR. SARA HULL: GREAT. >> DR. SCOTT KIM: SO HERE'S THE USUAL DISCLAIMER, NOTHING THAT -- WELL EVERYTHING THAT WE SHARE TODAY OUR VIEWS THAT ARE OURS THEY DON'T REPRESENT THE POSITION OR POLICY OF THE NIH, DHHS OR THE US GOVERNMENT. SO HERE'S OUR PLAN TODAY WE'VE BROKEN IT INTO SORT OF FOUR BIG TOPICS AND GO BACK AND FORTH AND INTERRUPT EACH OTHER OCCASIONALLY WITH QUESTIONS AND COMMENTS, I'M GOING TO START OUT WITH HISTORY, HAND IT OFF TO SARA FOR ROLE, COME BACK TO ME FOR A BIT ABOUT SCOPE, BACK TO SARA ABOUT RESPONSIBILITIES, AND AS I SAID, WE'LL -- WE'RE HAPPY TO TAKE QUESTIONS AT ANY POINT DURING THE SESSION TODAY, I'M GOING TO KEEP ONE EYE ON THE DISCUSSION BOARD. SO LET'S START WITH A LITTLE HISTORY. I REALLY LIKE HISTORY AND HISTORY OF RESEARCH ETHICS, AND SO I JUST WANTED TO RUN THROUGH A BIT OF HISTORY FOR YOU, WITH YOU. SO IF WE THINK BACK TO THE NUREMBERG, BACK TO DAY ONE, WHERE WE MENTIONED THE NUREMBERG THE FIRST INTERNATIONAL CODE THAT CAME OUT OF THOSE NUREMBERG TRIALS THERE WAS NO MENTION OF ETHICAL REVIEW THE FOCUS WAS ON INFORMED CONSENT AND VOLUNTARY PARTICIPATION. THE FIRST FEDERAL STANDARD WAS HERE AT THE NIH INTRAMURAL PROGRAM, JUST AS A REMINDER INTRAMURAL REFERS TO THE RESEARCH THAT HAPPENS HERE ON CAMPUS, AT THE NIH THE EXTRAMURAL RESEARCH IS A RESEARCH THAT GOES ON OUT THERE IN ALL OF YOUR ACADEMIC MEDICAL CENTERS AND IS FUNDED BY THE NIH. SO THE FIRST ACTION WAS GROUP CONSIDERATION OF CLINICAL RESEARCH HERE IN THE CLINICAL CENTER, THEY REALLY FOCUSED MORE ON SCIENCE THAN ON ETHICS, THIS WAS REALLY AN ACKNOWLEDGMENT THAT AT LEAST TWO HEADS ARE OFTEN BETTER THAN ONE, THAT IT WOULD BE IMPORTANT FOR COLLEAGUES TO REVIEW THE SCIENCE THAT THEY WERE PROPOSING. SO IN THE 1950S INDIVIDUAL DEPARTMENTS AT ACADEMIC MEDICAL CENTERS STARTED ADOPTING SOMETHING SIMILAR A SCIENTIFIC REVIEW PRIOR TO SUBMITTING IT FOR FUNDING OR FOR CONDUCTING IT ON THEIR CAMPUS WITH NO FUNDING. THE FIRST STUDY OF THIS PHENOMENON TOOK PLACE IN THE 1960S, THE GROUP REFERRED TO AS THE LAW MEDICINE AND RESEARCH INSTITUTE WENT OUT TO ACADEMIC MEDICAL CENTERS AND SAID HEY ARE YOU GUYS -- GUYS LIKELY, PROBABLY SOME GALS -- WHAT ARE YOU DOING IN TERMS OF REVIEW PRIOR TO SUBMITTING YOUR PROJECTS FOR FUNDING? AND AT THAT TIME THERE WAS A DOCUMENTATION OF CERTAINLY THIS SCIENTIFIC REVIEW THAT HAD BEGUN, YOU KNOW, IN THE 1950S AND A BIT OF WHAT WE MIGHT THINK OF TODAY AS ETHICAL REVIEW. IT REALLY WASN'T UNTIL 1964, JUST A COUPLE YEARS LATER, THAT THE IDEA OF AN INDEPENDENT REVIEW, THAT IS LOOKING AT ETHICS, WAS ADOPTED IN THE FIRST VERSION OF THE DECLARATION OF HELSINKI IN 1964, THE -- THE LANGUAGE THERE WAS THE PROTOCOL SHOULD BE TRANSMITTED TO AN INDEPENDENT COMMITTEE FOR CONSIDERATION, COMMENT AND GUIDANCE. SO REMEMBER I MENTIONED JUST PREVIOUSLY IT WAS REALLY COLLEAGUES THINKING AND REVIEWING THE RESEARCH OF COLLEAGUES. THIS IS ALSO WHERE WE GET THIS FIRST IDEA OF AN INDEPENDENT COMMITTEE, MEANING INDEPENDENT FROM THE RESEARCH TEAM OR FROM THE DEPARTMENT CONDUCTING THE RESEARCH. SO IN 1966 WE GOT THE FIRST STATEMENT FOR AN EXPECTATION OF REVIEW BY EXTRAMURAL PROGRAMS SUBMITTING RESEARCH TO THE NIH AND OTHER FEDERAL AGENCIES -- EXCUSE ME -- CONDUCTING AN ETHICAL REVIEW. SO 1966, SORRY, AND IT WASN'T UNTIL 1974 THAT THIS IDEA WAS THEN CODIFIED IN THE CODE OF FEDERAL REGULATIONS. YOU MAY REMEMBER THE TIMELINE, WHICH I'M GOING TO REMIND YOU OF IN A MOMENT, THAT THE NATIONAL RESEARCH ACT WAS PASSED IN 1974, IN RESPONSE TO TUSKAGEE AMONG OTHER PROBLEMATIC TRIALS THAT CAME TO LIGHT THE VERY FIRST DRAFT OF THE CODE OF FEDERAL REGULATIONS HAPPENED IN 1974 AND IT BEGAN TO IDENTIFY THE ROLES AND RESPONSIBILITIES OF IRBS. SO WE THEN GET THE NATIONAL RESEARCH ACT, WE GET BOTH THE BELMONT REPORT, WHICH I'M SURE ALL OF YOU HAVE READ AT LEAST ONCE BY NOW, AND A REPORT ON IRBS THE NATIONAL COMMISSION ACTUALLY PUBLISHED, I THINK, AT LEAST 10, PROBABLY MORE LIKE 15, DIFFERENT REPORTS ON DIFFERENT COMPONENTS OF RESEARCH AND RESEARCH REVIEW. AND THE REPORT AND THE BELMONT REPORT THEN SERVED AS THE INFORMATION THAT WAS USED TO REVISE THE CODE THE FEDERAL REGULATIONS. SO THAT FIRST REVISION OR YEAH I GUESS IT WAS THE FIRST REVISION OF THE 1974 DOCUMENT CAME OUT OF 1981 AND ONLY APPLIED TO THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, SO ONLY RESEARCH CONDUCTED BY, AT THE TIME, YOU KNOW, THE NIH, THE -- ALL THE OTHER PUBLIC HEALTH SERVICE AGENCIES, SO THE CENTERS FOR DISEASE CONTROL, AGENCY FOR CHILDREN AND FAMILIES, ET CETERA. 10 YEARS LATER, WE GET THE FIRST VERSION OF WHAT WE CALL THE COMMON RULE. AND IT'S REFERRED TO AS THE COMMON RULE BECAUSE MANY ADDITIONAL FEDERAL AGENCIES SIGNED ON, SO FROM 1991 FORWARD ALL -- MANY FEDERAL AGENCIES HAVE -- FOLLOW THE COMMON RULE, ONE EXCEPTION THAT WE'VE MENTIONED PREVIOUSLY, IS THE FDA, THE FDA HAS A VERY SIMILAR BUT SLIGHTLY DIFFERENT REGULATIONS, THAT APPLY TO PHARMACEUTICALS AND OTHER BIOLOGIC PRODUCTS THAT FOLKS ARE INVESTIGATING TOWARDS MARKET APPROVAL. AND THEN, VERY RECENTLY, IN 2018, THAT CAPPED A NUMBER OF YEARS WHERE THE COMMON RULE WAS UNDER REVISION A LOT OF BACK AND FORTH, A LOT OF PUBLIC COMMENT, AND WE HAVE NOW THE REVISED COMMON RULE, WHICH IS THE ONE THAT'S CURRENTLY IN PLACE, THE ONE THAT'S IN YOUR PACKET, THE ONE THAT SCOTT WAS JUST REVERSI REFERRING TO IN TERMS OF THE REQUIREMENTS OF INFORMED CONSENT AND ALTERATION OF INFORMED CONSENT. IT TURNS OUT WHEN YOU LOOK AT THE REVISED COMMON RULE MOST OF IT HAS TO DO WITH THE INSTITUTIONAL REVIEW BOARD, WHAT IT LOOKS LIKE, WHAT IT DOES, WHAT ITS RESPONSIBILITIES ARE. I TOOK A CLASS, I DON'T REMEMBER IF YOU TOOK THIS CLASS SARA WITH NORM FOST, MANY MANY YEARS AGO, WHERE NORM WHO IS AN EMERITUS PROFESSOR AT THE UNIVERSITY OF WISCONSIN PART FRT CLA OF THE CLAS /* /- OF THE CLASS WAS TO MEMORIZE, AND I REMEMBER AT THAT TIME THINKING OH, MY GOSH THERE'S SO MUCH IN HERE ABOUT IRBS STRUCTURE WHAT THEY'RE SUPPOSED TO DO, THERE'S REALLY NOT A LOT OF HELPFUL HINTS ABOUT HOW TO DO ANY OF THIS STUFF. THEY'RE KIND OF TOLD WHAT DO BUT NOT GIVEN MUCH IN ADDITION TO THAT. SO I JUST WANT TO END O THIS SLIDE AND I'LL HAND IT OVER TO SARA, THIS IS A SLIDE OF SARA THAT QUOTES A MILL BANK ARTICLE BACK IN 1995 THAT TALKS ABOUT THE ROLE OF IRBS AND HOW THEY'VE TRANSFORMED HUMAN SUBJECT RESEARCH. SO UNQUESTIONABLY THEIR VERY EXISTENCE HAS TEMPERED THE INEVITABLE PROPENSITY TO PURSUE INVESTIGATIONS WITHOUT DISPARTIAL NATELY WEIGHING THE RISK THEY ARE ASKING OTHERS TO ASSUME OR FULLY INFORMING THEIR SUBJECTS OF THEM. WE TALK ABOUT PILLARS OF HUMAN SUBJECTS OVERSIGHT, ONE PILLAR BEING THE INSTITUTIONAL REVIEW BOARD ITS SXEF ITS REVIEW AND OVERSIGHT AND THEN SECONDLY, FULLY INFORMED CONSENT. SO WITH THAT, I'M GOING TO HAND OFF TO SARA, WHO'S GOING TO PICK UP ON THE ETHICS AND THE ETHICAL MANDATE FOR INDEPENDENT REVIEW AND THEN TALK A BIT MORE. LET ME SEE IF WE'RE GOING TO GET TO THE ROLE OF THE IRB. SO HERE'S YOUR SLIDE, SARA, THE ETHICAL REQUIREMENTS OF INDEPENDENTREVIEW. DR. SARA HULL: RIGHT THANK YOU VERY MUCH. I WOULD LIKE TO JUST REFLECT ON THE -- WELL THAT TRANSITION SLIDE FOR A MOMENT. I -- I WANTED TO LET FOLKS KNOW THAT I'VE BEEN INVOLVED WITH IRBS EVER SINCE GRADUATE SCHOOL, SINCE WORKING AT THE NIH WHICH STARTED IN 1999, I HELPED TO BUILD A NEW IRB FOR THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE AND I'VE SEEN A LOT OF CHANGE, NOT ONLY IN THE RULES THEMSELVES, BUT IN THE STRUCTURE OF THIS SYSTEM AT CNIH. FOR MY COMMENTS TODAY IN ADDITION TO THE DISCLAIMER THAT HOLLY'S SHARED APPROPRIATELY, I ALSO WANT TO MAKE CLEAR THAT I'M NOT HERE SPEAKING ON BEHALF OF THE IRB SYSTEM, ALTHOUGH I WILL STRIVE TO BE AS ACCURATE AND PRECISE AS POSSIBLE WHEN IT COMES TO THOSE KINDS OF QUESTIONS, THIS IS JUST A LITTLE BIT OF REFLECTION ON HOW I AND HOW DIFFERENT PEOPLE HAVE THOUGHT ABOUT IMPLEMENTING THE FORMAL AND FAIRLY STREAM LINED REQUIREMENTS EVEN THOUGH THE COMMON RULE IS QUITE DETAILED WHEN IT COMES -- OR QUITE FOCUSED ON IRBS IT LEAVES OPEN A LOT OF DISCRETIONARY CHOICES ABOUT EXACTLY HOW TO IMPLEMENT THEM. BUT ONE OF THE QUESTIONS ALL THESE YEARS, ALL THESE DECADES I'VE SPENT ON THE IRBS IS THE QUESTIONS OF DOES IT REALLY MATTER, DO WE -- DO WE MAKE A DIFFERENCE? DO WE TAKE THESE ETHICAL -- HISTORICAL VIOLATIONS THAT WE'VE STUDIED IN THIS CLASS AND THINK THAT IRBS SOLVE THAT PROBLEM? AND I CAME ACROSS THIS QUOTE, AND I LIKE IT, ALTHOUGH IT DOES HAVE A SLIGHTLY NEGATIVE VIEW OF INVESTIGATORS THAT IT OFFERS, I THINK IT -- IT TOUCHES ON THIS IDEA THAT THE IRB PLAYS AN IMPORTANT ROLE IN THE CULTURE OF CREATING A CULTURE OF ETHICS AND THAT'S HOW I LIKE TO THINK ABOUT IT AND HOW I LIKE TO OPERATIONALIZE ALL OF THE DIFFERENT RULES AND FORMAL REQUIREMENTS. SO NOW GOING ONTO THE NEXT SLIDE, YOU KNOW W DESH YOU STUDIED THE -- WELL HOLLY TALKED ABOUT THE PILLARS, THERE'S THIS PAPER WHAT MAKES CLINICAL RESEARCH ETHICAL, AND THE FORMAL REQUIREMENTS FOR HAVING AN IRB FULFILL THE REQUIREMENTS THAT THEY -- THAT THIS PAPER SPECIFIES FOR INDEPENDENT REVIEW ON A SERIES OF STEPS TO TAKE A CLOSE LOOK AT WHO IS INVOLVED WITH THE RESEARCH, WHAT THE SCIENTIFIC DESIGN LOOKS LIKE, WHETHER THE RISKS ARE JUSTIFIED IN RELATION TO THE ANTICIPATED SOCIETAL BENEFITS OF RESEARCH, BUT PEOPLE OTHER THAN THE RESEARCHERS THEMSELVES BOTH TO MITIGATE AGAINST INVESTIGATOR CONFLICTS OF INTEREST AS WELL AS A FORM OF -- PLAYING AN INTERMEDIARY ROLE BETWEEN THE PUBLIC WHO WANTS TO BE ASSURED THAT RESEARCHERS ARE CONDUCTING THEMSELVES WITHIN A CODE OF ETHICS AND WITHIN A CODE OF REQUIREMENTS THAT HOLDS THEM ACCOUNTABLE. OKAY SO ONTO THE NEXT SLIDE. SO I TOUCHED ON THIS, THE -- WE FORMALLY TALK ABOUT IT AND ACTUALLY THE ACCREDITATION FOR IRBS TALKS ABOUT THE IDEA OF HAVING -- MY DOG'S BARKING IN THE BACKGROUND, YAY. >> DR. HOLLY TAYLOR: HI HUDSON. >> DR. HOLLY TAYLOR: FEDERAL EXPRESS JUST PULLED UP. WE CALL THIS UMBRELLA OF THE CODE OF ETHICS THE HUMAN RESEARCH PROGRAM WHICH IS THE IDEA THAT IT'S NOT JUST THE IRB I DON'T LIKE THE PHRASE THE ETHICS POLICE, WE'RE NOT PLAYING A POLICING ROLE, BUT RATHER A COMPONENT OF A LARGER SYSTEM WHERE MANY DIFFERENT ENTITIES FROM RESEARCHERS TO THE INSTITUTIONAL RESEARCH ITSELF, TO LOTS OF OTHER PLAYERS WORKING TOGETHER IDEALLY COLLABORATIVELY AND AMONG OTHER THINGS THIS HELPS MITIGATE OR MEDIATE CONFLICTS OF INTERESTS THAT INVESTIGATORS WHO HAVE LOTS OF DIFFERENT ROLES THAT THEY'RE PLAYING THAT MAY SOMETIMES COME INTO CONFLICT. SO IT'S A CHECK ON THOSE CONFLICTS AND THOSE ROLES. AND IT ENSURES THAT OTHERS KIND OF HAVE THEIR BACK AND ENSURES THAT WE'RE LOOKING AT A NUMBER OF KEY ISSUES, GO AHEAD I HAVE THE NEXT SLIDE UP THERE. THERE ARE SOME FORMAL REQUIREMENTS STRUCTURAL REQUIREMENTSES THAT DEFINE HOW THE IMPROVEMENT I /* IRB OPERATES, THE REGULATIONS REQUIRE A MINIMUM OF FIVE MEMBERS TO BE PRESENT FOR A QUORUM TO HAVE THE ADEQUATE NUMBER AND THESE REQUIREMENTS WILL SOUND FAMILIAR TO IF YOU'VE PAID ATTENTION TO ROBERTS RULE OF ORDER OR OTHER FORMAL WAYS TO HOLD MEETINGS THIS MODELS A LOT OF THOSE KINDS OF REQUIREMENTS. INTERESTINGLY THE IRB MEETING THAT I CHAIRED LAST WEEK HAD EXACTLY FIVE MEMBERS, IT'S UNUSUAL TO HAVE, IN MY EXPERIENCE, TO HAVE THAT FEW, BUT THOSE MEMBERS CAN HOLD MULTIPLE ROLES AND THE REGS HAVE SOME VERY BASIC EXPECTATIONS ABOUT WHO THOSE FIVE PEOPLE NEED TO BE, THEY DO WANT TO SEE DIVERSITY IN TERMS OF GENDER, RELEVANT EXPERIENCE, THERE IS AN ABSOLUTE REQUIREMENT TO HAVE AT LEAST ONE MEMBER WHOSE PRIMARY -- I FORGET THE EXACT LANGUAGE -- PRIMARY OF INTERESTS ARE IN CONCERNS OTHER IN AREAS OTHER THAN SCIENCE AND IDEALLY WE WANT PEOPLE UNUNAFFILIATED WITH THE INSTITUTION WHICH IS A WAY TO MITIGATE INSTITUTIONAL CONFLICTS OF INTEREST, AND SO THEN IT LEAVES OPEN FROM THERE THE OPPORTUNITY TO SELECT AND DECIDE WHO OUGHT TO SERVE ON THIS IRB. I THINK THIS IS A REALLY -- IT'S -- IT'S SOMETHING THAT A TRAINEE AND I, A FORMER FELLOW IN THE DEPARTMENT OF BIO ETHICS HAVE BEEN STUDYING LOOKING' AT THE ROLE OF THE MEMBERS OF THE IRB AND WHAT THE ROLE OF THEIR EXPERTISE IS AND THE VARIOUS PERSPECTIVE THEY BRING TO THE DELIBERATIONS AND HOW THIS PLAYS OUT. BUT THIS IS ALL A MATTER OF IMPLEMENTATION AT THAT LEVEL, BECAUSE AS YOU CAN SEE THERE'S RELATIVELY FEW REQUIREMENTS SPECIFIED IN THE FORMAL REGULATION REQUIREMENTS THEMSELVES. NEXT SLIDE. >> DR. HOLLY TAYLOR: WE HAPPEN -- HI SARA, WE HAPPEN TO HAVE A QUESTION ABOUT A COMMUNITY MEMBER SO I THOUGHT I WOULD BARGE IN. DR. SARA HULL: GREAT. >> DR. HOLLY TAYLOR: SO LET'S SEE, PIETRA ASKS DO THE COMMUNITY MEMBERS WEIGH INTO IRB DECISION MAKING ABOUT THINGS LIKE FUNDING, INSTITUTIONAL INTERESTS, AND HOW MIGHT THEIR CAMARADERIE WHICH I THINK MEANS FEELING A PART OF THE GROUP, INFLUENCE THEIR DECISION? DR. SARA HULL: YEAH, THIS IS A GREAT QUESTION, A REALLY CRITICAL QUESTION, AND ONE THAT I PAY PARTICULAR ATTENTION TO IN MY ROLE AS THE CHAIR. IDEALLY YOU DO ABSOLUTELY WANT THE NON SCIENTIST MEMBER OR MEMBERS TO BE FULLY ENGAGED IN THE DELIBERATIONS OF THE IRB. NOW WE DON'T LOOK CLOSELY YOU MENTIONED THINGS LIKE FUNDING AT LEAST IN THE INTRAMURAL PROGRAM WE DON'T ALWAYS TAKE A CLOSE LOOK AT THAT PARTICULAR VARIABLE, BUT I THINK IT'S REALLY IMPORTANT TO -- AND ACTUALLY A CHALLENGE TO BOTH IDENTIFY NON SCIENTISTS WHO FEEL COMFORTABLE SPEAKING UP SITTING SIDE BY SIDE WITH SDIEN TIFK EXPERTS WITH SOME OF THE OTHERS WHO MAKE UP THIS CITY, AND IT'S ALSO A ROLE OF THE CHAIR TO GIVE THEM THE SPACE TO RESPOND AND TO VALIDATE AND TAKE SERIOUSLY WHAT THEY HAVE TO OFFER, BUT I'VE ALWAYS USED THAT AS A VERY IMPORTANT PART OF THE COMMITTEE DYNAMIC AND IT ABSOLUTELY DOES DEPEND ON THINGS LIKE THE ABILITY TO ESTABLISH RAPPORT, THE ABILITY TO -- I THINK I'M REPEATING MYSELF A LITTLE BIT, BUT TO JUST SORT OF VALIDATE AND MAKE CLEAR THAT THEIR VOICE IS RELEVANT TO THE DELIBERATIONS THERE ACTUALLY HAVE BEEN STUDIES ON THIS TO WHAT EXTENT THE MEMBERS THEMSELVES VIEW THEMSELVES AS HAVING A VOICE AND WHAT ROLE THEY'RE FULFILLING. I APPRECIATE THE QUESTION. I SPENT QUITE A BIT OF TIME ON THIS EXACT TOP SXIK SHARED SOME OF THAT DATA I WOULD BE HAPPY TO FOLLOW UP AND SHARE SOME INTERESTING MANUSCRIPTSES ON THAT POINT AFTER THIS SESSION. >> DR. HOLLY TAYLOR: SARAH ONE OTHER QUICK COMMENT BASICALLY WHAT YOU WERE JUST TALKING ABOUT HOW EFFECTIVE IS THE VOICE OF A COMMUNITY MEMBER AND I'LL CHIME IN HERE TO REITERATE WHAT SARA SAID THAT I TOO HAVE MANY, MANY EXPERIENCES ON IRBS ON WHOLE RANGE, PRIVATE, PUBLIC, GOVERNMENT, ACADEMIC MEDICAL CENTER, I WOULD SAY THE MOST IMPORTANT THING IN TERMS OF THE COMMUNITY MEMBERS' VOICE IS THE CHAIR'S COMMITMENTED COMMITMENT TO MAKING SURE THEY HAVE AN OPPORTUNITY TO SPEAK. AS SARA MENTIONED RIGHT IT CAN BE INTIM DEY DAIDATING TO BE IN A ROOM LET'S SAY IT'S FIVE YOU'RE ONE OF THOSE FIVE IN A SMALL GROUP LIKE THAT THERE ARE FOUR OTHER SCIENTISTS IN THE ROOM AND THE CHAIR'S SORT OF ABILITY AND SORT OF -- I DON'T MEAN THIS IN A BAD WAY BUT ROUTINELY ASKING FOR INPUT NOT PUTTING THEM ON THE SPOT BUT ASSURING HIM OR HER THAT THERE IS A PLACE FOR THEIR VOICE IS IMPORTANT. I'LL ALSO MENTION THE US IS A BIT OF AN OUTLIER. OTHER COUNTRIES HAVE REQUIREMENTS THAT THERE ARE MORE THAN JUST ONE PERSON REFLECTING AGAIN WHAT WE'RE SORT OF PROTOTYPICALLY OR WHATEVER CALLING THE COMMUNITY MEMBER, EVEN I THINK IF YOU ASK COLLEAGUES I THINK HAVING TWO IS DEFINITELY BETTER THAN JUST ONE, NEW ZEALAND IS THE REAL OUTLIER THEY REQUIRE THAT THERE ALWAYS BE ONE MORE COMMUNITY MEMBER THAN SCIENTISTS. DR. SARA HULL: I DIDN'T KNOW THAT. >> DR. HOLLY TAYLOR: I'M LET YOU GO AHEAD SARA. DR. SARA HULL: THAT'S INTERESTING I DIDN'T KNOW THAT LAST POINT. AND SOMETHING ELSE THAT I'LL JUST MENTION QUICKLY IS THAT THE -- OOPS DID I LOSE MY TRAIN OF THOUGHT -- THAT I THINK THINGS LIKEN COURAGING DISSENT, ALLOWING PEOPLE TO FEEL COMFORTABLE VOTING AGAINST THE MAJORITY, AND ENSURING THAT CONSENSUS ISN'T REQUIRED IS ANOTHER WAY TO ENSURE THAT A COMMUNITY MEMBER'S VOICES CAN BE HEARD AND RECORDED AND, IN FACT, THEY ARE THE ONE ESSENTIAL MEMBER OF THE QUORUM YOU CAN'T PROCEED WITH A MEETING UNLESS YOU HAVE AT LEAST ONE NON-SCIENTIST MEMBER PRESENT. SO THE -- I THINK THAT WAS THE WAY THAT THE REGULATIONS ADDED SOME PRIORITY TO THAT, TO THEIR PRESENCE TO THE MEETING. OKAY. NEXT SLIDE. SO IT'S INTERESTING THAT THE D -- THE IRB IS SITUATED AT A LOCAL INSTITUTION, AND OFTEN ORGANIZATIONALLY IT FITS INTO THE INFRASTRUCTURE OF THAT INSTITUTION AND IT'S AUTONOMOUS IF IT'S GIVEN THE DISCRETION TO REVIEW THE STUDIES AT THAT SITE, THERE ARE OPPORTUNITIES WHERE THEY MAY ALSO BE REVIEWING RESEARCH AT OTHER RESEARCH INSTITUTIONS, BUT THE POINT HERE IS THAT THEY ARE AUTONOMOUS, THEY ARE MADE UP OF SPECIFIC INDIVIDUALS WHO HAVE THE ABILITY TO REVIEW STUDIES ON A CASE-BY-CASE BASIS AND MAKE DECISIONS. BUT WHAT THIS DOES LEAD TO IS THAT THERE ARE SOMETIMES VARIABILITY IN HOW CERTAIN CITIES MIGHT BE VIEWED AT DIFFERENT SITES AND THERE'S ACTUALLY SOME RESEARCH ONE OF MY VERY FIRST STUDIES THAT I PUBLISHED WAS LOOKING AT VARIABILITY IN THE MULTI SITE IRB REVIEW OF A SINGLE STUDY AND HOW DIFFERENT INSTITUTIONS IRBS USE KEY POINTS RELATED TO DETERMINATION OF RISK AND OTHER IMPORTANT ASPECTS OF THE STUDY. SO THIS CAN BE A STRENGTH TO HAVE A VERY TAYL TAILORED REVIEW APPROACH HOW AN INSTITUTION IS GOING TO IMPLEMENT A STUDY AT THEIR SITE BUT IT DEPENDS TO WHAT EXTENT THE VARIABILITY IS ARBITRARY OR REALLY GROUNDED IN THE SPECIFICS OF THE POPULATION BEING STUDIED AND KEY FEATURES RELEVANT FEATURES OF THE STUDY. NEXT -- NEXT SLIDE. WE TALKED A LITTLE BIT ALREADY ABOUT SOME OF THE CHALLENGES THAT COME INTO PLAY WITH RESPECT TO GROUP DYNAMICS, IT CAN BE THE CASE THAT AN IRB THAT WORKS TOGETHER A LOT OVER MANY YEARS WITHOUT A CHANGE OVER IN MEMBERSHIP CAN START TO EITHER DEVELOP SHORT CUTS THINKING OH, WE'VE SEEN THIS, HERE'S ANOTHER STUDY, LET'S REVIEW THIS EXACTLY THE SAME WAY AS OUR PREVIOUS PRECEDENT OR A COUPLE MORE KEY MORE VOCAL MEMBERS OF THE GROUP TONED SWAY THE WAY THAT THE DYNAMIC GOES. WHAT'S BEEN A VERY INTERESTING EXPERIENCE FOR ME, AT THE NIH OUR INTRAMURAL IRB SYSTEM ENSURES THAT AT EVERY MEETING I AM WORKING WITH A DISTINCT GROUP OF MEMBERS, THERE'S A LARGE POOL FROM WHICH EACH COMMITTEE MEETING IS DRAWN, AND SO THIS CHANGES UP, ALTHOUGH I'M A CONSTANT, AS A CHAIR AT MY MEETINGS, THE MEMBERS AND THE DYNAMIC THAT SURROUNDS THEIR INTERACTION IS HIGHLY VARIABLE. THIS HAS BEEN A REALLY INTERESTING THING BOTH FOR ME TO LEARN HOW TO MANAGE BUT ALSO A WAY TO ENSURE THAT SOME OF THESE CHALLENGES ABOUT SORT OF PATTERNS THAT ARE STALE OR THAT ARE NOT NECESSARILY CONDUCIVE TO -- TO RIGOROUS REVIEW ARE -- CAN BE CONFRONTED, IT MAY MAKE IT MORE CHALLENGING TO DEVELOP RAPPORT AND COMFORT FOR A GROUP OF PEOPLE TO SPEAK UP THAT THEY DON'T KNOW AS WELL. I HAVE FOUND THAT'S AGAIN ON ME AS THE CHAIR TO FIGURE OUT HOW TO DRAW PEOPLE OUT AND I HAVEN'T FOUND THAT THAT'S BEEN A PROBLEM TO DO IN DIFFERENT SETTINGS, IT'S A -- IT'S A CREATIVE CHALLENGE. ANOTHER -- I MENTIONED CONFLICTS OF INTERESTS AND OF COURSE WE HAVE TO PAY CLOSE ATTENTION TO THE CONFLICTS OF INTEREST THEMSELVES MIGHT CARRY, THERE ARE MANY SPOUSES WHO WORK TOGETHER AT THE NIH, THERE ARE SUPERVISORS WHOSE DIRECT REPORTS SERVE ON THE IRB, THERE ARE WAYS IN WHICH WE HAVE TO LOOK CLOSELY AT WHO IS REVIEWING THESE STUDIES AND ENSURE THAT THESE CONFLICTS OF INTERESTS DON'T GET IN THE WAY OF THE INDEPENDENT REVIEW IN THOSE WAYS, AS WELL. INSTITUTIONAL CONFLICTS OF INTEREST IS AN INTERESTING QUESTION AND ONE THAT MAY SEEM -- MAY STRIKE YOU AS INHERENT AS AN INSTITUTIONAL REVIEW BOARD WE HAVE THESE COMMITTEES THAT ARE SITUATED AT THE INSTITUTION MAID UP OF MEMBERS THAT WE -- SOME MEMBERS FROM THAT INSTITUTION REVIEWING IT'S CONDUCTS OF RESEARCH THAT TAKES PLACE THERE. AND THERE'S A LOT OF DEBATE ABOUT WHETHER THIS -- AND HOW EXACTLY HOW PROBLEMATIC THIS IS, BUT THERE ARE MEASURES IN PLACE LIKE HAVING EXTERNAL MEMBERS LIKE REMOVING LINES OF AUTHORITY TO ENSURE INDEPENDENCE OF IRB DETERMINATIONS, ENSURING THAT IRB DECISIONS STAND AND CAN'T BE ADJUDICATED AT A HIGHER LEVEL WITHIN THE INSTITUTION, THESE ARE MEASURES THAT ARE TAKEN TO MITIGATE AGAINST THOSE CONFLICTS. I THINK HOLLY IT'S MY TURN TO TURN THIS BACK OVER TO YOU. >> DR. HOLLY TAYLOR: IT IS AND I'LL PICK UP REALLY QUICKLY ON THE COMMENT THAT YOU MADE, SO SAZ SARA MENTIONED THE PROTOTYPICAL IRB THAT WE OFTEN TALK ABOUT IS ONE SIMILAR MAYBE TO THE ONES THAT WE HAVE HERE AT THE INTRAMURAL PROGRAM, OR AN INSTITUTIONAL REVIEW BOARD CONNECTED TO AN ACADEMIC MEDICAL CENTER. ONE AT THE VERY OTHER END OF THE SPECTRUM ONE WAY TO ADDRESS INSTITUTIONAL DN INSTITUTIONAL CONFLICT OF INTEREST IS TO HIRE A PRIVATE IRB. SO NOW THERE ARE BOTH FOR PROFIT AND NON-PROFIT COMMERCIAL IRBS THAT INSTITUTIONS CAN CONTRACT WITH FOR THE REVIEW OF THEIR RESEARCH. NOW OF COURSE THERE ARE CONFLICTS THERE, AS WELL. IF THEY'RE A BUSINESS THERE'S A BOTTOM LINE THERE MIGHT BE A TENDENCY TO BE -- WANT TO FOCUS ON EFFICIENCY, TO KEEP CLIENTS, ET CETERA. SO I GUESS -- I GUESS TO SAY THAT THERE ARE CONFLICTS -- THERE ARE LIKELY CONFLICTS IN ANY SORT OF SYSTEM THAT WE WOULD DEVELOP, AND IT'S REALLY IMPORTANT TO ACKNOWLEDGE THOSE AND SAZ SAAS SARA SAID TRY TO ADOPT WAYS TO MEDIATE THOSE POTENTIAL CONFLICTS. I'M GOING TO VERY QUICKLY TALK A BIT ABOUT SCOPE AND SARA'S GOING TO TALK ABOUT RESPONSIBILITIES OF THE IRB. SO WHY -- WHY DO WE NEED THIS IRB? WHY IS IT WE'RE SPENDING 45 MINUTES TALKING ABOUT IT? SO THE REASON WHY ACADEMIC MEDICAL CENTERS NEED AN IRB IS FOR A COUPLE OF REASONS, FIRST, IF YOU ARE GOING TO BE CONDUCTING FEDERALLY FUNDED HUMAN SUBJECT RESEARCH AT YOUR INSTITUTION YOU HAVE TO HAVE AN IRB, YOU HAVE TO HAVE A LOCAL REVIEW OF THE RESEARCH, I'LL MENTION THIS AGAIN IN A SECOND BUT THE INSTITUTION HAS TO AGREE AS IN TAKING THE MONEY THAT THEY WILL REVIEW THE RESEARCH THAT'S FEDERALLY FUNDED. AND OTHER FUNDERS, OTHER PRIVATE FOUNDATIONS LIKE THE ROBERT WOOD JOHNSON FOUNDATION, THE GREEN WOOD FOUNDATION, YOU NAME IT THESE DAYS ALMOST ALWAYS SAY WE WILL NOT FUND YOUR RESEARCH UNLESS IT'S BEEN REVIEWED BY AN IRB. AND THE FDA REQUIRES IRB REVIEW. REMEMBER I MENTIONED THAT THEY HAVE REGULATIONS THAT ARE VERY PHARMACEUTICAL COMPANIES FOLLOW REGULATIONS OF THE FDA THAT ARE VERY SIMILAR TO THOSE APPLIED TO OTHER HHS AGENCIES AND OTHER AGENCIES OUTSIDE OF HHS AND IN ORDER FOR A PHARMACEUTICAL COMPANY TO EVEN INITIATE THINKING ABOUT SUBMITTING AN APPLICATION TO THE FDA FOR APPROVAL AND MARKETING HAS TO HAVE IT APPROVED BY AN IRB. I THINK WE MENTIONED THIS BEFORE, THAT MIGHT LEAVE OUT SOME ENTITIES. I'LL MENTION HERE, THAT I MENTIONED THAT INSTITUTIONS THAT AGREE TO -- INSTITUTIONS THAT ARE TAKING FEDERAL FUNDING AGREE TO REVIEW THE RESEARCH THAT IS GOING TO BE FEDERAL FUNDED -- FEDERALLY FUNDED. THEY ALSO HAVE TO AGREE THAT THEY WILL REVIEW ALL RESEARCH AT THEIR INSTITUTION WITH AN IRB. SO IT'S REGARDING -- SORRY -- REGARDLESS OF FUNDING MECHANISMS, IF I WANT TO SUPPORT A PROJECT WITH MY DISCRETIONARY FUNDS, I STILL HAVE TO GO THROUGH THE IRB. THAT FEDERAL LIGHT ASSURANCE ALSO COMMITS THE INSTITUTION TO FOLLOWING THE PRINCIPLES OF BELMONT OR IF THEY'RE AN IRB OUTSIDE OF THE US THAT THEY ARE FOLLOWING INTERNATIONALLY RECOGNIZED STANDARDS AND THAT MIGHT BE THE DECLARATION OF HELSINKI THE EUROPE UNION JAPAN HAVE REGULATIONS SIMILAR TO -- PRINCIPLES SIMILAR TO OURS THAT THEY MAY BE FOLLOWING. AND SO THERE'S VERY LITTLE RESEARCH THAT GETS CONDUCTED THAT'S NOT BEING CONDUCTED IN AN ACADEMIC MEDICAL CENTER OR BY A PHARMACEUTICAL COMPANY THAT IS GOING TO SEEK APPROVAL IN MARKETING. SO WHILE IT'S POSSIBLE THAT SOME RESEARCH IS HAPPENING WITHOUT THAT IRB REVIEW IT'S RELATIVELY YOU THINK LIKELY. I WILL MENTION VERY BRIEFLY I'M THE EDITOR OF A JOURNAL AND I GOT A SUBMISSION RECENTLY, THE -- TWO OF THE REVIEWERS POINTED OUT THAT THERE WAS NO MENTION IN THE ARTICLE THAT LOCAL REVIEW HAD BEEN CONDUCTED. WE WENT BACK TO THE AUTHOR AND SAID YOU KNOW YOU'RE GOING TO HAVE TO CONFIRM THAT THIS DATA WAS REVIEWED AND APPROVED BY A LOCAL IRB AND THEY WITHDREW THE PUBLICATION. SO EVEN TODAY, THERE ARE APPARENTLY CIRCUMSTANCES WHERE PEOPLE AREN'T FOLLOWING THIS VERY IMPORTANT RULE. SO I'M GOING TO HAND IT OVER TO SARA TO TALK A BIT ABOUT RESPONSIBILITIES OF THE IRB AND TAKE IT AWAY SARA. DR. SARA HULL: SURE. SO HOW DOES THIS ALL PLAY OUT? THERE ARE A SERIES OF REVIEW STANDARDS THAT ARE ARTICULATED IN 45CFR46 THAT GUIDE THE CONDUCT OF REVIEWS IN THE CONTEXT OF A COMMITTEE MEETING OR IN THE OTHER WAYS THAT AN IRB CAN BE CHARGED WITH REVIEWING PROTOCOLS. THERE'S -- I LIKE THAT SCIENTIFIC REVIEW IS STUCK ON THIS SLIDE AS A REMINDER OF HOW MANY TIMES THE IRB HAS BEEN ACCUSED OF MISSION INCREASE, SO THERE ARE QUESTIONS ABOUT THE SCOPE OF OUR RESPONSIBILITY EVEN AS THEY APPLY TO THESE FORMAL REVIEW CRITERIA. NOW SCIENTIFIC REVIEW IS SOMETHING THAT TAKES PLACE IN A NUMBER OF DIFFERENT WAYS, IDEALLY PRIOR TO THE IRB GETTING A PROTOCOL IN ITS HANDS TO TAKE A LOOK AT THERE'S PER REVIEWED PROCESSES, SCIENTIFIC REVIEW HERE IN THE INTRAMURAL PROGRAM, IDEALLY AN IRB IS TAKING A LOOK AT A STUDY THAT HAS BEEN WELL VETTED AND WELL DESIGNED IN A WAY THAT OUGHT TO ACHIEVE VALUABLE SCIENTIFIC AIM. BUT THERE ARE ELEMENTS OF OUR REVIEWS THAT DO REQUIRE US TO TAKE A CLOSE LOOK AT THE SCIENCE AND I WOULD SAY THAT IF THERE ARE ISSUES RELATED TO -- RELATED -- ETHICAL ISSUES RELATED TO THE SCIENTIFIC DESIGNS THAT GET IN THE WAY OF US BEING ABLE TO MEET OR APPLY THE CRITERIA THAT WE'RE CHARGED WITH APPLYING, WE WILL SOMETIMES NOT PROVIDE A REVIEW OF THE SCIENCE ITSELF BUT OF HOW THAT SCIENCE COULD BE BETTER DESIGNED TO FULFILL ETHICAL CRITERIA, FOR EXAMPLE. JUST GOING ONTO THE NEXT SLIDE, I'M GOING TO JUST TALK THROUGH WHAT THE DIFFERENT CRITERIA ARE THAT ARE ARTICULATED IN THIS PARTICULAR SUBSECTION OF THE REGULATIONS. THE FIRST COUPLE OF REQUIREMENTS TAKE A LOOK AT THE RISKS, THE RISKS THAT WE ARE ASKING VEFRP PARTICIPANTS TO UNDERTAKE -- TO UNDER TAKE AS PART OF THIS STUDY, AND THE IRB IS CHARGED WITH MAKING SURE THAT MINIMIZED TO THE EXTENT POSSIBLE AND THAT ON BALANCE THAT THEY ARE REASONABLE TO ASK PEOPLE TO ASSUME. WHEN WE LOOK AT THE OVERALL BENEFITS OF THIS STUDY, WHICH CAN INCLUDE A COMBINATION OF -- MORE -- MOST IMPORTANTLY IS THE BENEFIT THE SOCIETAL BENEFIT THE VALUE OF THE RESEARCH, BUT ALSO WEIGHED IN THERE MIGHT BE THE DIRECT BENEFITS OF ANY PARTICULAR RESEARCH SUBJECT MIGHT EXPERIENCE, MIGHT BE EXPECTED TO EXPERIENCE AS PART OF THEIR ENROLLMENT IN THIS STUDY. SO THESE I THINK THESE ARE APPROPRIATE AN APPROPRIATE PLACE TO BEGIN AND -- AND WE TEND TO ACTUALLY TO WALK THROUGH THESE AT LEAST FOR A NEW STUDY IN ORDER, ALTHOUGH REALLY QUESTIONS LIKE WHO THE SUBJECTS ARE THAT ARE BEING TARGETED FOR A PARTICULAR STUDY, HOW ARE THEY BEING SELECTED, AND ARE THEY APPROPRIATE, THOSE ARE ALSO QUITE INTEGRAL TO QUESTIONS ABOUT STUDIES DESIGN AND THE OVERALL STRUCTURES OF THE STUDY. AND SO -- AND THIS TIES INTO -- YOU'LL SEE THAT THESE CRITERIA MAP ON VERY CLOSELY TO THE PRINCIPLES OF THE BELMONT REPORT. ARE WE ATTENDING TO GOOD AND NOT GOOD, JUSTICE PRINCIPAL RELATES VERY CLOSELY TO THE SUBJECT SO WE'RE TAKING A LOOK AT THE RECRUITMENT PLAN AND THE DEFINITION OF THE ELIGIBILITY CRITERIA AND EXACTLY WHO THE STUDY IS PAYING ATTENTION TO AS PART OF OUR REVIEW AND THIS IS HOW THE PROTOCOL NEEDS TO BE STRUCTURED TO PROVIDE US WITH ADEQUATE INFORMATION TO BE ABLE TO MAKE THESE JUDGMENTS. NEXT SLIDE PLEASE. >> DR. HOLLY TAYLOR: SARA SOMEHOW WE NOW ONLY HAVE EIGHT MINUTES LEFT. DR. SARA HULL: OH, MY WOW. >> DR. HOLLY TAYLOR: I KNOW. DR. SARA HULL: SOMEHOW BECAUSE I TALK A LOT. >> DR. HOLLY TAYLOR: IF YOU WANT TO COVER THESE CRITERIA I'M GOING TO SUGGESTS THAT WE GO TO THE REVIEW PROCESS JUST TO GIVE FOLKS A TASTE OF THAT. DR. SARA HULL: THAT'S GREAT. THANK YOU. SO LET ME TRY TO EM BED A LITTLE BIT ABOUT THE REVIEW PROCESS. WHEN WE GET A STUDY, WHETHER IT'S AN INITIAL REVIEW OR A CONTINUING REVIEW, WHICH IS SOMETHING WE DO AT NO -- NO MORE THAN EVERY 12 MONTHS -- NO LESS THAN EVERY 12 MONTHS AFTER A STUDY IS INITIALLY REVIEWED FOR AN AMENDMENT WE'RE BRINGING THESE PROTOCOLS TO A MEETING, GOING THROUGH THESE ARE THE INITIAL REVIEW CRITERIA, WE ARE -- WE HAVE A PRACTICE OF ASSIGNING A MEMBER OF THE COMMITTEE TO LEAD THE DISCUSSION OF THESE REVIEW CRITERIA. OFTENTIMES IT WILL BE PAIRED WITH A SECONDARY REVIEWER TO REALLY HELP TO NAVIGATE AND BRING US THROUGH THE REVIEW. SO THE INITIAL REVIEWER WILL GO THROUGH, THE PRIMARY REVIEWER OF AN INITIAL REVIEW WILL GO THROUGH ALL OF THIS DOCUMENTATION, ACTUALLY EVERY MON MEMBER OF THE IRB IS CHARGED WITH REVIEWING THE DOCUMENTATION BUT THE PRIMARY REVIEWER WILL LEAD THE DISCUSSION AT THE MEETING. SO IN ADDITION TO THE REVIEW CRITERIA I ALREADY MENTIONED, SORRY I'M MAKING YOU GO BACK AND FORTH IF WE CAN JUST GO BACK TO THOSE REVIEW CRITERIA REAL QUICKLY WE'RE ALSO LOOKING CLOSELY AT THE PROCESS UNDER WHICH INFORMED CONSENT WILL BE COLLECTED, WHAT IS THE CONTENTS OF THE CONSENT FORM DOCUMENT ITSELF, AND WHETHER CERTAIN REVIEW -- WHETHER CERTAIN CONTENT AREAS ARE ADEQUATELY COVERED, WHAT PROVISIONS ARE IN PLACE TO MONITOR THE SAFETY OF THE STUDY AS IT'S TAKING PLACE, AND THAT IS GAUGED BASED ON WHAT THE RISK LEVEL OF THE STUDY. AND THEN THERE'S ATTENTION TO SPECIAL PROTECTIONS THAT MIGHT BE REQUIRED FOR VULNERABLE SUBJECTS, PARTICULARLY FOR CHILDREN, FOR PREGNANT WOMEN, FOR PRISONERS WHO MIGHT BE ENROLLED AND THEN AT THE NIH WE HAVE ADDITIONAL POLICY REQUIREMENTS FOR EXAMPLE FOR ADULTS WHO LACK THE CAPACITY TO CONSENT THAT GO BEYOND WHAT THE FORMAL REQUIREMENTS OF THE COMMON RULE 45CFR46 ARE. NEXT -- NEXT SLIDE. >> DR. HOLLY TAYLOR: YOU TALK ABOUT THAT A LITTLE ALREADY, SO MAYBE YOU CAN TALK ABOUT THIS. DR. SARA HULL: YEAH, SURE. SO AFTER THE PRIMARY AND SECONDARY REVIEWER HAD PRESENTED THE CASE, SO TO SPEAK, HAD MADE THE CASE THAT EITHER THE REVIEW CRITERIA HAVE OR HAVE NOT BEEN MET IN RELATION TO A PARTICULAR SUBMISSION AND ONCE ALL OF THE OTHER MEMBERS OF THE COMMITTEE HAVE HAD A CHANCE TO WEIGH IN AND HAVE THEIR SAY, WE -- WE VOTE, THIS IS A DEMOCRATIC PROCESS, AND WE VOTE TO APPROVE OUTRIGHT, IT HAPPENS SOMETIMES, MOST COMMONLY I THINK WHAT WE SEE IS APPROVE WITH STIPULATIONS. SO WE REQUIRE CERTAIN CHANGES TO BE MADE THAT ARE TWEAKS THAT CAN EASILY BE REVIEWED BY THE CHAIR, THAT THEY -- ONCE YOU MAKE THESE WE BELIEVE THAT THE ACTION HAS MET THE REGULATORY CRITERIA. IF THE CHANGES THAT ARE NEEDED ARE MORE SUBSTANTIVE WE CAN VOTE TO DEFER APPROVAL UNTIL THE INVESTIGATES TORE SUBMITS A SUBSTANTIAL REVISION TO GO BACK TO THE IRB FOR RECONSIDERATION AND OCCASIONALLY WE CAN OUTRIGHT DISAPPROVE AN ACTION TO AN AMENDMENT TO THE STUDY OR EVEN THE ORIGINAL STUDY. AND AGAIN THIS REQUIRES A MAJORITY VOTE NOT A UNANIMOUS DECISION IN -- IN ANY OF THESE CASES. BUT WE -- WE SORT OF HAVE THIS FORMAL STRUCTURE TO THE MEETINGS AS SPECIFIED BY AN AGENDA, A CERTAIN NUMBER OF ITEMS ON THE AGENDA WE HAVE TO GET THROUGH, AND THEN, YOU KNOW, WE PUT IT THROUGH A VOTE IN THESE WAYS. >> DR. HOLLY TAYLOR: I'M JUST GOING TO CHIME IN HERE SARA AND GIVE AN ANECDOTAL EXPERIENCE. WHEN I WAS A DOCTORAL STUDENT MAYBE AFTER I GRADUATED SARA I DON'T REMEMBER THE TIMING, WHEN HE WILL ELLEN ROCHE DIED, I WAS TASKED TO A COMMITTEE ATTEMPTED TO RE-REVIEW ALL RESEARCH CONDUCTED BY PUBLIC HEALTH SCHOOL FACULTY THAT HAD PREVIOUSLY BEEN REVIEWED BY THE SCHOOL OF MEDICINE AND THAT REVIEW HAD TO HAPPEN BEFORE THE RESEARCH COULD RESTART, WE HAD 70 PROTOCOLS AND WE HAD ONE THAT WAS APPROVED WITHOUT STIPULATIONS. THE -- ALL THE OTHERS WENT BACK TO THE INVESTIGATOR WITH SOME SORT OF CLARIFICATION OR QUESTION. AND I DON'T SAY THAT BECAUSE I THINK THE INITIAL REVIEW WAS, YOU KNOW, GOOD OR BAD, IT'S THAT, YOU KNOW, THERE'S ALWAYS SOMETHING ELSE ONE CAN FIND IN TERMS OF THE NUANCE OR THE SPECIFICS ABOUT A PROTOCOL, AND THAT STRAIGHT UP APPROVAL IS PRETTY RARE. DR. SARA HULL: YES. SO IN MOST CASES THERE IS A REQUIREMENT THAT ONCE A STUDY IS APPROVED THAT IT WILL NEED SOME FORM OF CONTINUING REVIEW, WHETHER THIS IS DONE IN A MORE EXPEDITED MATTER OR HAVE TO COME BACK TO THE FULL BOARD LIKE MANY ACTIONS DEPENDS ON THE RISK LEVEL OF THE STUDY AND THE -- THAT'S BASICALLY IT, THERE ARE SOME LEVELS OF RISK OR CERTAIN PROCEDURES THAT DON'T REQUIRE THE FULL BOARD TO REVIEW AN IRB, WE DIDN'T REALLY GET INTO THAT HERE, BUT SO THAT MEANS THAT ONCE A YEAR, AT LEAST, AND SOMETIMES WE'LL DECIDE WE WANT TO SEE THIS AGAIN IN SIX MONTHS, THE INVESTIGATOR PROVIDES THE IRB WITH AN UPDATE AS TO THE PROGRESS OF THE STUDY, HOW MANY PEOPLE HAVE BEEN ENROLLED, WHAT SORTS OF PROBLEMS, HAVE THERE BEEN ANY CHANGES MADE TO THE STUDY ALONG THE WAY, AND THAT GIVE GIVENS THE IRB A CHANCE TO MONITOR AND SEE HOW A STUDY IS GOING. ALTHOUGH MANY KIND OF GO THROUGH AND I WOULD SAY IT'S MUCH MORE COMMON TO SEE A REVIEW APPROVED WITHOUT STIPULATION WE WILL OCCASIONALLY NEED TO DO A COURSE CORRECTION OR RESPOND TO THE FACT THAT THE RISKS DON'T QUITE SEEM TO BE THE SAME AS WE ORIGINALLY PROJECTED THEM TO BE BASED ON THE NUMBER OF ADVERSE EVENTS THAT WE'RE SEEING AND/OR MAYBE THE ENROLLMENT PLAN ISN'T ADEQUATE BECAUSE THEY'RE NOT ENROLLING ADEQUATE NUMBERS. AND SO WE PAY ATTENTION TO THAT IN AN ONGOING WAY, WHICH IS ONE OF THE WAYS THAT WE MAINTAIN AN ENGAGEMENT WITH THE VELTH TORS AND ENSURE THAT IT'S NOT A ONE-TIME RUBBER STAMP BUT MORE OF AN ONGOING PROCESS. >> DR. HOLLY TAYLOR: SARA I'M GOING TO INTERRUPT WE HAVE ABOUT 40 SECONDS LEFT, AND WE HAVE A QUESTION. DR. SARA HULL: WOW. >> DR. HOLLY TAYLOR: -- ABOUT A SINGLE IRBS SO I'M GOING TO INVITE TO YOU TALK JUST BRIEFLY ABOUT THE SINGLE IRB REVIEW CHANGE AND INVITE PEOPLE WHO ARE INTERESTED TO STAY ON FOR THE NEXT, YOU KNOW, FIVE OR SIX MINUTES, OTHERWISE YOU'RE WELCOME TO LOG OFF, BUT WE'RE GOING TO SPEND JUST THESE LAST COUPLE OF MINUTES TALKING ABOUT THE QUESTION HERE WAS: I THOUGHT THE REQUIREMENTS CHANGED ABOUT REGARDING CENTRAL IRBS FOR MULTI SITE ACADEMIC STUDIES. SO WHY DON'T YOU JUST INTRODUCE THE IDEA TO FOLKS AND OTHERWISE THANK YOU ALL AND WE'LL SEE YOU NEXT WEEK. DR. SARA HULL: THE RULES HAVE INDEED CHANGED. THERE'S BEEN AN NIH REQUIREMENT THAT TOOK EFFECT IN I BELIEVE JANUARY OF 2018, AS WELL AS A COMMON RULE REQUIREMENT THAT IN MOST CASES REQUIRES NIH FUNDED RESEARCH AND FEDERALLY FUNDED RESEARCH THAT INVOLVES MULTIPLE SITES TO BE REVIEWED BY A SINGLE IRB. AND THIS WAS IN RESPONSE TO AFTER A LENGTHY DIALOGUE, A CONCERN ABOUT THE UNREASONABLE VARIABILITY ACROSS DIFFERENT SITES AS WELL AS A LACK OF EFFICIENCY WHEN YOU HAVE A STUDY THAT HAS A DOZEN SITES BUT ESSENTIALLY THE SAME THING IS HAPPENING AT EVERY ONE OF THOSE SITES, IT OUGHT TO BE THE CASE THAT THERE'S SOME CONSISTENCY IN HOW THE PROTOCOL IS REVIEWED. AND SO THIS -- A LOT OF ATTENTION HAS BEEN PAID TO HOW TO IMPLEMENT THIS. WE HAVE A NICE POLICY THAT SPELIT OUT IN THE INTRAMURAL PROGRAM WE MIGHT EITHER TAKE ON THE RESPONSIBILITY OR ANY ONE IRB CAN EITHER TAKE ON THE RESPONSIBILITY TO BE THE SINGLE IRB OF RECORD OR CAN WORK THROUGH A PROCESS TO CEDE THAT AUTHORITY TO ANOTHER IRB, THOSE AGREEMENTS ARE CALLED RELIANCE AGREEMENTS, AND ALTHOUGH THEY WERE ALWAYS OR HAVE FOR A LONG TIME BEEN IN EFFECT AS SOMETHING THAT COULD BE DONE ON AN OPTIONAL BASIS IT IS NOW A REQUIREMENT IN MOST CASES FOR DOMESTIC RESEARCH WITHIN THE UNITED STATES, WITH SOME NOTABLE EXCEPTIONS, FOR EXAMPLE AROUND TRIBAL IRB REVIEW AND SOME OTHER POLICY EXCEPTIONS THAT ALLOW -- MIGHT ALLOW A SINGLE STUDY TO BE REVIEWED AT MORE THAN ONE SITE. >> DR. HOLLY TAYLOR: GREAT THANK YOU SARA AND I'LL JUST ADD THAT A CAN COMPLICATION THAT I HAVE A PARTICULAR SORT OF CONCERN ABOUT IS IF YOU IMAGINE YOU KNOW MULTIPLE MULTI SITE TRIALS GOING ON ALL OVER THE COUNTRY, THERE ARE GOING TO BE PRINCIPLE INVESTIGATORS AT A GIVEN SITE WHO ARE CON DUCTING TRIALS IN COLLABORATION WITH MULTIPLE SETS OF MULTI SITE STUDIES. AND WHILE ON ONE HANDS THE GOAL OF THE IH POLICY AND THE COMMON RULE REQUIREMENT WERE TO ADDRESS SOME INEFFICIENCY I THINK IT'S GOING TO TAKE US A LITTLE WHILE TO MAYBE CATCH UP IN TERMS OF FINDING OUT HOW THIS NEW SYSTEM WORKS AND WHETHER THERE ARE NEW ISSUES THAT WE MIGHT NEED TO BE PAYING ATTENTION TO MOVING FORWARD. BUT THANK YOU FOR THAT QUICK INTRODUCTION AND I HOPE THE PERSON WHO ANSWERED THE QUESTION WAS ABLE TO STAY ON FOR A COUPLE OF MINUTES. AND WITH THAT, THANK YOU VERY, VERY MUCH FOR JOINING ME AND US AND SAY HUDSON WE SAY HELLO AND HAVE A NICE REST OF YOUR DAY.