THIS MORNING WE HAVE AGAIN THREE SESSIONS. WE HAVE FIRST WE'LL TALK ABOUT THE ETHICS OF RESEARCH WITH CHILDREN. THEN WE'LL TALK ABOUT RANDOMIZED CONTROL TRIALS AND CLINICAL EQUIPOISE AND THEN IN THE THIRD SESSION THE ETHICS OF RESEARCH PRAGMATIC TRIALS AND HOW THEY DIFFER OR DON'T FROM OTHER KINDS OF RESEARCH. SO TO GET US STARTED THIS MORNING ON DISCUSSING THE ETHICS OF RESEARCH WITH CHILDREN WE HAVE DR. SKIP NELSON THE DIRECTOR OF ETHICS AND THE DEPUTY DIRECTOR OF THE OFFICE OF PEDIATRIC THERAPEUTICS AT THE U.S. FOOD AND DRUG ADMINISTRATION. AND PROBABLY MOST IMPORTANTLY DR. NELSON IS A PEDIATRICIAN OR A NEONATOLOGIST. HE KNOWS LOTS ABOUT RESEARCH WITH CHILDREN. >> I LIKE TO WALK AROUND -- WHEN YOU WORK IN INTENSIVE CARE I TEND TO WANDER AROUND AND I FOUND OVER THE YEARS I THINK BETTER WHEN I'M WALKING. IF I'M TIED TO A PODIUM MY BRAIN FREEZES. SO RESEARCH INVOLVING CHILDREN. WHAT I'LL SAY IS THE SAME FOR HHS FUNDED AND CONDUCTED. I'LL POINT OUT THE CITATIONS TO THE FDA COMPONENT. HERE'S THE DISCLAIMER, THE TOPICS I'M GOING TO COVER -- AND FOR PEOPLE -- WHEN I'VE DONE THIS IN THE PAST I MADE THIS A LITTLE DIFFERENT BECAUSE I'VE ADDED A DISCUSSION OF THIS CASE AND I'LL GO EVER THAT SO PEOPLE CAN HEAR ABOUT TO. I'LL START WITH THE BASIC ETHICAL PRINCIPLES AND TALK ABOUT THE TWO CONCEPTS OF THE LOW RISK AND HIGHER RISK PATHWAY. AS I GO THROUGH THIS, IF SOMEONE DOES HAVE A QUESTION, FEEL FREE TO GET UP AND STAND AT THE MIC AND I'LL BE HAPPY TO ANSWER QUESTIONS AS WE GO THROUGH THIS. THIS IS A DIFFERENCE EXPERIENCE THAN LECTURING IN THE OTHER ONE BUT IT'S NICE TO NOT LOOK LIKE THIS THE WHOLE TIME TO SEE ANYBODY SINCE IT'S QUITE A STEEP INCLINE IN THE OTHER AUDITORIUM. THERE'S FOUR PRINCIPLES. ONE REASON I DEVELOPED THE PRINCIPLES AND THEY'RE BASED ON REGULATIONS AND DISCUSSIONS IN LITERATURE AND READING THE NATIONAL COMMISSION REPORT. IF I STARTED WITH THE REGULATIONS PEOPLE WOULDN'T THINK I'M NOT DOING AN ETHICS TALKS BUT THERE'S FOUR PRINCIPLES. THE FIRST IS CHILDREN SHOULD ONLY BE ENROLLED IF YOU CANNOT GET CONSENT PERSONALLY LIKE ADULTS. IT SHOULD ONLY BE TO ANSWER A QUESTION RELEVANT TO CHILDREN. SO I CALL THAT THE PRINCIPLE OF SCIENTIFIC NECESSITY. THE SECOND IS ABSENT OF THERAPEUTIC THERAPY THE RISK MUST BE LOW AND WE'LL WALK THROUGH THE REGULATORY LANGUAGE FOR THAT. THE THIRD IF THE RESEARCH RISKS ARE HIGHER CHILDREN SHOULD NOT BE EXPOSED TO EXCESSIVE RISK OR FAILING TO GET NECESSARY HEALTH CARE. WE'LL TALK ABOUT THAT. TIME FINALLY, VULNERABLE POPULATIONS SHOULD HAVE A SUITABLE PROXY. I'D LIKE TO FRAME THE FOUR PRINCIPLES AND THE PROTECTIONS ASSOCIATED WITH THEM -- SOMEONE JUST DIMMED THE LIGHTS? MAYBE A DRUM ROLL TOO? ANYWAY, NESTED PROTECTIONS. I LIKE TO THINK OF THIS AS A SERIES OF NESTED PROTECTION. YOU HAVE THE LARGE PRINCIPLE AND THEN YOU WORK YOUR WAY INTO MORE FOCUSSED PRINCIPLE. THE SCIENTIFIC NECESSITY IS THE TREE. IF YOU DON'T HAVE TO DO THE RESEARCH IN CHILDREN, FULL STOP. YOU'RE NOT GOING TO GO ANYWHERE. THE SECOND IS THE NEST WHICH IS THE APPROPRIATE BALANCE OF RISK AND BENEFIT. THAT'S PRINCIPLES TWO AND THREE. THE RISK SHOULD BE LOW IF THERE'S NO BENEFIT. IF THERE IS BENEFIT THEY COULD BE HIGHER BUT BALANCED AND FINALLY PARENTAL PERMISSION AND MAMA AND PAPA BLUE JAY AND THE FOUR BABY CHICKS. I WON'T TALK ABOUT PARENTAL PERMISSION. THERE'S A LOT OF IMPORTANT ISSUES AROUND THAT BUT IF YOU GET THE PROTOCOL RIGHT GENERALLY THEY CAN BE SOLVED. THERE'S A LOT OF PROCESS ISSUES IN HOW TO APPROACH PARENTS AND CILDREN WHICH IS AN IMPORTANT DISCUSSION BUT I WON'T SPEND MUCH TIME ON THAT. HAPPY TO DISCUSS QUESTIONS. HERE'S ETHICAL NECESSITIES. I SAID THEY SHOULDN'T BE ENROLLED UNLESS IT'S IMPORTANT TO ANSWER THE QUESTION ABOUT THE PUBLIC HEALTH OF CHILDREN. WE SOMETIMES TALK ABOUT EXTRAPOLATION WHERE YOU CAN USE IT. I DON'T KNOW IF THERE'S STATISTICIANS. IT'S THE SAME PRINCIPLE WHEN YOU CAN BORROW DATA FROM ONE POPULATION TO ANOTHER. THAT'S BASICALLY THE IDEA. THIS DERIVES FROM THE REQUIREMENT OF EQUITABLE SOLUTION. WHEN THEY TALK ABOUT EQUITABLE SOLUTION THEY TALK ABOUT ADULTS BEFORE CHILDREN. IF YOU LOOK AT THE BELMONT REPORT THEY EXPLICITLY TALK ABOUT THAT UNDER RESPECT FOR PERSONS. THIS IS WHERE I LINK IT INTO THE REGULATIONS BUT IF YOU LOOK YOU WON'T FIND IT. IT'S BUILDING ON THE EQUITABLE SELECTION IDEA. FOR RESEARCH INVOLVING ADULTS, BASICALLY THIS IS THE LANGUAGE. I'VE GIVEN YOU THE FDA SIDE OF THE HOUSE 2156 AND THE HHS IS 45CFR46. THE RISKS TO SUBJECTS ARE REASONABLE IN RELATIONSHIP TO THE ANTICIPATED AND KNOWLEDGE. WHAT'S KEY IS THE PHRASE "IF ANY." WHAT IT MEANS IS YOU CAN BALANCE RISK -- RESEARCH RISK IN ADULTS AGAINST KNOWLEDGE, HAVE APPROPRIATE INFORMED CONSENT. YOU DON'T NEED BENEFIT TO BALANCE AGAINST RISK ALL THE TIME YOU CAN ASK ADULTS TO DO RISKY STUFF IF YOU HAVE CONSENT. HOWEVER, IN KIDS YOU HAVE A CAP ON THE AMOUNT OF KNOWLEDGE CAN JUSTIFY. THIS IS THEN THE LANGUAGE. RESEARCH INVOLVING CHILDREN MUST IN RESTRICT TO MINIMAL RISK OR MINOR INCREASE OVER MINIMAL RISK ABSENT DIRECT BENEFIT. WE'LL TALK ABOUT WHAT THAT CONCEPT MEANS OR PRESENT RISKS JUSTIFIED BY THE BENEFIT SO A RISK/BENEFIT BALANCE AND THIS IS WHERE THE COMPONENT OF NOT BEING PLACED AT A RESEARCH COMES IN AND FOR EXPERIMENTAL INTERVENTION MUST BE AT LEAST FAVORABLE AS ANY ALTERNATIVES. THAT'S ALTERNATIVES WITHIN TRIAL OR WITHIN THE TWO ARMS OR BETWEEN WHAT THEY MIGHT OTHERWISE HAVE RECEIVED. YOU LOOK AT WHAT WE CALL SUBPART D WHICH IS SHORTHAND. IF YOU HEAR PEDIATRICIANS SAY SUBPART D THEY'RE PROBABLY REFERRING TO PROTECTIONS. YOU SEE THREE CATEGORIES I'VE HIGHLIGHTED. THE CASE I'LL GIVE YOU, YOU HAVE THREE CATEGORIES. THESE ARE CATEGORIES AN IRB CAN APPROVE OR DISAPPROVE IF APPROPRIATE WITH ANY FEDERAL PANEL REVIEW. THIS ONE, WHICH I'M GOING TO TALK ABOUT AND PRESENT THE CASE OF A FEDERAL PANEL REVIEW, IF IT'S NOT OTHERWISE APPROVAL BUT CAN ALLEVIATE A PROBLEM CAN GO FORWARD AFTER PANEL REVIEW AND PERMISSION FROM PARENTS AND GUARDIANS. SO THERE'S TWO KEY CONCEPTS THAT REST BEHIND THESE. FIRST IS THE IDEA OF DIRECT BENEFIT. IN DECIDING HOW MUCH RISK YOU CAN EXPOSE A CHILD TO YOU HAVE TO LOOK AT WHETHER IT OFFERS DIRECT BENEFIT. WHAT IS DIRECT BENEFIT? THE IDEA IS THE CHILD WILL BENEFIT. THIS IS USUALLY LIMITED TO CLINICAL OR HEALTH OR COULD BE PSYCHOLOGICAL -- SOME BENEFIT TO THE CHILD. IT'S NOT A FINANCIAL BENEFIT, FOR EXAMPLE. MOST OF US FEEL WE BENEFIT WHEN WE GET OUR PAYCHECK OR IF SOMEONE GIVES US MONEY. BUT THE DIRECT BENEFI IS NOT PAYING A CHILE OR COMPENSATING THE CHILD FOR INVOLVEMENT. SO IT'S AN ESSENTIAL ASPECT OF ASSESSING THIS AND RELATED TO THE INTERVENTION ITSELF. WELL TALK ABOUT COMPONENT ANALYSIS BUT WHAT'S IMPORTANT IS IN ASKING THE RISK AND POTENTIAL BENEFIT FOR THAT INTERVENTION IT'S THAT INTERVENTION. IT'S NOT THAT THERE'S BENEFIT OVER HERE AND HAVE YOU AN INTERVENTION THAT DOESN'T OFFER BENEFIT. YOU HAVE TO ANALYZE IT ACCORDING TO THE COMPONENT BECAUSE A PROTOCOL IN TERM OF COMPONENT ANALYSIS OFTEN CONTAINS MULTIPLE INTERVENTIONS. YOU CAN HAVE AN EXPERIMENTAL DRUG AND YOU MAY HAVE A BIOPSY. THE CASE I'LL TALK ABOUT HAS A MUSCLE BIOPSY THAT DOESN'T OFFER POTENTIAL BENEFIT. WHEN THE NATIONAL COMMISSION SET THIS UP THE IDEA IS YOU NEED TO LOOK AT A BENEFIT AND SAY THIS OFFERS BENEFIT AND NOT. AS AN IRB CHAIR I WOULD TAKE PAPER WITH A LINE DOWN THE MIDDLE AND PROSPECT ON ONE SIDE AND PUT THE PROCEDURES UNDER EACH SIDE TO SAY THESE UNDER PROSPECT OF NO DIRECT BENEFIT THE RISK HAS TO BE LOW AND OVER HERE, WHAT'S THE RISK/BENEFIT BALANCE. I'LL TALK MORE ABOUT COMPONENT ANALYSIS WHEN WE GET TO THE CASE ITSELF. WHEN I REFER TO LOW RISK AND HIGHER RISK PATHWAYS I'M BUILDING ON REGULATIONS. THE LOWER RISK PATHWAY IS WHERE THERE'S SUFFICIENT EVIDENCE IT KNOW THE EXPOSURE OF A CHILD TO THAT INTERVENTION OR PROCEDURE WHETHER IT'S AN EXPERIMENTAL DRUG OR OTHERWISE IS LOW RISK. NOW, I USE THE WORD LOW. THAT'S FOUND IN ICHE6 THE GOOD CLINICAL PRACTICE DOCUMENT. I THINK LOW RISK WAS PICKED ON THE INTERNATIONAL CONCEPT OF HARMONIZATION IS BETWEEN JAPAN AND CANADA AND THE UNITED STATES. EUROPE NOW CHINA, SOUTH KOREA, BRAZIL -- I THINK ONE MORE INVOLVED. BUT THE IDEA IS TO COME UP WIN HARMONIZED GUIDANCE AND WE HAVE CATEGORIES OF MINOR RISK AND EVERYWHERE ELSE THEY HAVE LOW RISK SO HARMONIZE WAS PICKED. THE OTHER PATHWAY IS WHERE YOU HAVE TO SAY THE ADMINISTRATION OF THAT PRODUCT JUSTIFIES THE HIGHER RISKS. SO WHAT IS LOW RISK MEAN? MINIMAL RISK IS DEFINED AS THOSE RISKS ORDINARILY ENCOUNTERED IN EVERY DAY LIFE WITH ROUTINE EXAMINATIONS OR TESTS. I GAVE YOU THE FDA CITATION. OVER THE YEARS, WHEN THE NATIONAL COMMISSION FIRST PROPOSED THIS IS HEALTHY CHILDREN. WHO'S LIFE IS IT? THE HEALTHY CHILD. I THINK ALL ETHICS COMMISSIONS OVER THE YEARS IN THE UNITED STATES SAID THAT'S THE WAY IT SHOULD BE INTERPRETED BUT THAT'S NOT IN THE REGULATIONS. FDA DOESN'T GENERALLY CONSIDER GIVING A DRUG TO A CHILD MINIMAL RISK. WHAT'S INTERESTING IS IF YOU LOOK ABROAD, THEY DEFINE MINIMAL RISK USUALLY IN CANADA AND RECENTLY IN THE 2014 REAUTHORIZATION OF THE CLINICAL TRIALS IN EUROPE THEY DEFINE IT AS RELATIVE TO PROCEDURES OR EXPERIENCE OF THE RESEARCH SUBJECT IN THE TREATMENT OF THEIR CONDITION. SO IT'S MORE OF A RELATIVE DEFINITION. WHEREAS, WE END UP WITH A MORE RELATIVE DEFINITION IS WITH THE INCREASE OVER MINIMAL RISK. IT'S SUPPOSED TO BE SLIGHTLY MORE BUT IT'S RELATE TO A DISORDER OR CONDITION. NOW, THE REASON I PUT CAVEAT RELATIVE DEFINITION AND WE'LL TALK ABOUT MUSCLE BIOPSIES IN THE EXAMPLE, WE'RE OVER THE LAST TWO DECADES USING A RELATIVE INCREASE OVER MINIMAL RISK. I DON'T THINK WE'RE TAKING THE ABSOLUTE DEFINITION OF MINIMAL RISK AND DOING SLIGHTLY MORE -- WHATEVER THAT MEANS. SO I SUSPECT IF YOU THINK ABOUT THE KINDS OF EXAMPLES BEING APPROVED UNDER THE MINOR INCREASE OVER MINIMAL RISK IT PROBABLY FITS OF WHAT'S BEING APPROVED BY RESEARCH ETHICS COMMITTEES AS MINIMAL RISK OR BURDEN WITH A RELATIVE DEFINITION THAT I'M HAPPY TO ANSWER QUESTIONS BUT I'LL SHOW AN EXAMPLE WHEN WE GET TO IT. PART OF THE CHALLENGE IS RISK ASSESSMENT. THE DEFINITION WHEN YOU TALK ABOUT PROBABILITY AND MAGNITUDE IMPLIES YOU CAN DO MATHEMATICS WITH RISK. I DON'T THINK YOU CAN. MAGNITUDE IS A MORAL EVALUATION. SO THE DISVALUE OF A HARM OR RISK CANNOT BE QUANTIFIED. THERE IS AN AREA IN PSYCHOLOGY IN PUTTING EXPECTED UTILITY AND YOU PUT NUMBERS. I THINK -- DO I WANT MY LEFT HAND OR RIGHT HAND TO BE CUT OFF OR INJURED. I CAN PUT A VALUE OF . 6 ON THE RIGHT HAND AND .3 ON THE LEFT HAND AND DO MATHEMATICS WITH RISK. I PERSONALLY THINK THAT MAKES NO SENSE. WE DON'T DO THAT. WE COMPARE RISKS PUT NOT MATHEMATICALLY. I THINK IT'S TAKING A MORAL EVALUATION AND TRYING TO REDUCE IT TO AN EMPIRICAL ONE WHICH IS DIFFICULT. BECAUSE WE HAVE THE DEFINITION OF DAILY LIFE DOESN'T MAKE IT LEGITIMATE TO DO THE RISK IN RESEARCH. THE EXAMPLE -- WELL, YEARS AGO IRB APPROVED AN INSULIN CLAMP STUDY AND STARTED BY SAYING IT pPEOPLE SAID MAYBE IT'S A MINOR RISK. WHEN THEY FIRST MET THE MINUTES ENDED UP IN THE PUBLIC DOMAIN SAYING AN INSULIN CLAMP STUDY NOT RISKIER THAN LETTING CHILDREN PLAY IN THE STREET. I DON'T KNOW HOW MANY OF YOU PLAY CHILDREN. HOW MANY OF YOU SAY GO OUT AND PLAY IN THE STREET? YOU DONT. UNLESS YOU LIVE ON A CUL-DE-SAC AND YOU PLAY STREET HOCKEY AND YOU'RE GOING TO BLOCK OFF THE END OF THE CUL-DE-SAC MAYBE THEN YOU CAN PLAY IN THE STREET BUT JUST BECAUSE CHILDREN PLAY IN THE STREET DOESN'T MAKE IT APPROPRIATE TO EXPOSE AS A RESEARCH RISK. THAT'S ONE EXAMPLE. NOW, THE OTHER ISSUE IS THE SORT OF CONDITION. HOW MANY PEOPLE -- ANYBODY DOING WORK IN VACCINES? SO NEW MEASLES ARE BEING TESTED IN HEALTHY CHILDREN BUT WERE THEY AT RISK FOR MEASLES? WE SEE THAT IN POPULATIONS WHEN THEY DECIDE NOT TO GET IMMUNIZED AND SUDDENLY THERE'S A MEASLE OUTBREAK OR OTHERWISE. THE IDEA IS YOU CAN BE AT RISK BUT STILL BE HEALTHY. THAT WAS PART OF THE DEBATE ABOUT TESTING ANTHRAX VACCINE. ARE CHILDREN AT RISK FOR ANTHRAX? I WOULD ARGUE NO UNLESS YOUR LIVING DOWN WIND OF A BIOLOGICAL STORAGE FACILITY WITH A BREAK. SMALLPOX MAY NOT EVEN BE WIND BORN SO THAT'S APPROPRIATE BUT THAT'S EVALUATING RISK DISORDER OR CONDITION. YOU HAVE TO KNOW THE RISK AND HAVE TO BE ABLE TO GENERATE AN ACCURATE ESTIMATE. IF THEY'RE NOT LOW YOU HAVE LOOK AT A DRUG DATA WHERE YOU HAVE A SINGLE DOSE TO GET A PHARMACOGENETIC LEVEL AND YOU NEED SOME PROOF OF CONCEPT. WHEN THE NATIONAL COMMISSION DEVELOPED THIS CATEGORY OF GREATER THAN MINIMAL RISK IT WAS SIMILAR TO CLINICAL DECISION MAKING. WITHOUT NECESSARILY GETTING INTO DISCUSSION OF WHAT PEOPLE TALK ABOUT THE THERAPEUTIC DISCUSSION THAT IT'S CLINICAL CARE. IS THIS JUSTIFIED OR FAVORABLE AND WHEN YOU THINK ABOUT WHAT ARE THE OTHER ALTERNATIVES THAT MAY OR MAY NOT APPLY. THAT REASONING GOES INTO THE ASSESSMENT. IF THE RISK IS HIGH IT STILL HAS TO APPLY. SAY WITH PHASE 1 ONCOLOGY RESEARCH. THE IDEA YOU'RE PICK A POPULATION THAT'S EXHAUSTED. IF YOU LOOK AT THE CHILDREN HES ONCOLOGY GROUP THERE'S PHASE 3 OVER PHASE 2 AND PHASE 1 IS IFFY OPPOSED TO AN ADULT WHERE YOU SAY DO YOU WANT TO GO INTO PHASE 1. YOU HAVE OTHER OPTIONS. WITH CHILDREN YOU HAVE TO DESIGN THE PHASE 1 TRIAL TO OFFER BENEFIT. THE BENEFITS ARE SINGLE-DIGIT PERCENTAGES BUT THESE ARE CHILDREN WHO HAVE NO OTHER OPTION. YOU'RE BALANCING THAT. WHEN I SAY NO OTHER OPTION LET ME QUALIFY THAT, BUT THAT'S THE KIND OF BENEFIT. WEN -- WHEN I THINK OF THE IDEA OF A SLIDING THRESHOLD YOU WANT SOME DATA. OFTEN IN THE RARE DISEASES IN CHILDREN THERE IS NO ADULT WITH THAT DISEASE OR NO ADULT WITH THE DISEASE WHERE IT WOULD BE INFORMATIVE WHETHER INTERVENTION OFFERS A PROSPECT OF DIRECT BENEFIT. YOU'RE GOING FROM A NON-CLINICAL ANIMAL MODEL TO A CHILD. RECENTLY THERE WAS AN ADVISORY COMMITTEE MEETINGS AND THERE WAS A DEFECT THE DOG MODEL WAS 100% CURE IF THEY GOT THE VECTOR WHERE IT NEEDED TO BE. AN ACCIDENT DOG MODEL. YOU'VE DEVELOPED A MAXIMUM TOLERATED DOSE IN ADULTS SO DO YOU GO BACK DOWN TO 1/1,000 OF A DOSE? NO, YOU PICK A DOSE AND THAT'S WHERE YOU START IN PEDIATRICS BAU YOU START CLOSER TO A DOSE THAT MAY OFFER A BENEFIT. YOU'RE INCREASING THE RISK TO OPTIMIZE THE BENEFIT. THAT'S WHAT OFTEN HAPPENS. IT'S EASIER IN THE AREA OF TOXICOLOGY BUT HARDER TO FIGURE OUT WHEN THERE'S NO NTD BUT SORTING OUT THE DOSE I MAY NOT BE THE DOSE WITH NO OBSERVED ADVERSE EFFECT. IT MAY BE A DOSE WHERE YOU SEE POTENTIAL BENEFIT. NOW I REALIZE THAT'S A BIT OF A WHIRLWIND THROUGH A NUMBER OF ISSUES. BUT SINCE THIS PANEL AND THERE'S A FEDERAL PANEL REVIEW UNDER 5004. THIS IS THE ESSENCE PROTOCOL. THE ESSENCE PROTOCOL. THERE'S A HUGE PROTEIN AND YOU GET MUTATIONS ALL ALONG. MUTATION AT 51 IS MOST COMMON. I DON'T KNOW HOW MANY PEOPLE PEOPLE HEARD THE CONTROVERSY OVER TEPLERSON. SO BASICALLY FDA DECIDED EXXON 51 FOR ACCELERATED APPROVAL. THAT RESULTED IN AN INTERESTING CONTROVERSY WITH JANET WOODCOCK APPROVED IT AND GETTING IT TO THE DEPUTY COMMISSIONER AND THE COMMISSIONER AT THE TIME HAD TO GIVE AN OPINION. IT'S ALL POSTED AT DRUGS AT FDA. IF YOU'RE INTERESTING, JUST LOOK UP TEPLER SON OR E-X-O-Y-D-N-S AND YOU'LL SEE THE LETTERS GOING BACK AND FORTH. AN INTERESTING DISCUSSION. IT'S INTERESTING BUT SKIPPING 54 AND 53. AS THE RNA IS RED, I MAY BE GETTING THIS WRONG, I'M NOT A MOLECUL MOLECULAR BIOLOGIST. THERE'S A STOP CODE ON READ. AND WHAT THE EXXON SKIPPING DOES IT SKIPS THAT TYPOGRAPHICAL ERROR, IF YOU WILL, AND PRODUCE AS A LONGER PROTEIN THAT MAY BE FUNCTIONAL. IT'S STILL MUTATED BUT AT LEAST CLOSER TO WHAT IT WOULD HAVE BEEN IF IT WAS JUST TRUNCATED AT 45 OR 51 HERE'S THE PROTOCOL. THERE'S A 96 WEEK PERIOD AND THE KEY THING HERE IS THAT IT'S PLACEBO CONTROLLED AND THERE'S WEEKLY INFUSIONS. SO INFUSING A BOY WITH DESCHENN WITH IT OR SALINE FOR YEARS. THERE'S MUSCLE BIOPSIES AT BASELINE AND AT WEEK 48. SO THES IS WHAT HAPPENS. SO IN 2015 THE ESSENCE PROTOCOL WAS SUBMITTED TO THE FDA TO ALLOW THE VENUS ACCESS PORT AT THE INVESTIGATOR AT ALL SITES. WHEN THEY REVIEWED AND WE WERE CONSULTED AS ETHICISTS WE NOTICED THE PLACEBO ARM DIDN'T OFFER BENEFIT. I'LL WALK THROUGH THE ANALYSIS WITH YOU. IT'S A BASED ON COMPONENT ANALYSIS. THE ARGUMENT WAS YOU SHOULDN'T BE PUTTING PORTS FOR TWO YEARS INTO KIDS THAT WERE GETTING PLACEBO. WE SAID IT'S NOT APPROVABLE UNLESS REVIEWED UNDER A PANEL. IT DIDN'T GET REFERRED BUT THE UCLA IRB RECEIVED A COMPLAINT. COMPLAINT IS IN QUOTES BECAUSE THAT'S WHAT THEY CALL A PARENT REPORTING SOMETHING TO THE IRB. I GOT A CERTIFIED LETTER FROM A MOTHER OF A CHILD IN TEXAS ASKING WHY PORTS COULDN'T BE USED. HE WAS HAVING PROBLEMS WITH VENUS ACCESS. IT'S THE ONLY TIME I GOT A CERTIFIED LETTER FROM ANYBODY. I E-MAIL BACK AND EXPLAINED THE PROCESS OF APPROVAL AND COMPLAINED TO THE IRB WHO REFERRED IT. THAT'S HOW IT HAPPENED. THEY DETERMINED IT MET THE CRITERIA FOR 5054 AND THE USE OF CENTRAL ACCESS WAS SUBMITTED FOR REVIEW. ALTERNATIVE VENUS AXIS METHODS AND THOSE WITH DESCHENN'S MUSCULAR DYSTROPHY AND THEY HAVE TERRIBLE PROBLEMS FRAGILE VEINS, AND APPROXIMATELY 23% WERE LOST AND SOME WERE DUE TO PATIENT PREFERENCE IN ANOTHER STUDY 83% OF THE PATIENTS WERE CALLING IT TOTALLY IMPLANTABLE CENTRAL VENUS AXIS. AND THERE WAS A BRAND NAME INVOLVED. 83% HAD IN THE FIRST 48 WEEKS. VARIOUS TECHNIQUES TO VISUALIZE THIS USING ULTRA SOUND AND THEY DON'T WORK WELL IN GENERAL BUT THEY DON'T WORK WELL PRETTY MUCH AT ALL WITH THE MUSCULAR DYSTROPHY. AND INCLUDING PERIPHERALLY INSERTED CATHETER. ONE GETS INSERTED HERE AND CENTRAL VENUS CATHETERS YOU MAY PUT HERE. A TUNNELLED CENTRAL VENUS CATHETER WHERE YOU HAVE IT TUNNELLED COMING OUT, THE ADVANTAGE OF THE TICVAB IS UNDER THE SKIN AND THEY CAN REMAIN IN PLACE FOR YEARS. THE DOWNSIDE IS GENERAL ANESTHESIA IS REQUIRED TO REPLACE IT. LET'S TALK ABOUT COMPONENT ANALYSIS. THERE'S DIFFERENT SUBJECT POPULATIONS. NOW, THE NATIONAL COMMISSION IN 1978 YOU MAY SEE 1977 AS THE DATE FOR THIS BUT 1978 IN JANUARY IS WHEN IT WAS PUBLISHED IN THE FEDERAL REGISTER TO DETERMINE THE OVERALL ACCEPTABLE OF THE AND THE RISK OF BENEFIT DESCRIBED IN THE PROTOCOL MUST BE EVALUATED INDIVIDUALLY AS WELL AS COLLECTIVELY. THEY REFRAINED FOR MINOR INCREASE OVER MINIMAL RISK AND THEY READ INTERVENTION OR PROCEDURE. DOESN'T READ RESEARCH PROTOCOL. THE NATIONAL COMMISSION CLEARLY INTENDED PEOPLE TO ASSESS AND THE IDEA IS INTERVENTIONS OR PROCEDURE THAT HOLD OUT TO DIRECT BENEFIT ARE CONSIDERED UNDER THE CATEGORY OF DIRECT BENEFIT. PROCEDURES THAT DON'T ARE MINOR RISK OR MINOR INCREASE OVER MINIMAL RISK. YOU SEPARATE IT OUT IN THE PROTOCOL AND EVALUATE THEM SEPARATELY. THAT'S CHASSIC COMPONENT ANALYSIS. THERE'S DEBATE AROUND COMPONENT ANALYSIS AROUND EQUIPOISE. I DON'T KNOW WHAT BOB HAS TO SAY ABOUT EQUIPOISE BUT YOU'LL HERE COMMENT I HAVE TO MAKE PROPOSED BY CHARLES WARE AND HE'S A CANADIAN BIOETHICIST AND THE NET RISK PROPOSED BY FRANK WIMLER WHICH THEY PROPOSED AS A CRITICISM OF WHAT CHARLES PROPOSED. HERE'S COMPONENT ANALYSIS ACCORDING TO CHARLES WARE. YOU ESTABLISH THERAPEUTIC AND NON THERAPEUTIC PROCEDURES. YOU SAY SOUND SCIENTISTS, RISK REASONABLE AND VULNERABLE POPULATION. THEN YOU GO TO THIS GROUP AND IT'S ACCEPTABLE ON THIS SIDE. YOU WALK THROUGH THERAPEUTIC PROCEDURES CONSISTENT WITH COMPETENT CARE, RISK REASONABLE AND THE POTENTIAL BENEFITS TO SUBJECT. WHAT'S IMPORTANT IS FIRST, IT DISTINGUISHES PROCEDURES AND WHETHER THEY OFFER THE PROSPECT OF DIRECT BENEFIT. HE'S THROWN CLINICAL EQUIPOISE IN THIS ARM HERE. I CALLED HIM AND SAID WHAT'S THE POINT? WHAT ARE YOU DOING? THEY WERE COMING UP WITH A DIFFERENT APPROACH THAT REMOVED EQUIPOISE FROM COMPONENT ANALYSIS AND THEY STARTED OFF WITH CLINICAL BENEFIT AND HAVE TAKEN THE QUESTION, THEY'VE TAKEN THE TWO QUESTIONS, IS THERE A DIRECT BENEFIT, YES, NO. IS THAT DIRECT BENEFIT COMPENSATED SUFFICIENT TO JUSTIFY THE RISK. THEY'VE TAKEN THE TWO QUESTIONS AND PUT IT INTO ONE QUESTION. THEY STILL DISTINGUISHED THAT AND IF THE ANSWER'S YES OR NO THEY TALK ABOUT NET RISKS WHICH IS A WAY OF GETTING INTO THE MINOR INCREASE OVER MINIMAL RISK. I CONFESS, I DON'T USE THE LANGUAGE. I'VE NEVER FELT IT VERY HELPFUL. TO TALK ABOUT NET RISKS IN MY MIND IMPLIES YOU CAN DO MATHEMATICS. LIKE A NET WORTH STATEMENT. I DON'T THINK RISK ASSESSMENT INVOLVES THAT SO THE WORD NET -- I KNOW PEOPLE THAT DO THIS I UNDERSTAND WHAT THEY'RE DOING. I DON'T THINK IT'S INCOMPATIBLE BUT I NEVER FOND THE LANGUAGE TO BE THAT HELPFUL. HERE'S EQUIPOISE. AND THERE'S LITERATURE ON WHAT IT MEANS. THERE'S TWO MEANS. ONE IS THE WAY MOST PEOPLE USE IT WHICH IS I'M UNCERTAIN ABOUT THE ANSWER TO I'M IN EQUIPOISE WHETHER THE ANSWER IS A OR B. I THINK THAT'S HOW MOST OF US USE THE TERM. BUT CHARLES WAS USING IT IN A DIFFERENT WAY. HE WAS ARGUING KNOWN EFFECTIVE TREATMENT SHOULD BE PROVIDED TO A SUBJECT AND THE ONLY WAY TO RECONCILE THE DUTIES TO A CLINICIAN TO A RESEARCHER OF THAT SAME PATIENT IS TO UNDERSTAND THEY'RE OFFERING SOMETHING THAT'S COMPATIBLE WITH A STANDARD OF CARE OR SOME OTHER TREATMENT EVEN IF THAT'S NOT THE TRENT -- TREATMENT THEY'RE GETTING. HE WAS ARGUING THERE'S A FIDUCIA FIDUCIARY DUTY OF CARE BEHIND RESEARCH. IT'S THIS CLAIM THEY WERE ARGUING AGAINST. AND FRANK PUBLISHED ARGUING AGAINST THE FIDUCIARY DUTY OF CARE. NOW, THAT WOULD BE A LONGER DISCUSSION. I THINK I AGREE WITH THAT CRITICISM. PART OF THAT IS BECAUSE THERE ARE CIRCUMSTANCES WHERE WE DO WITHHOLD KNOWN EFFECTIVE TREATMENT. I'LL GET INTO THAT A LITTLE BIT WHICH WOULD VIOLATE TO SOME EXTEND THE FIDUCIARY DUTY OF CARE AND THAT WILL PLAY OUT IN THE DEBATE OVER PLACEBO CONTROLS. I HAVE BEEN TALKING. THE RISKS JUSTIFIED BY THE RISK BENEFIT AND COMPARABLE TO THE RISK ALTERNATIVE. THAT'S WHAT 5052 SAYS. WE HAVE A WAY OF UNDERSTANDING THE CONTROL GROUP IN A DIFFERENT WAY WITHIN A PEDIATRIC PROTOCOL. BOTH ACCEPT WE SHOULD DO COMPONENT ANALYSIS. THE DEBATE'S NOT ABOUT COMPONENT ANALYSIS BUT ABOUT THE FIDUCIARY DUTY OF CARE. I USE THE TERM CLASSIC. I DO IT LIKE THE NATIONAL COMMISSION DOES IT. WHY IS THIS IMPORTANT? IF YOU DON'T ANALYZE IT SEPARATELY YOU CAN LOOK THE A HIGH RISK RESEARCH ONLY PROTOCOL THAT SHOULD NOT BE COMPENSATED BY ANY DIRECT BENEFIT OFFERED THROUGH SOME OTHER COMPONENT OF THE PROTOCOL. SO THE ESSENCE PROTOCOL. MUSCLE BIOPSIES. THERE'S BASELINE AND AT 48 WEEKS. AT THIS POINT YOU DON'T NEED A MUSCLE BIOPSY TO DIAGNOSE DUCHENNE. WE DON'T NEED TO DO THAT ANYMORE. YOU CAN'T SAY IT OFFERS A BENEFIT. IF THEY'RE NON BENEFICIAL IT HAD TO INCLUDE THE PROCEDURAL SEDATION. THERE'S NEVER BEEN A PROTOCOL REFERRED UNDER HHS WOULD BE 407. YOU CAN INCLUDE MUSCLE BIOPSIES HAVE BEEN DETERMINED AND AS A PRIOR IRB CHAIR WE MADE THAT DETERMINATION AND ONE CAN ARGUE IT'S A DEBATABLE POINT. I'M IN THE SAYING IT'S THE RIGHT ANSWER OR IRB'S ARE NOT ANALYZING IT AS A NON- NON-THERAPEUTIC PROCEDURE. I PRESENTED IT HIT AT NIH AND AN INVESTIGATOR SAID I SUSPECT IRBs AREN'T DOING IT RIGHT AND THEY DIDN'T THINK IT WAS A MINOR INCREASE OVER MINIMAL RISK. BUT IT'S NOT BEING REFERRED. WHAT ABOUT DIFFERENT SUBJECT POPULATION AND INTERVENTION AND CONTROL. NOW, WITHOUT GOING INTO DETAIL WE'VE DECIDED THESE ARE PROTOCOLS FOR REVIEW UNDER 407 OR 5054. THESE WERE INTERVENTIONS WITH A MINOR INCREASE OVER MINIMAL RISK. THIS WAS AN NIMH PROTOCOL WHERE THEY WANTED TO GIVE A SINGLE DOSE OF DEXTROAMPHETAMINE SO ALL THE EXAMPLES IS WHERE IT US A MINOR INCREASE OVER MINIMAL RISK BUT THE CONTROL GROUP LACKED THE DISORDER OR CONDITION. THE MINOR INCREASE OVER MINIMAL RISK REQUIRES KNOWLEDGE ABOUT THE CHILD'S DISORDER OR CONDITION. WE'VE ALREADY -- OVER THE YEARS WE'VE LOOKED AT PROTOCOLS AND DIVIDED IT OUT BY THE INTERVENTION GROUP AND DID A COMPONENT ANALYSIS IN THAT WAY. WHAT MAKES IT A LITTLE BIT MORE INTERESTING IS WHEN YOU'VE GOT A SINGLE POPULATION WHO ARE RANDOMIZED THROUGH INTERVENTION OR CONTROL AND I'LL GIVE YOU A LITTLE BIT OF HISTORY. I DON'T THINK THIS PANEL WAS CONVENED UNDER 407 BUT IN 1992 NIH CONVENED A PANEL FOR CONTROVERSY IN THE LITERATURE. THIS WAS A CONTROL TRIAL WHERE KIDS WITH SHORT STATURE OR TURNER SYNDROME WERE BEING RANDOMIZED FOR GROWTH HORMONE OR PLACEBO THREE TIMES A WEEK UP TO SEVEN YEARS. THEY ASKED IF THIS IS APPROVALABLE OR APPROVABLE OR FOT? THEY TALKED ABOUT A PRE OR POST RANDOMIZATION OF RISK SAYING SHOULD THE RISK BE CALCULATED BEFORE RANDOMIZATION. I MAY BE RANDOMIZED A PLACEBO BUT I HAVE A BENEFIT BECAUSE I HAVE A 50% CHANCE OF GETTING THE DRUG OR SHOULD IT BE AFTER RANDOMIZATION? THAT WAS THE QUESTION. THEY DIDN'T DECIDE THAT QUESTION. THOUGH WHAT'S INTERESTING IS THEY SAID A MAJORITY DID FAVOR PRE-RANDOMIZATION OF ANALYSIS OF BENEFIT. I'M GOING TO ARGUE AGAINST THAT. NOWHERE IN THE DOCUMENT DO THEY TALK ABOUT COMPONENT ANALYSIS. THEY WERE ABLE TO IGNORE THE SECOND CRITERIA OF 405 WITH THE RISK AND BENEFIT BECAUSE IN 1992 THERE WAS NO AVAILABLE ALTERNATIVE. IT WAS RANDOMIZATION BETWEEN DRUG OR NO DRUG. THEY DID DETERMINE THE RISK OF THE PLACEBO GROUP THREE TIMES A WEEK UP TO SEVEN YEARS WAS NO MORE THAN A MINOR INCREASE OVER MINIMAL RISK. WE COULD DEBATE THAT AND I WOULD ARGUE IT'S UNDER THESE TWO CIRCUMSTANCES THAT'S WHY THEY DIDN'T HAVE TO DECIDE WHETHER TO DO A PRERANDOMIZATION BECAUSE OF THE FEATURES OF THE CASE IS WHERE THE RESULT WAS NO DIFFERENT. IT COULD HAVE BEEN DIFFERENT. IF THEY'D DECIDED INJECTING KIDS WITH A PLACEBO THREE TIMES A WEEK UP TO SEVEN YEARS THE SUB CUTANEOUS INSECTION THEY -- INJECTION THEY HAD TO EVALUATE WHETHER PRERANDOMIZATION WAS A PREFERRED WAY TO DO IT. WHAT WOULD THIS LOOK LIKE AND IN FACT THERE WAS AN ALTERNATIVE AVAILABLE TREATMENT. IF YOU LOOK AT EXISTING INTERNATIONAL GUIDANCE, IF YOU WITHHOLD NON EFFECTIVE TREATMENT. THE DECLARATION OF HELSINKI SAID THERE SHOULD BE NO ADDITIONAL RISKS OF SERIOUS OR ADDITIONAL HARM AND THIS CONTROL DOCUMENT SAID THERE SHOULD NOT BE SERIOUS HARM SUCH AS DEATH OR IRREVERSIB IRREVERSIB IRREVERSIBLE MORBIDITY. HERE'S THE STANDARD PLACEBO CONTROLLED TRIAL. COULD BE AN ACTIVE CONTROLLED TRIAL SO NO KNOWN TREATMENT IS BEING WITHHELD FROM THE SUBJECTING GET THE INVESTIGATIONAL DRUG IN CASE IT'S AN ADD-ON TRIAL BUT IN THIS CASE IT'S NOT AND THE RISKS AND BENEFITS ARE BELIEVED TO BE COMPARABLE. EQUIPOISE. WE THINK THE EXPERIMENTAL DRUG IS JUST AS GOOD AS WHAT IS OTHERWISE AVAILABLE. SO WE'RE IN EQUIPOISE ABOUT THAT QUESTION. WITH AN ACTIVE CONTROLLED TRIAL NON EFFECTIVE TREATMENT IS PROVIDED TO THE CONTROL GROUP. THAT'S NOT AN ISSUE FOR THE CONTROL GROUP. WHETHER YOU DO IT AS A SUPERIORITY DESIGN OR TRY TO BEAT THE KNOWN EFFECTIVE TREATMENT OR TRY TO MOVE IT'S THE SAME THERE'S IMPORTANT ISSUES AROUND THAT AND IF YOU'RE UNABLE TO ESTIMATE A NON-INTERIORITY MARGIN THE DOCUMENT WHICH IS AN FDA GUIDANCE SAYS -- WITH THE PLACEBO CONTROLLED GROUP NO KNOWN TREATMENT IS WITHHELD. SO A PRERANDOMIZATION WOULD JUSTIFY THE FACT GIVEN ALL THE PARTICIPANTS WERE IN THE LOTTERY EEN IF HOLDING KNOWN EFFECTIVE TREATMENT WOULD RESULT IN HARM SUCH AS DEATH OR IRREVERSIBLE MORBIDITY. THAT MAKES NO SENSE IN MY MIND AND YOU HAVE TO ANALYZE PROTOCOLS. SOME COMMENTS WERE TAKEN BY LOOKING AT WHAT THE 1992 COMMITTEE SAID ABOUT POST RANDOMIZATION AND I'M NOT SAYING THE DRUG WORKS AND THE PLACEBO DOESN'T. ALL I'M SAYING IS PLACEBO IS INERT. THAT'S THE INTENT OF THE PLACEBO. IT'S INSERT. I'M NOT ASSUMING THERE'S BENEFIT WITH THE DRUG. SO THE RISKS ARE NOT INCURRED BUT BY FAILING THE GET THE DRUG BUT THE TREATMENT. YOU CAN'T DECIDE TO DO PRERANDOMIZATION. YOU HAVE TO DECIDE WHICH MAKES SENSE AND BE CONSISTENT. DO IT POST RANDOMIZATION THAT'S THE ONLY TO DO IT THAT'S CONSISTENT WITH FDA GUIDANCE. SO ACTIVE TREATMENT I'LL RUN THROUGH TO LEAVE TIME FOR QUESTIONS. ACTIVE TREATMENT THE RISK OF THE CATHETER OR TIC FED ARE JUSTIFIED BY THE DRUG. THAT CAN BE APPROVED UNDER 5052 OR 405 AS A PROSPECT OF BENEFIT. THE PLACEBO THEY'RE NOT GETTING BENEFITS. YOU CAN'T BALANCE THE RISK OF GETTING ET -- IT PLACED. A MIDLINE CATHETER IS PROBABLY THE SAME AS A MIDLINE CATHETER. THE RISK IS NOT LARGE BUT IT WON'T LAST TWO YEARS. BOTTOM LINE IT EXCEEDS 5053 AND A FEDERAL PANEL IS REQUIRED AND WHAT WE TOLD THE SPONSOR. WE HAVE TAKEN A PROCEDURE APPROACH AND HAVE CRITERIA THAT SHOULD BE ABOUT MINIMALIZATION OF RISK AND IN SAYING THEY COULDN'T AGREE IT WASN'T AS IF THE ETHICISTS ALL SAID IT WAS MORE THAN A MINOR INCREASE OVER RISK. IT WAS MORE COMPLEX. THERE WERE ETHICIST WHO'S THOUGHT IT FIT AND AN AND THESE -- AN ANISE WE ASKED ARE THERE USE WHERE'S THE CATHETER SHOULD BE ALLOWED AND THE ANSWER WAS YES, 14-0. I RIN IN I INVITED A FAMILY TO JOIN ME AND THEY GAVE A COMPELLING PRESENTATION AND SHOWED A VIDEO OF THE TRAUMA THAT NICHOLAS, THE 13-YEAR-OLD BOY WAS GOING THROUGH. IN THE DISCUSSION SOME COMMITTEE MEMBERS WERE USING THE LANGUAGE LIKE CRUEL AND UNUSUAL PUNISHMENT AND WHETHER A PERIPHERAL IV IS RISK AND THEY VOTED 15-0 TO PLACE IT AND BASICALLY SAID THERE DOESN'T NEED TO BE CRITERIA. WE MADE A DETERMINATION THE TIC VAB WAS PREFERRED AND PLACED AT THE DISCRETION OF PARENT AND CHILD. THE EXPERTISE, THE CONSULTING SURGEON SHOULD BE DOCUMENTED AND THEN AND I'VE SHOWN YOU HOW THAT PLAYED OUT IN TERMS OF THE PLAYED OUT. I'VE LEFT EIGHT MINUTES FOR Q&A. I'M HAPPY TO ADDRESS SOME QUESTIONS. >> YOU DIDN'T TALK ABOUT THE INCREASED INCLUSION OF CHILDREN. I KNOW THERE'S A TENSION BETWEEN THE GOAL OF INCLUDING MORE CHILDREN AND PROTECTING THEM FROM RISK. MAYBE SAY SOMETHING ABOUT THAT BUT I'VE BEEN THINKING ABOUT THE MORE RECENT TREND AS I UNDERSTAND IT TO ALLOW INCLUSION OF CHILDREN IN LIKE CHEMOTHERAPY TRIALS DESIGNED FOR ADULTS BUT SHOULDN'T HAVE A LOWER AGE CUT-OFF OR SOMETHING. I WAS THINKING ABOUT YOUR POINT OF SCIENTIFIC NECESSITY AND HOW THAT FITS UNDER THAT RUBRIC. >> SO A FEW KEY POINTS. WE PROTECT CHILDREN THROUGH RESEARCH NOT FROM RESEARCH. THE FRAMEWORK AROUND APPROPRIATE EXPOSURE TO RESEARCH RISK PROVIDES A CONTEXT WITHIN WHICH YOU CAN ASK WHEN SHOULD WE ENROLL CHILDREN. THE IDEA IS IF YOU HAVE ENOUGH DATA TO GO FORWARD AND THERE'S A SUFFICIENT PROSPECT OF DIRECT BENEFIT AND JUSTIFY THE RISK YOU SHOULD MOVE FORWARD. NOT WAIT UNTIL YOU GET ADULT DATA. THERE'S CASES YOU WANT IT FOR SAFETY REASONS BUT IT'S IMPORTANT TO DO THAT. TAKE TARGETED THERAPY. THERE'S A LOT OF INTEREST IN BIOMARKERS IN THE ONCOLOGY SPACE. THEY CALL IT ISSUE AGNOSTIC OR INDICATION AGNOSTIC. I THINK KEYTRUDA AND WHETHER YOU'RE A 15-YEAR-OLD OR 25-YEAR-OLD OR 45-YEAR-OLD DOESN'T MATTER. YOU STILL HAVE THE SAME DATA. IN FACT SOME PEOPLE POINTED OUT ONE OF THE INDICATIONS THAT WERE APPROVED THERE WERE NO PEDIATRIC DATA BUT APPROVED BECAUSE THE BIOMARKER WAS PRESENT. YOU HAVE TO LOOK AT EACH CASE. QUESTION. >> THANK YOU. THIS IS A EXCELLENT TALK. ONE QUESTION IS PATIENTS ON PLACEBO ARMS OF TRIALS. ALMOST ALL -- THE VAST MAJORITY END UP ON A CLINICAL TRIAL AT SOME POINT. SOMETIMES THERE'S BENEFIT JUST ROM BEING ON THE CHILD EVEN IF THEY'RE ON THE PLACEBO ARM THEY'RE GETTING EXCELLENT ROUTINE CARE. THEY'RE GETTING MORE FOLLOW-UP THAN THEY MIGHT OTHERWISE GET. HOW DO YOU ACCOUNT FOR THAT IN THE RISK BENEFIT? THERE ARE DATA THAT SUGGEST AN INCLUSION BENEFIT. WE WOULDN'T ARGUE THE EXPOSURE WOULD THEN OFFER BENEFIT. INCLUSION BENEFIT IS SAYING WHY RESEARCH CAN MOVE FORWARD OR IN THE CONTEXT OF TALKING TO PARENTS AND CHILDREN ABOUT THAT THERE'S SOME DATA TO SAY YOU'RE GETTING BETTER PROTOCOL THAN STANDARD OF CARE. ONCOLOGY MAY NOT BE THE CASE BECAUSE STANDARD OF CARE IS PRETTY MUCH THE RESEARCH SETTING. WHAT'S KEY AND IT GOES BACK TO CHRISTINE'S QUESTION, I DON'T WANT TO SAY THE ONLY VALIDATED EVIDENCE FOR TREATING A CHILD IS IN AN APPROVED ABLE BUT SAY EVERYTHING THAT HAPPENS OFF-LABEL IS EVIDENCE-BASED. A LOT OF HAPPENS OFF-LABEL THAT'S NOT EVIDENCE BASED. >> THANK YOU FOR THE TALK. I'LL HAVE TO ASK DAVID ABOUT THE WHOLE NET RISK ISSUE. YOU MENTIONED YOU CAN'T PICK ONE OR THE OTHER IN RANDOMIZATION DEPENDING ON THE CASE. HAS ANYONE TRIED TO ARGUE THIS CASE BY CASE THAT CAN VARY? BACK IN THE '90s THERE WAS AN ARGUMENT. WHAT I'M ARGUING IS THERE'S NO WAY TO DO IT WITHOUT DOING POST-RANDOMIZATION. AT THIS POINT I'D ARGUE THAT'S WHAT ONE OUGHT TO DO. THERE'S NOT BEEN A RESURRECTION IN THE LITERATURE SINCE THE CASE CAME OUT. THE MUSCULAR DYSTROPHY EXAMPLE YOU SHARED HOW LONG DID IT TAKE TO THE POINT THE MODIFICATION TO THE PROTOCOL WAS ALLOWED. I'M CURIOUS? >> NINE WEEKS. >> THANK YOU. >> NOW, FLUSH THAT OUT. IT WAS FASTER BECAUSE IT WAS THE FIRST PROTOCOL THAT WAS ONLY FDA AND DIDN'T NEED TO GO TO THE ASSISTANT SECRETARY FOR HEALTH FOR DETERMINATION. I WAS ALSO PRIMED TO GET IT AND SITTING AROUND A YEAR WONDERING WHERE IT DIDN'T GET REFERRED. AS SOON AS IT HAPPENED I CALLED THE IRB AND SAID SEND IT TO ME. WE SET UP THE MEETING BEFORE THE REFERRAL WAS IN HA-HOUSE. AT THIS POINT IT TAKES SEVEN WEEKS TO GET A FEDERALLY REGISTERED APPROVED. I THINK IF THIS HAPPENED AGAIN WITHOUT HAVING TO DEAL WITH THE NEXT STEP OF GOING TO THE ASSISTANT SECRETARY FOR HEALTH I THINK WE COULD DO IT WHEN I ASKED MY STAFF BETWEEN SEVEN AND NINE WEEKS. OFTEN FASTER THAN AN IRB. >> SO IN THE NEXT SESSION WE'RE GOING TO CONTINUE DISCUSSION OF CLINICAL EQUIPOISE AND RANDOMIZED TRIALS AND ACTUALLY THE CASE THAT YOU'LL HEAR ABOUT IS ALSO WITH NEONATES. THE BAD NEWS IS OUR SPEAKER WHO IS AN EXCELLENT SPEAKER WAS UNABLE TO COME. HE HAD A FAMILY EMERGENCY SO HE'S NOT ABLE TO BE HERE TODAY. SO WHAT I DECIDED TO DO BECAUSE HE'S SO GOOD AND I DON'T WANT YOU TO MISS HIS TALK, IS TO SHOW HIS LECTURE FROM LAST YEAR. HE HAS DONE THIS SEVERAL YEARS FOR US. SO TO SHOW YOU THAT LECTURE ON A VIDEO. NOW VIDEOS ARE NOT AS MAYBE INTERACTIVE AS HAVING SOMEBODY IN THE FRONT OF THE ROOM BUT WE'RE GOING TO DO OUR BEST TO MAKE IT INTERACTIVE. YOU'LL SEE PEPPERS HIS TALK TO GET QUESTIONS WHEN WE STOP THE TAPE WE CAN HAVE A CONVERSATION IN WHAT YOU'VE SEEN. BOB TROUB IS A NEONATOLOGIST AT HARVARD GOOD MORNING, EVERYONE. THANKS FOR BEING HERE. THIS IS A REAL HONOR TO TALK TO PEOPLE WHO ACTUALLY DO THIS WORK AND ALL OF THOSE WHO ARE WATCHING, YOU KNOW, THROUGH THE MEDIA AS WELL. WE'RE GOING ON TALK TODAY ABOUT ETHICAL CAN CONFLICTS IN RANDOMIZED CONTROLLED TRIALS, I WILL GIVE YOU AN OVERVIEW OF WHAT I WILL TELL YOU OVER AND OVER DURING THE PRESENTATION. HERE IS THAT OVERVIEW. WE'LL INVOLVE A CASE STUDY WHICH INVOLVES A TECHNOLOGY CALLED ECHMO, MY SINGLE-MOST IMPORTANT POINT FOR THE MORNING IS HOW TO BE REALLY CLEAR ABOUT THIS FUNDAMENTAL CONFLICT THAT MANY OF YOU WILL EXPERIENCE BETWEEN THE ROLES OF BEING A CLINICIAN AND AN INVESTIGATOR, AND THEN WE'LL TALK ABOUT A COUPLE WAYS OF MITIGATING THAT CONFLICT, ADAPTIVE RANDOMIZATION AND RANDOMIZED CON SEN, WHAT'S OFTEN CALLED ZELEN RANDOMIZATION AND CLOSE WITH SOME REFLEXES ABOUT WHETHER RCT'S ARE THE ONLY WAY TO LEARN. LET'S BEGIN WITH THAT CASE STUDY. SO THIS WAS A RANDOMIZED CONTROL TRIAL OF THIS NEW TECHNOLOGY ECMO AND AT THE TIME THIS WAS DONE, I WAS A FELLOW IN PEDIATRIC CRITICAL CARE MEDICINE AND ANESTHESIOLOGY AT BOSTON CHILDREN'S HOSPITAL, SOIFS INVOLVED IN CARING FOR THESE PATIENTS BUT NOT ACTUALLY A PART OF THE STUDY. SO LET ME BEGIN BY TELLING YOU A LITTLE BIT ABOUT ECMO AS A TECHNOLOGY. HOW MANY OF YOU ARE FAMILIAR WITH ECMO AND HEARD ABOUT IT? SO HARD TO SEE, BUT IT LOOKS LIKE LESS THAN HALF OF YOU ANYWAY. SO WE USE ECMO FOR PATIENTS WHO HAVE LIFE-THREATENING HEART OR LUNG FAILURE, AND THE TECHNOLOGY LOOKS LIKE THIS. AN INCISION IS MADE IN THE PATIENT'S NECK AND TWO TUBES OR CANNULA ARE PLACED, ONE DOWN HERE INTO THE RIGHT ATRIUM WHERE VENOUS BLOOD IS DRAINED DOWN INTO A RESERVOIR WHERE MEDICATIONS ARE ADDED, MOST PARTICULARLY HEM RIN TO PREVENT THE BLOOD -- HEPARIN TO PREVENT THE BLOOD FROM CLOTTING, THEN IT GOES THROUGH A PUMP OR THE ARTIFICIAL HEART WHICH PUMPS THE BLOOD UP THROUGH THE MEMBRANE OXYGEN A TORE. IT'S A LARGE SILICON ENVELOPE WRAPPED UP INTO A CYLINDER AND BLOOD IS PUMPED IN ONE DIRECTION THROUGH THE INSIDE OF THE ENVELOPE, FRESH GAS IS PUMPED IN THE OTHER DIRECTION THROUGH THE OUTSIDE OF THE ENVELOPE, YOU GET GAS EXCHANGE ACROSS THE SILICON MEMBRANE, SO OXYGEN IN, CARBON DIOXIDE OUT, THE BLOOD IS WARMED BACK UP TO BODY TEMPERATURE AND THEN PUT BACK INTO THE ASCENDING AORTA HERE. SO WE'VE BYPASSED BOTH HEART AND LUNG FUNCTION WITH THE TECHNOLOGY. WHEN THESE PATIENTS COME TO THE INTENSIVE CARE UNIT, THEY'RE TOO SICK TO GO DOWN TO THE OPERATING ROOM, SO WE BRING THE OPERATING ROOM UP TO THE ICU, CREATE A STERILE ENVIRONMENT, THESE ARE TWO OF OUR SURGEONS HERE PLACING THE CANNULA, AND THEN THIS IS WHAT AN ECMO BED SPACE LOOKS LIKE. SO THE BABY OF COURSE AND YOU CAN SEE THE CANNULA HERE, BLOOD BEING DRAINLD DOWN TO THE RESERVOIR WHERE MEDICATIONS ARE ADDED, THEN HERE IS OUR PUMP, OUR ARTIFICIAL HEART GOING THROUGH THE MEMBRANE OXYGENATOR, THE ARTIFICIAL LUNG RIGHT HERE, THERE'S A SILVER DEVICE BACK HERE CHESS THE WARMER, THAT WARMS THE BLOOD BACK UP TO BODY TEMPERATURE AND THEN BACK INTO THE BABY, AND YOU CAN SEE THAT THIS REQUIRES A NURSE 24/7 TO TAKE CARE OF THE BABY AND AN ECMO TECHNOLOGIST 24/7 TO TAKE CARE OF THE PUMP. IT'S NOT AS EXPENSIVE AS YOU MIGHT THINK OF. THE OXYGENATORS ARE PROBABLY SOMEWHERE AROUND $1,000, THAT'S THE ONLY PART OF THE CIRCUIT THAT'S NOT REUSABLE EXCEPT FOR THE TUBING, SO IT'S JUST THE LABOR AND THINGS LIKE THAT THAT ADD UP TO THE EXTRA COST OF ECMO. HERE YOU SEE WHAT A BABY LOOKS LIKE ON ECMO. FOR THOSE OF YOU WHO HAVE WORKED IN INTENSIVE CARE UNTSZ, YOU MIGHT NOTICE THAT ONE ASPECT OF THIS IS THAT THE ENDOTRACHEAL TUBE IS NOT CONNECTED TO THE VENTILATOR, WHICH KIND OF DRAMATICALLY MAKES THE POINT THAT YOU DON'T NEED TO BREATHE WHEN YOU'RE ON ECMO. ACTUALLY WE DO LEAVE THE TUBES HOOKED UP TO A VENTILATOR BUT PRIMARILY JUST TO PROVIDE SOME POSITIVE PRESSURE TO KEEP THE LUNGS EXPANDED, NOT REALLY TO VENLT LATE. THEN IF YOU MAYBE USE YOUR IMAGINATION A LITTLE BIT HERE, YOU CAN CONVINCE YOURSELF THAT THE BLOOD IN THE LOWER TUBE THERE IS A LITTLE DARKER THAN THE BLOOD IN THE UPPER TUBE, SO THAT'S THE VENOUS BLOOD THAT'S BEING DRAINLD OUT AND THE ARTERIAL BLOOD THAT'S BEING PUT BACK IN. SO THAT'S THE TECHNOLOGY. AT A FEW POINTS IN MY TALK TODAY I'LL STOP AND WE'LL BE ABLE TO HAVE MAYBE A QUESTION OR A COMMENT OR TWO. I WANT TO MAKE SURE, ARE THERE ANY QUESTIONS ABOUT THE TECHNOLOGY ITSELF IN TERMS OF UNDERSTANDING THE CASE STUDY? OKAY. DIDN'T SEE ANY HANDS OUT THERE. I'M KIND OF BOTTOM LINED BY THE LIETSZ, SO SAY SOMETHING IF I'VE MISSED YOU. LET ME GIVE YOU A LITTLE BACKGROUND TO THE HARVARD TRIAL THAT WE'LL BE DISCUSSING. SO A RANDOMIZED CONTROL TRIAL IN 19 P 0 SHOWN THAT ECMO WAS NOT EFFECTIVE AT TREATING ADULTS WITH THE ACUTE RESPIRATORY DISTRESS SYNDROME. IN 1970-H ONE OF THE SURGEONS INVOLVED IN THAT WORK, NAMED BOB BARTLETT, HE REASONED THAT PERHAPS THE REASON FOR THIS WAS THAT THESE ADULTS ALREADY HAD IRREVERSIBLE LUNG DISEASE SO ECMO KEEPS YOU ALIVE HOPEFULLY LONG ENOUGH THAT YOU CAN HEAL AND RECOVER, BUT IF YOU'VE ALREADY GOT IRREVERSIBLE DAMAGE ON THE ORGAN, THAT'S NOT GOING TO HAPPEN. SO ECMO MAYBE PREDICTABLY WAS NOT USEFUL IN ADULTS FOR THIS REASON, SO HE THOUGHT, GEE, IF WE COULD FIND A DISEASE THAT GETS BETTER IN THE RELATIVELY SHORT PERIOD OF TIME THAT ECMO CAN BE USED, SAY TWO OR THREE WEEKS, THAT MAYBE IT WOULD BE USEFUL. SO IT'S SORT OF A TECHNOLOGY IN SEARCH OF A DISEASE, IF YOU WILL, AND HE WENT ON AND THOUGHT THAT THERE'S A DISEASE OF NEWBORNS CALLED PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN WHICH IS BASICALLY A SPASM OF THE PULMONARY ARTERIES THAT SEVERELY REDUCES BLOOD FLOW TO THE LUNGS, IS A DISEASE WHICH IF YOU CAN KEEP THE PATIENT ALIVE LONG ENOUGH, THAT SPHASM WILL RELAX AND THEY'LL BE ABLE TO GO ON AND SURVIVE. HE THOUGHT THAT MIGHT BE A GOOD TARGET FOR THIS NEW TECHNOLOGY ECMO. SEW STARTED TO USE IT ON BABIES IN THE EARLY 1980S IN MICHIGAN AND HIS RESULTS WERE VERY, VERY IMPRESSIVE. YOU KNOW, BABIES WERE COMING IN, EVERYBODY THOUGHT FOR SURE THEY WERE NOT GOING ON SURVIVE, PUT THEM ON ECMO AND THEY JUST DID GREAT. BUT PEDIATRICIAN SAYS WERE VERY RELUCTANT TO ADOPT ECMO WITHOUT CONVINCING DATA FROM A RANDOMIZED CONTROL TRIAL WHICH HAD NOT BEEN DONE. SO HERE IS A QUESTION I WOULD LIKE TO ASK YOU ABOUT. IMAGINE THAT YOU WERE BOB BARTLETT, YOU GOT THIS NEW TECHNOLOGY THAT YOU THINK IS JUST AMAZING, BUT PEOPLE WERE SAYING UNLESS YOU DO AN RCT, WE'RE NOT GOING TO BELIEVE YOU, SO WOULD YOU DO AN RCT RECOGNIZING THAT THIS WOULD NECESSARILY MEAN THAT SOME PATIENTS WOULD BE RANDOMIZED TO THE CONTROL ARM AND QUITE POSSIBLY PATIENTS THAT YOU BELIEVE YOU COULD HAVE SAVED THEIR LIFE WOULD END UP DYING. SO PLEASE PARTICIPATE A LITTLE BIT HERE. WOULD SOMEBODY -- LET'S DO A SHOW OF HANDS. HOW MANY OF YOU WOULD SAY IF YOU WERE BOB BARTLETT IN THIS SITUATION, THAT YOU WOULD SAY OKAY, IN ORDER TO MAKE MY TECHNOLOGY AVAILABLE TO THE REST OF THE WORLD, I'VE GOT TO DO AN RCT, THAT MIGHT SACK FIELS A FEW BABIES. -- THAT MIGHT SACRIFICE A FEW BABIES. HOW MANY OF YOU WOULD DO THAT? HOW MANY WOULD NOT? OH, SO THE OVERWHELMING MAJORITY OF YOU WOULD NOT. OKAY. WOULD MAYBE ONE OF YOU WHO WOULDN'T, WOULD YOU MIND COMING TO THE MICROPHONE AND JUST A COUPLE SENTENCES ABOUT WHY? DON'T BE SHY. THERE WERE A LOT OF YOU WHO RAISED THEIR HAND. HERE WE HAVE SOME WONDERFUL VOLUNTEER. THANK YOU. >> I'M JUST MAKING AN ASSUMPTION THAT THE DATA THAT HE WAS SEEING WITH THE PATIENTS HE WAS TREATING WAS PRETTY OUTSTANDING, SO I MEAN, HIGHLY CONVINCING THAT THIS WAS FAR MORE SUCCESSFUL. SO MY THINKING IS THAT YOU CAN ACTUALLY PROVE THIS IN ANOTHER WAY AS OPPOSED TO DOING A RANDOMIZED CONTROL TRIAL. SO LOOKING AT OUTCOMES, HISTORICAL OUTCOMES OF BABIES WHO ARE UNDERGOING TRADITIONAL TREATMENT AND WHAT OCCURRED WITH THEM AND THEN LOOKING AT, YOU KNOW, THE NUMBER OF BABIES THAT HE WOULD HAVE TREATED OVER A PERIOD OF TIME AND COMPARING THE PROPORTIONS AND YOU CAN EVEN DO MATCHING OF THE BABIES. SO I'M JUST THINKING THAT THERE IS BETTER METHODOLOGY THAT WOULD BE MORE ETHICAL. >> >> ROBERT TRUOG: THANK YOU. GREAT COMMENT. HISTORICAL CONTROL, SOMETHING LIKE THAT. ARE YOU GOING ON SPEAK TO THE SAME SIDE OR ARE YOU GOING TO OFFER A REBUTTAL? >> SAME SIDE, JUST A DIFFERENT POINT. TO DO A RANDOMIZED CONTROL TRIAL YOU HAVE TO HAVE JUSTIFICATION TO THINK THAT IT'S UNKNOWN WHICH OF THE TREATMENTS IS BETTER, AND IF YOU HAVE A DISEASE IN WHICH THE CURRENT STANDARD OF CARE LEADS TO VERY POOR OUTCOMES AND YOUR NEW TREATMENT IS HIGHLY EFFECTIVE, YOU DON'T -- IT'S NOT ETHICAL TO DO RANDOM ISLESSED CONTROL TRIAL, IF THE DATA ARE CONVINCING ENOUGH AND YOU CAN DO OTHER WAYS AS PREVENTION TOO. >> >> ROBERT TRUOG: THANK YOU VERY MUCH. WOULD THE SMALL NUMBER OF YOU WHO REBUTTED MAKE A COMMENT? >> I SHOULD PROBABLY DISCLAIM THAT I'M NEITHER A PHYSICIAN NOR A LAWYER, BUT I CERTAINLY, WHILE I WOULD LOOK AT DOING AN RCT, I WOULD CERTAINLY TRY TO BE FLEXIBLE AND TRY TO GET AS MANY OF THE INFANTS SUPERIOR TREATMENT AS SOON AS POSSIBLE, BUT IF THAT'S WHAT IT TAKES TO CONVINCE THE -- YOU KNOW, SOMETIMES VERY CONSERVATIVE MEDICAL ESTABLISHMENT THAT THIS NEW THERAPY IS USABLE, THAT THEY CAN GO AHEAD IN GOOD CONSCIENCE AND THAT IT HASTEN HE IS THE BROAD ADOPTION OF SUCH A THERAPY, THEN I THINK MAYBE THERE'S NO CHOICE. NOT THAT I WOULDN'T LOOK FOR OTHER CHOICES. >> >> ROBERT TRUOG: OKAY. ALL RIGHT. WONDERFUL. GREAT COMMENT. SO BOB BARTLETT STRUGGLED WITH THIS, AND HE SAID OKAY, IF I HAVE TO DO A RANDOMIZED CONTROL TRIAL, I'LL DO A RANDOMIZED CONTROL TRIAL, BUT HE DID IT IN KIND OF AN ODD WAY. HERE IS HIS PAPER. EXTRACORPOREAL CIRCULATION IN NEONATAL RESPIRATORY FAILURE, A PROSPECTIVE RANDOMIZED STUDY. IT WAS DIFFERENT IN THE FOLLOWING WAY. HE USED WHAT'S CALLED A PLAY THE WINNER DESIGN. HE STARTED OFF WITH A BUCKET HERE THAT HAD TWO MASH BELLS IN IT -- MARBLES IN T LET'S SAY THE YELLOW MARBLE IS ECMO, BLACK MARBLE IS CONVENTIONAL THERAPY, PATIENT COMES ALONG, MEETS CRITERIA, YOU REACH IN AND GET A MARBLE, THAT'S WHAT THE PATIENT GETS. LISTEN CAREFULLY, IT'S A LITTLE CONFUSING, THEN I'LL EXPLAIN IT A SECOND TIME. THE RULE IS THAT IF THAT FIRST PATIENT SURVIVES, THEN FOR THE NEXT DRAW ANOTHER MARBLE OF THE SAME COLOR GOES INTO THE BUCKET, IF THAT PATIENT DIES, THEN ANOTHER MARBLE OF THE OPPOSITE COLOR GOES INTO THE BUCKET FOR THE NEXT DRAW. SO I KNOW THAT'S CONFUSING. LET ME EXPLAIN IT TO YOU AND SHOW YOU HOW IT ACTUALLY HAPPENED IN HIS STUDY. SO THE FIRST PATIENT DREW AN ECMO MARBLE AND SURVIVED. SO THAT MEANS FOR THE NEXT DRAW ANOTHER MARBLE OF THE SAME COLOR GOES INTO THE BUCKET. THAT PATIENT ACTUALLY GOT THE BLACK MARBLE, GOT CONVENTIONAL THERAPY AND DIED, SO ANOTHER MARBLE OF THE OPPOSITE COLOR IN THIS CASE YELLOW WOULD GO INTO THE BUCKET AND SO ON AND SO FORTH UNTIL THERE WERE 11 PATIENTS WHO WERE ENROLLED, 10 OF WHOM GOT ECMO AND SURVIVED, ONE OF WHOM GOT CONVENTIONAL THERAPY AND DIED, AND AT THIS POINT THE STATISTICIANS CLAIM THAT THIS WAS STATISTICALLY SIGNIFICANT AND THE STUDY WAS TERMINATED WITH ECMO BEING SHOWN TO BE SUCCESSFUL. JUST TO SHOW YOU SOME OF THE EMOTIONAL DIFFICULTIES OF DOING THIS, BECAUSE, AGAIN, HE WAS SO CONCERNED ABOUT HAVING PATIENTS DIE WHEN HE THOUGHT HE COULD SAVE THEM, THIS ONE HERE, THE ONE WHO DIED APPROXIMATE, HE'S TOLD ME THIS STORY NOW A COUPLE OF TIMES, HE WAS IN ANN ARBOR, THIS WAS A BABY BORN IN KALAMAZOO ACROSS THE STATE TO A WOMAN IN HER FORTS WHO 40s WHO HAD FOR YEARS BEEN DOING FERTILITY TREATMENTS AND HAD A HYSTERECTOMY DURING HER DELIVERY. YOU COULDN'T MAKE THUP. THE WORST POSSIBLE SITUATION. THE BABY IS NOW VERY SICK, DIRECTOR IN KALAMAZOO CALLS UP BARTLETT AND SAYS I HEAR YOU'VE GOT THIS GREAT NEW THERAPY, I WOULD LIKE STOANLD THE BABY TO YOU -- TO SEND THE BABY TO YOU, WHICH WOULD HAVE BEEN THE FIRST TRANSFER BETWEEN THESE TWO HOSPITALS THAT HAD EVER TAKEN PLACE AND BOB BARTLETT SAYS WE DO HAVE THIS NEW THERAPY BUT I HAVE TO WARN YOU WE'RE NOW DOING THIS STUDY AND THE CHILD IS GOING TO HAVE TO BE EN ROASM IN THE STUDY AND THE GUY SAYS NO, NO, YOU HAVE TO MAKE AN EXCEPTION HERE, YOU CAN'T DO THAT. BARTLETT SAID NO, I'M AFRAID WE DO. AS HE TOLD ME, INITIALLY THE BABY CAME, DIDN'T GET ECMO, A COUPLE DAYS, WAS LOOK BETTER, PEOPLE WERE JUST ABOUT RED DIFFICULT TO HAVE A SIGH OF RE-- ABOUT READY TO HAVE A SIGH OF RELIEF, ENDED UP GETTING WORSE AND NOT SURVIVAL. TO THIS DAY IT WAS ALSO A PAINFUL THING FOR HIM. LATER ON HIS NIECE WAS BORN WITH ME ASPIRATION MECONIUM SYNDROME, TRANSFERRED UP TO HIS HOSPITAL, SHE NEVER QUALIFIED FOR ECMO, BUT HE INSISTS IF SHE WOULD HAVE, HE WOULD HAVE ENROLLED HER. THE STUDY SAYS ECMO IS BETTER. SHOW OF HANDS. IMAGINE YOU WERE A NEONATOLOGIST IN BOSTON OR WASHINGTON OR WHEREVER AND YOU READ THIS ARTICLE. WOULD YOU HAVE TOLD YOUR HOSPITAL ADMINISTRATOR THAT YOU NEEDED TO START AN ECMO PROGRAM? IN OTHER WORDS, WAS THE DATA YOU JUST SAW CONVINCING TO YOU? DOES THIS TELL YOU THAT ECMO WAS BETTER? HOW MANY WOULD SAY YOU CAN -- HOW MANY WOULD SAY HE DID THE RANDOMIZED CONTROL TRIAL, HE GAVE US WHAT WE WANTED, HOW MANY WOULD CHANGE YOUR APPROACH? MAYBE A THIRD OF YOU. HOW MANY WOULD SAY WOULD NOT? SOME. I GUESS THERE'S A LOT OF UNDECIDED OUT THERE. SO PROBABLY MORE WOULD -- HOW ABOUT JUST FOR ONE OF YOU WHO WOULD NOT BE CONVINCED. MAIBL ONE QUICK COMMENT? GO AHEAD. THANK YOU FOR DOING THAT. >> I THINK IT'S REALLY HARD TO BE CONVINCED BY ONE PATIENT ABOUT ANYTHING, SO IF THERE'S ONLY ONE PATIENT WHO HAD A BAD OUTCOME, IT JUST DOESN'T TELL ME THAT MUCH. THAT SAID, I'M WORKING ENTIRELY ON THOSE 11 PATIENTS, WHICH ISN'T PARTICULARLY TRUE, SO IN OTHER WORDS, AS AN ACTUAL PHYSICIAN, IF I HAD ACTUAL EXPERIENCE WITH THIS AND KNEW IT IN MY EXPERIENCE PATIENTS LIKE THIS USUALLY PRETTY MUCH ALWAYS DIED, THEN I WOULD BE KIND OF WORKING ON A FRAMEWORK AND SAY WELL, YEAH, MAYBE THIS IS VERY CONVINCING AND IT MIGHT CHANGE. >> >> ROBERT TRUOG: VERY GOOD. I THINK YOU'VE CAPTURED SORT OF THE UNCERTAINTY HERE. WE HAD TWO PHYSICIANS IN BOSTON, JIM WAIR, AT THAT TIME ONE OF THE DEANS OF THE SCHOOL OF PUBLIC HEALTH, MIKE EPSTEIN, CHIEF OF NEONATOLOGY AT BOSTON CHILDREN'S WHO WROTE THE EDITORIAL TO THIS AND THEY WERE SKEPTICAL. THE CLINICAL IMPLICATIONS FOR THIS NEW AND COMPLEX TREATMENT REMAIN UNDEFINED. FURTHER RANDOMIZED CONTROLLED TRIALS WILL BE DIFFICULT BUT REMAIN NECESSARY, SO OF COURSE IN TRUE ACADEMIC FASHION, THEY WENT AHEAD AND DID THE NEXT TRIAL, WHICH THEY THOUGHT WOULD BE DEFINITIVE AND THAT'S THE ONE WE'RE GOING TO DISCUSS HERE. SO LET ME GIVE YOU A LITTLE BIT MORE DETAIL ON THIS TRIAL. HERE IS HOW IT WAS DESIGNED. THE IDEA WAS TO TREAT PATIENTS IN TWO DIFFERENT LOCATIONS, ECMO PATIENT IN THE PEDIATRIC ICU ON THE FIFTH FLOOR, CONVENTIONAL THERAPY IN THE NEONATAL ICU ON THE 7TH FLOOR, SO THIS CREATES KIND OF A HEALTHY COMPETITION IF YOU WILL AND THEY'RE STAFFED DIFFERENTLY. NICU HAS NEONATOLOGISTS, PICU HAS ANESTHESIOLOGISTS AND SURGEONS, KIND OF A DIFFERENT MINDSET TOWARDS TREATING DISEASES, YOU KNOW, SURGICAL VIEW, A CHANCE TO CUT IS A CHANCE TO HEAL KIND OF THING WHEREAS A VERY DIFFERENT APPROACH IN THE NICU. I WAS ACTUALLY WORKING IN THE PICU AT THE TIME. LY IT'S ALSO RELEVANT THAT IN THE NICU NO PATIENTS HAD EVER BEFORE BEEN OFFERED ECMO FOR THIS PARTICULAR DISEASE, PPHN. SO WE DIDN'T HAVE THE PROBLEM THAT BOB BARTLETT HAD WITH THE WOMAN FROM KALAMAZOO OF HAVING TO SAY, WELL, YEAH, A MONTH AGO YOU COULD HAVE GOTTEN ECMO AS ONE OF OUR CLINICAL TREATMENT, BUT NOW WE'RE DOING A STUDY, SO YOU'RE GOING TO HAVE TO BE RANDOMIZED AND YOU MAY NOT GET IT. ECMO HAD NEVER BEEN OFFERED FOR THIS DISEASE, SO WE DIDN'T HAVE THAT PROBLEM. ANOTHER ADVANTAGE, THOUGH, WAS THAT WE HAD BEEN DOING ECMO IN THE PICU ON THE FIFTH FLOOR BUT FOR A DIFFERENT DISEASE, CONGENITAL DIE FORMAT I CAN HERNIA OF THE -- D I APHRAMID YIRKS HERNIA OF THE NEWBORN. IT'S A STEEP CURVE TION MOST OF YOUR PATIENTS DON'T DO THAT WELL WHEN YOU START DOING IT. WE WERE ALREADY PAST THE STEEP PART OF THE LEARNING CURVE WITH PATIENTS WITH A DIFFERENT DISEASE, SO WE KNEW HOW TO DO ECMO WELL SO IT'S GOING TO BE A REALLY FAIR COMPARISON ABOUT THESE TWO APPROACHES. SO WITH THAT KIND OF NICE HEALTHY COMPETITIVE WAY, WE EMBARKED ON THIS. ELIGIBLE NEWBORNS HAD PPHN AND A PREDICTED MORTALITY OF 85% BASED ON RETROSPECTIVE DATA. REMEMBER THAT NUMBER, 85%. AND WHAT THE CLINICIANS DID NOT KNOW BUT THE STATISTICIAN KNEW IS THAT THE STUDY WAS DIVIDED INTO TWO PHASES. IN PHASE I THERE WOULD BE 50/50 RANDOMIZATION, UP UNTIL THERE WERE FOUR DEATHS IN ONE ARM OF THE STUDY, AND THEN THE STUDY WOULD ENTER PHASE II 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 FINALLY, THE PLAN WAS TO SEEK CONSENT ONLY FROM THOSE WHO WERE RANDOMIZED TO THE EXPERIMENTAL THERAPY, ECMO. BABIES WHO WENT INTO THE CONTROL ARM, THE FAMILIES WERE NOT APPROACHED FOR CONSENT AND DID NOT KNOW THAT THEIR CHILDREN WERE A PART OF THE STUDY. WE'LL TALK ABOUT ALL THESE BUT I WANT TO MENTION, PEOPLE ASK ME, WHERE DID THIS NUMBER FOUR COME FROM, WHY FOUR DEATH SNS SO IFD DAIRK WHY FOUR DEATHS? IFD THE PLEASURE OF TEACHING THIS CASE A NUMBER OF TIMES WITH JIM WARE WHO WAS THE STATISTICIAN ON THIS STUDY, I ASKED HIM, SEW REFERRED ME TO THIS JOURNAL, STATISTICS IN MEDICINE, AND IT WAS AN ENTIRE ISSUE PUBLISHED ON THIS STUDY AND ON THE STATISTICS IT SAID GO LOOK AT MY ARTICLE AND IT WILL EXPLAIN IT. SO I DID. AND HERE IS THE PAGE WHERE THAT OCCURRED. YOU'LL NOTICE THAT THERE'S A FOUR HERE AND THERE'S A FOUR DOWN HERE AND THAT'S ABOUT AS MUCH AS I CAN SAY ABOUT WHERE THAT NUMBER FOUR CAME FROM. YOU KNOW, WHEN I SHOW THE SLIDE AND KIND OF MAKE A JOKE WITH HIM, UNFORTUNATELY HE DIEFD IN THE LAST YEAR -- HE DIED IN THE LAST YEAR, BUT LAUGH A LITTLE BIT, BUT HE HAD THIS PERPLEXED LOOK ON HIS FACE, BUT YEAH, THAT'S THE ANSWER, WHAT DON'T YOU GET ABOUT IT? SO PEOPLE WHO ARE GOOD AT MATH, WHAT CAN YOU SAY? SO HOW DID THE TRIAL WORK OUT? SO IN PHASE I THERE WERE NINE PATIENTS RANDOMIZED TO ECMO, ALL NINE SURVIVED. THERE WERE TEN PATIENTS RANDOMIZED TO CONVENTIONAL THERAPY, SIX SURVIVED AND FOUR DIED. WHEN THAT FOURTH DEATH OCCURRED, THE STUDY ENTERED PHASE II WHERE ALL THE PATIENTS ARE RANDOMIZED TO THE MORE SUCCESSFUL THERAPY, WHICH IN THIS CASE WAS ECMO, SO IN PHASE II EVERYONE GOT ECMO, THERE WERE AN ADDITIONAL 20 PATIENTS ENROLLED, 19 SURVIVED, ONE DIED, AND AT THIS POINT STATISTICAL SIGNIFICANCE WAS ACHIEVED. AND THE STUDY WAS STOPPED. I JUST WANT TO POINT OUT ONE I THINK KIND OF INTERESTING FACT HERE IS THAT REMEMBER THE ENROLLMENT CRITERIA WERE THAT YOU HAD TO HAVE A PREDICTED MORTALITY OF 85% BASED ON THE MOST RECENT RETROSPECTIVE DATA FROM OUR HOSPITAL. 85%. SO WHAT WAS THE MORTALITY THAT WAS ACTUALLY SEEN IN THESE TEN PATIENTS? 40%, RIGHT? NOW, IT'S OF COURSE SMALL NUMBERS AND EVERYTHING ELSE, AND THAT MAY EXPLAIN IT, BUT IT'S A LITTLE BIT IN RESPONSE TO THE COMMENT THAT WAS MADE EARLIER, WHY COULDN'T WE USE A HISTORICAL CONTROL STUDY, WHICH IS A GOOD STUDY, BUT, YOU KNOW, YOU MIGHT NOW IN RETROSPECT WONDER IF THAT WOULD HAVE BEEN ADEQUATE, THINKING ABOUT THE HAWTHORNE EFFECT AND THINKING THAT PEOPLE PERFORM BETTER WHEN THEY KNOW THEIR RESULTS ARE BEING WATCHED, ET CETERA. WHY IN BABIES DID WE EXPECT 85% WOULD DIE, DID ONLY 40% ACTUALLY DIE. I WANT TO TURN NOW TO THE ETHICS OF THIS CASE AND I WANT TO HONE IN HERE ON WHAT I WOULD SAY IS THE SINGLE-MOST IMPORTANT POINT I WANT YOU TO GET AND THAT IS THE CONFLICT BETWEEN THE ROLES THAT PARTICULARLY THOALZ OF YOU WHO ARE -- THOSE OF YOU WHO ARE CLINICIANS WILL EXPERIENCE BETWEEN BEING A DOCTOR OR A NURSE FOR A PATIENT VERSUS BEING AN INVESTIGATOR. SO AS JAY KATZ REALLY PUT IT WELL MANY YEARS AGO, A DILEMMA PRENLTS PHYSICIAN INVESTIGATORS. AS PHYSICIANS, THEY'RE DEDICATED TO CARING THIS YEAR THEIR PATIENTS. AS INVESTIGATORS, THEY'RE DEDICATED TO CARING FOR THEIR RESEARCH. THESE CONFLICT WITH AN PHYSICIAN/INVESTIGATOR COMES FACE TO FACE WITH AN INDIVIDUAL PATIENT/SUBJECT. I GUESS THE POINT I WOULD LIKE YOU TO TAKE AWAY IS THAT THIS CONFLICT REALLY GOES ALL THE WAY DOWN TO THE BONE. THERE'S A LOT OF WAYS THAT WE TRY TO MINIMIZE T GET AROUND IT, BUT I THINK IT'S A FUNDAMENTAL CONFLICT THAT REALLY CAN NEVER BE COMPLETELY RESOLVED. THE PUBLIC IS AWARE OF THIS TOO , YOU KNOW, BEING A MEMBER OF THE PLACEBO GROUP MIGHT NOT WORK OUT ALL THAT WELL FOR YOU. SO HOW DO WE ADDRESS IT? ONE SOLUTION ADVOCATED BY RE REBECCA DRESSER IS THAT WE SHOULD HAVE A FULL SEPARATION OF ROLES. RESEARCHERS MUST GIVE PATIENTS STARK, BOLD AND DRAMATIC SIGNS THAT RESEARCH IS DIFFERENT FROM CLINICAL CARE. INSTEAD OF THE WHITE COATS ASSOCIATED WITH MEDICAL CARE, INVESTIGATORS COULD WEAR RED ONES. SO, YOU KNOW, YOU CAN IMAGINE MAYBE YOU'RE AN INVESTIGATOR, DEPENDING ON WHAT ROLE YOU'RE IN, THAT'S GOING TO DECIDE WHAT COLOR COAT YOU WEAR, IT'S GOING TO BE VERY CLEAR IT THE PATIENT AS TO EXACTLY WHERE YOUR ALLEGIANCES LIE IN ANY PARTICULAR SITUATION. ARE YOU THERE PRIMARILY FOR THEM OR PRIMARILY FOR THE RESEARCH? I THINK SEPARATION OF THE ROLES WHEN YOU CAN DO IT IS A VERY GOOD THING AND IN FACT WE DO OFTEN DO IT. WE HAVE SEPARATE PEOPLE WILL APPROACH FAMILIES WHEN THAT'S POSSIBLE. IT'S NOT ALWAYS POSSIBLE, YOU KNOW, PATIENTS COME HERE TO THE NIH WITH RARE MALIGNANCIES, LET'S SAY, AND IT'S NO SURPRISE THAT THE PERSON WHO THEY WANT TO TAKE CARE OF THEM, WHO IS THE MOST EXPERT PERSON AT THAT DISEASE IN THE WHOLE WORLD IS ALSO THE PERSON WHO IS DOING THE RESEARCH. SO SOMETIMES THEY CANNOT BE SEPARATED. BUT IN GENERAL, I THINK THIS IS A GOOD RECOMMENDATION, BUT IT CAN'T ALWAYS BE DONE. POSSIBLE SOLUTION NUMBER WITH 2 IS PERSONAL EQUIPOISE, THE IDEA THAT REQUIRES THE PERSON TO BE PERFECTLY BALANCED ON THE EDGE OF THE SWORD, IF YOU WILL, PERFECTED BALANCED -- TO BE PERSONALLY UNBIASED BETWEEN THE TREATMENT ARMS. YOUR VIEW, THIS IS WHY BOB BARTLETT COULD NOT DO THIS STUDY, HE WAS NOT HIMSELF IN EQUIPOISE, EFSZ CONVINCED THAT HE HAD A TREATMENT THAT WAS IMPROVEMENT. THERE ARE DIFFICULTIES WITH THIS. FIRST, RESEARCHERS USUALLY DO BELIEVE IN THE TREATMENTS THAT THEY STUDIED. SO IF YOU'RE A YOUNG INVESTIGATOR HERE AT THE NIH AND YOU'RE EMBARK OG A RANDOMIZED CONTROL TRIAL OF A NEW DRUG SHES YOU'RE GOING TO INVEST THE NEXT SEVERAL YEARS OF YOUR LIFE IN T IT'S PROBABLE THAT YOU BELIEVE THAT THIS DRUG IS GOING TO WORK. I MEAN, YOU ARE NOT IN PERSONAL EQUIPOISE AROUND THIS AND THE PROBLEM WITH REQUIRING PERSONAL EQUIPOISE IS IT'S GOING TO EITHER LEAVE YOU FEELING GUILTY, LIKE I REALLY SHOULDN'T BE ENROLLING PATIENTS IN THIS TRIAL BECAUSE I THINK THE EXPERIMENTAL DRUG IS BETTER OR IT WILL LEAVE YOU FEELING CYNICAL LIKE, YOU KNOW, OBVIOUSLY THERE'S SOMETHING WRONG WITH THIS ETHICS BECAUSE I'M A GOOD PERSON AND I'M TRYING TO DO A GOOD STUDY, SO THERE'S SOMETHING WRONG WITH HOW PEOPLE ARE THINKING ABOUT IT. AND SO THIS WAS THE GREAT CONTRIBUTION OF THE LATE BIOETHICIST BENJAMIN FRIEDMAN IN COMING UP WITH A THIRD POSSIBILITY HERE WHICH HE CALLS NOT PERSONAL EQUIPOISE BUT CLINICAL EQUIPOISE, THAT IS, UNCERTAINTY WITHIN THE MEDICAL COMMUNITY AS A WHOLE. THE IDEA HERE IS IMAGINE THAT YOU'RE ENROLLING A PATIENT IN A TRIAL MANY YOUR CLINIC AND YOU'RE SITTING DOWN WITH THEM AND YOU WOULD SAY, YOU KNOW, I HAVE TO BE HONEST WITH YOU, I BELIEVE THAT TREATMENT A IS BETTER, BUT I KNOW THAT IF YOUR APPOINTMENT HAD BEEN WITH MY COLLEAGUE DOWN THE HALL, SHE WOULD HAVE RECOMMENDED TREATMENT B. SO WOULD YOU AGREE TO HAVE YOUR TREATMENT DETERMINED BY A COIN FLIP SO THAT WE CAN LEARN FROM THIS EXPERIENCE? BASICALLY THE IDEA BEHIND THE CONCEPT OF CLINICAL EQUIPOISE. AM SO I'M GLAD WE SORT OF BROUGHT OUT THESE TWO THINGS IN THE DISCUSSION. BOB BARTLETT CLEARLY WAS NOT IN PERSONAL EQUIPOISE, BUT WE COULD SAY THAT ENROLLING PATIENTS IN A CLINICAL TRIAL WOULD HAVE BEEN ETHICAL FOR HIM BECAUSE THERE WAS A GENUINE STATE OF CLINICAL EQUIPOISE AROUND THE COUNTRY AS EVIDENCED BY THE FACT THAT SOME PEOPLE WERE DOING THIS TREATMENT AND OTHERS WEREN'T. YOU KNOW, WITH REGARD TO THE HARVARD ECMO TRIAL, IT'S LIKELY THAT NO SINGLE INVESTIGATOR WAS IN PERSONAL EQUIPOISE. WE HAD PEOPLE WHO BELIEVED IN ECMO AND THOSE WHO REALLY THOUGHT THAT THIS WAS A MISTAKE. BUT ACCORDING TO FRIEDMAN, THE COLLECTIVE UNCERTAIN TILL WOULD HAVE SAID THAT THE TRIAL WAS ETHICAL BECAUSE OF THE STATE OF CLINICAL EQUIPOISE THAING DID EXIST IN THE HOSPITAL AT THE TIME WE EMBARKED ON THE TRIAL. ALL RIGHT. LET'S GO ON AND TALK ABOUT A COUPLE OF WAYS THAT WE TRY TO MITIGATE THESE. FOR A LONG TIME I'VE TALKED ABOUT ADAPTIVE RANDOMIZATION AS SORT OF A THEORETICAL THING, BUT NOW I REALIZE IT'S REALLY IMPORTANT TO TALK ABOUT BECAUSE ADAPTIVE RANDOMIZATION IS EMERGING AS A VERY POWERFUL NEW TOOL AND A LOT OF THE LARGE STUDIES THAT ARE BEING FUNDED RIGHT NOW ARE USING THIS APPROACH, SO IT'S IMPORTANT THAT YOU UNDERSTAND IT AND SOME OF ITS ETHICAL IMPLICATIONS. SO THE IDEA OF ADAPTIVE RANDOMIZATION IS DETECTIVE YAITING FROM BALANCED -- IS DEVIATING FROM BALANCED OR 50/50 RANDOMIZATION WITH MORE PATIENTS ASSIGNED TO THE THERAPY THAT IS LEADING DURING THE TRIAL. IT'S A LITTLE BIT LIKE BETTING ON THE HORSE WHO IS OUT IN FRONT BEFORE WE KNOW HOW THE RACE IS GOING TO END. THE ADVANTAGES OF THIS IS THAT IT ATTEMPTS TO MINIMIZE THE NUMBER OF PAIRKTS ASSIGNED TO THE LESS SUCCESSFUL THERAPY. AS YOU SAW IN THE BARTLETT STUDY, IT DID EXACTLY THAT. WE ENDED UP WITH, WHAT, ONLY ONE PATIENT WHO ENDED UP NOT GETTING ECMO AND I THINK IT WAS 11 OR 12 THAT DID. SO IT WAS SUCCESSFUL IN THAT WAY. IT ALSO ATTEMPTS TO MITIGATE THE CONFLICT OF FEELER VERSUS INVESTIGATOR, IS -- OF HEALER VERSUS INVESTIGATOR, HIS CONCERN AND OUR CONCERN IS THAT WE WANT TO MINIMIZE THE NUMBER OF PATIENTS WHO DIE SO IT SEEMS TO HAVE ADVANTAGES IN THAT WAY. WHAT I THOUGHT WAS INTERESTING ABOUT THE ECMO TRIALS IN PARTICULAR IS THAT IN THE BARTLETT TRIAL THERE WAS 50/50 RANDOMIZATION GUARANTEED ONLY FOR THE FIRST PATIENT, AND IN THE EDITORIAL THAT JIM WARE AND MIKE EPSTEIN PUBLISHED, THEY CRITICIZED THAT ASPECT OF THE STUDY. BUT WHEN THEY WENT TO DESIGN A TRIAL THEMSELVES, THEY ALSO COONLT ESCAPE THE FACT THAT THEY -- COONLT ESCAPE THE FACT THAT THEY DID NOT WANT TO DO 50/50 RANDOMIZATION WITH A THERAPY THAT MIGHT BE REALLY TERRIFIC. SO THEY ALSO ADOPTED AN ADAPTIVE SCHEME BUT JUST A LITTLE BIT LESS SEVERE, THEY'RE GUARANTEED THE 50/50 RANDOMIZATION UNTIL THERE WAS A FOURTH DEATH IN ONE ARM. SAME APPROACH, JUST A LITTLE BIT LESES SEVERE. DISADVANTAGE OF DAPTIVE RANDOMIZATION IS THERE MUST BE ONLY ONE PRIMARY OUTCOME OF INTEREST BECAUSE YOU'RE GOING TO ADJUST THE RANDOMIZATION SCHEME DEPENDING ON THAT OUTCOME, THE OUTCOME MUST BE APPARENT WITHIN A SHORT PERIOD OF TIME, SO BOTH OF THOSE WERE TRUE IN THE ECMO STUDY, WE KNEW WHETHER THE PATIENTS SURVIVED OR DIED WITHIN A SHORT PERIOD OF TIME, SO THAT COULD GET FED BACK INTO HOW THE RANDOMIZATION WAS DONE, IT MAY SUFFER FROM A CRUEL BIAS, THAT IS, IF YOU ARE THINKING ABOUT ENROLLING IN A TRIAL AND YOU HAVE A CHOICE ABOUT T YOU'RE GOING TO WANT TO BE ENROLLED LATER, SO YOU MAY DEFER ENROLLING UNTIL LATER, WHILE THAT IS A PROBLEM IN GENERAL, IT WASN'T A PROBLEM IN THE ECMO TRIAL BECAUSE THESE BABIES NEEDED ECMO WITHIN A VERY SHORT PERIOD OF TIME. NOW, IN THE LITERATURE THIS TRIAL WAS CRITICIZED FROM BOTH DIRECTIONS, SO IN THIS JOURNAL OF STATISTICS AND MEDICINE, THE ISSUE THAT WAS PUBLISHED, THERE WERE ARTICLES THAT SAID, YOU KNOW, NO PATIENTS SHOULD HAVE BEEN DENIED ECMO, THERE WAS ALREADY CONVINCING EVIDENCE THAT ECMO WAS GOING TO BE SUPERIOR, JUST LIKE, YOU KNOW, YOU DON'T NEED TO KNOW AN RCT OR DO AN RCT ABOUT WHETHER TO STEP ON THE GAS OR STEP ON THE BRAKE AT A RED LIGHT. IT'S APPARENT VERY QUICKLY ABOUT WHAT'S THE SUPERIOR APPROACH. BUT THERE WERE OTHERS WHO SAID NO , YOU KNOW, HERE THECHED THE PERFECT CHANCE -- THEY HAD THE PERFECT CHANCE TO DO A REAL GOOD RANDOMIZED CONTROL TRIAL AND THEY BLEW IT, THEY WEREN'T COURAGEOUS ENOUGH TO DO A GOOD TRIAL AND THEY HAD TO USE THIS ADAPTIVE STUFF THAT'S REALLY DIFFICULT TO UNDERSTAND WITH COMPLEX MATH, ET CETERA. SO IN RETROSPECT, PROGRAMS THE APPROACH WAS A GOOD BALANCE -- PROGRAMS THE APPROACH WAS A GOOD BALANCE BETWEEN THESE FROM VIEWS, AND TO COME BACK TO NUMBER 4, THE CLINICIANS KNEW THAT THE PATIENTS WERE BEING RANDOMIZED, THE NURSES IN PARTICULAR, NURSES IN ICU ARE KIND OF LIKE THE CANARIES IN THE COAL MINE, THEY'RE THE FIRST TO SNIFF OUT WHEN SOMETHING FISHY IS GOING ON, SO AS MUCH AS THEY WERE PERHAPS OH POAMSED TO ECMO AT THE BEGINNING, VERY QUICKLY THEY WERE SEEING THAT THE ECMO WERE SURVIVING, THE ONES THEY WERE TREATING IN THE NICU WERE NOT AND BY THE TIME IT GOT TO THE FOURTH DEATH IN THE NICU THEY WERE JUST ABOUT READY TO SAY ENOUGH IS ENOUGH, WE'RE NOT GOING TO DO THIS ANYMORE. BUT AT THAT POINT ALL OF A SUDDEN ALL THE BABIES STARTED GETTING ECMO, PEOPLE REALIZED THERE WAS AN ADAPTIVE DESIGN SO THEY WERE ABLE TO COMPLETE THE TRIAL. SO I THINK THIS NUMBER 4 AND THE BALANCE ACTUALLY MAY HAVE ENDED UP BEING A VERY GOOD THING. SO I JUST WANT TO SAY ABOUT THIS HUGE TREND NOW THAT I'M SEEING TOWARDS MORE AND MORE ADAPTIVE TRIALS, THESE WERE A COUPLE OF PIECES PUBLISHED IN JAMA BACK IN KIND OF 2012 BUT MAYBE THE REAL POSTER CHILD FOR ALL OF THIS HAS BEEN THE ICES BY 2 TRIAL BREAST -- THE I-SPY 2 TRIAL, BREAST CANCER DESIGN, UNLIKE THE LITTLE MARBLES IN A BUCKET TRIAL I SHOWED YOU FROM BOB BARTLETT, THESE END UP BEING VERY COMPLEX, MULTICENTER TRIALS, RESULTS ARE BEING FED BACK ON A DAILY BASIS INTO A CENTRAL COMPUTER, THE RANDOMIZATION SCHEMES ARE BEING ALTERED LITERALLY ON A DAILY BASIS, AND I THINK THESE ARE BECOMING REALLY A NEW AND VERY DYNAMIC WAY TO DO BIG CLINICAL TRIALS. SO WHAT I'VE JUST TOLD YOU ABOUT I THINK IS SORT OF ETHICS 101 INTO THAT BUT I THINK THERE'S MANY OTHER ETHICAL ISSUES THAT THESE TRIALS ARE GOING TO RAISE. THE SECOND CONTROVERSIAL ASPECT OF THE ECMO TRIAL WAS THE USE OF DYED CONSENT, Z HE LEN RANDOMIZATION. LET ME TELL YOU A LITTLE BIT ABOUT THAT. TO THINK ABOUT A CONVENTIONAL RCT WITHOUT INFORMED CON ACCEPTABLE, YOU DECIDE A PATIENT IS ELIGIBLE AND THEN YOU RANDOMIZE THEM TO TREATMENT A OR B. OF COURSE WHAT'S MISSING HERE IS THE INFORMED CONSENT, SO YOU CAN DO THIS WITH YOUR RATS BUT YOU CAN'T DO THIS WITH YOUR PATIENTS. SO WITH PATIENTS, WE FIRST OF ALL HAVE TO GET THEIR INFORMED CONSENT, AND IF THEY SAY YES, WE RANDOMIZE THEM, AND IF THEY SAY NO, THEY'RE DROPPED FROM THE STUDY. ALREADY IT'S GETTING A LITTLE COMPLICATED HERE, RIGHT, BECAUSE YOU NEED TO SOMEHOW SHOW THAT THESE PATIENTS OVER HERE DON'T DIFFER IN ANY SIGNIFICANT WAYS FROM THESE PATIENTS UP HERE. SO MARVIN ZELEN WHO IS AT THE HARVARD SCHOOL OF PUBLIC HEALTH TOOK THIS A STEP FURTHER WITH A TECHNIQUE HE CALLED RANDOMIZED CONSENT, IT LOOKS LIKE THIS, YOU DECIDE A PATIENT IS ELIGIBLE AND THE FIRST THING YOU DO IS RANDOMIZE. IF THEY GO TO THE EXPERIMENTAL THERAPY, YOU SEEK THEIR CONSENT. AND IF THEY GIVE IT, THEY WILL GET THE EXPERIMENTAL THERAPY. IF THEY'VE RANDOMIZED TO THE CONTROL ARM, YOU DON'T SEEK THEIR CONSENT, YOU SIMPLY GIVE THEM THE CONTROL THERAPY. SO THAT WAS THE STRATEGY THAT WAS USED IN THIS STUDY. SO THE IDEA HERE BEING THAT SO, YOU KNOW, CHILDREN'S HOSPITAL WE DON'T HAVE ANY DELIVERIES, SO THE BABIES ARE ALL BORNE OUT OF THE HOSPITAL AND WHEN THEY'RE ON THE WAY INTO THE HOSPITAL IN THE AMBULANCE AND WE SUSPECT THAT THEY'RE GOING TO NEED ECMO, THE ENVELOPE GETS OPENED AND WE SEE, YOU KNOW, DO YOU RANDOMIZE TO ECMO OR CONVENTIONAL? IF YOU RANDOMIZE TO CONVENTIONAL, YOU GO STRAIGHT TO THE SEVENTH FLOOR AND YOU GET EXACTLY THE SAME TREATMENT THAT YOU WOULD HAVE GOTTEN IF WE HADN'T DONE A STUDY. EXACTLY THE SAME TREATMENT. AM IF IT SAYS ECMO, YOU GO TO THE FIFTH FLOOR AND SOMEBODY COMES UP TO YOU AND SAYS WILL YOU ACCEPT ECMO, AND IF YOU SAY YES YOU GET IT, IF YOU SAY NO, YOU'LL GET CONVENTIONAL THERAPY. NOW, FOR THOSE OF YOU WHO ARE DONE SOME STAT STIKSZ, YOU KNOW THAT IN A DESIGN LIKE THIS IT'S IMPORTANT TO ANALYZE THE DATA USING AN INTENTION TO TREAT ANALYSIS, SO THAT MEANS THAT EVEN BABIES WHO REFUSE THE EXPERIMENTAL TREATMENT WILL BE TREATED IN THE ANALYSIS AS IF THEY HAD GOTTEN ECMO, THAT'S THE INTENTION TO TREAT ANALYSIS. THE INTERESTING THING ABOUT THIS STUDY IS THAT THERE WAS NOBODY WHO SAID NO TO ECMO. SO THINK ABOUT WHY. THERE ARE MANY REASONS. BUT ONE, JUST TO DRAW TO YOUR ATTENTION, IS THAT THIS KIND OF A STRATEGY VERY MUCH CHANGES THE NATURE OF THE INFORMED CONSENT CONVERSATION. SO NORMALLY YOU WOULD SAY WE'RE DOING THIS NEW STUDY ABOUT TREATING A CHILD -- TREATING CHILDREN THAT HAVE PPHN, WE'RE GOING TO RANDOMIZE, YOU HAVE A 50/50 CHANCE OF BEING IN EXPERIMENTAL THERAPY, DO YOU AGREE OR NOT, THAT'S THE STANDARD APPROACH. BUT I DON'T WANT TO OVERCHARACTERIZE IT HERE, BUT THIS IS A LITTLE DIFFERENT. BY THE TIME WE SPOKE TO THESE FAMILIES, AND I WAS NEVER A PART OF ONE OF THESE CONVERSATIONS, BUT IT'S A LITTLE BIT LIKE THIS IS YOUR LUCKY DAY, YOU KNOW, YOUR BABY HAS GOT A HIGHLY THREATENING LIFE-THREATENING DISEASE, WE'RE DOING THIS STUDY, WE ALREADY KNOW YOU'VE BEEN RANDOMIZED TO THE ECMO GROUP, ALL YOU NEED TO DO IS SAY YES. AND I'M SURE TWEANLT LIKE THAT, BUT -- SURE IT WASN'T LIKE THAT, I'M SURE THERE WAS A LITTLE BIT OF A BIAS THAT WAY, THERE'S NO SURPRISE THAT PERHAPS ALL 29 OF THE PATIENTS THAT WERE RANDOMIZED THIS WAY DID SAY YES TO THE THERAPY. SO THE QUESTION, IMAGINE THAT YOU WERE ON THE IRB AT BOSTON CHILDREN'S HOSPITAL WHEN THIS STUDY WAS PROPOSED. WOULD YOU HAVE APPROVED THE Z HE LEN RANDOMIZATION SCHEME? WHY OR YNLT? I WOULD LIKE TO TAKE A COUPLE MINIMUM IN HERE. FIRST OF ALL, HOW MANY OF YOU WOULD HAVE APPROVED THIS GIVEN THE WAY I'VE DESCRIBED IT? AND HOW MANY WOULD HAVE SAID NO? THERE'S A WHOLE BUNCH OF YOU THAT ARE UNDECIDED. ONE OF THE WONDERFUL THINGS ABOUT MEDICAL ETHICS IS YOU REALLY CAN'T BE UNDECIDED. AT THE END OF THE DAY YOU HAVE TO MAKE A DECISION. SO IF YOU'RE THE IRB, YOU WOULD BE VOTING. BUT I'LL LET YOU REMAIN UNDECIDED FOR THE MOMENT. COULD WE JUST GET A COUPLE OF COMMENTS FROM SOMEBODY WHO WOULD SAY THIS IS NOT CORRECT? THANK YOU FOR VOLUNTEERING. >> I'M ONE OF THE UNDECIDED, AND MY PROBLEM IS I THINK THAT AS A LAYPERSON, THE ENCOUNTER WHEN YOU'VE BEEN RANDOMIZED INTO BEING THE ECMO INFORMED CONSENT OPTION, YOU'RE ALREADY IN A TRUST RELATIONSHIP WITH A PHYSICIAN AND YOU HAVE A DEFERRAL, YOU WOULD SAY, WELL, IF THIS IS WHAT YOU RECOMMEND, DOCTOR, PLEASE PROCEED. THE OTHER, WHICH SEEMS SORT OF UNCONSCIONABLE IN A WAY BECAUSE YOU'VE SORT OF -- YOU'RE CHALLENGING THAT TRUST RELATIONSHIP, REALLY. >> >> ROBERT TRUOG: YOU MEAN IN THE CONTROL ARM. >> IN THE CONTROL ARM, BY NOT OFFERING THE THERAPY THAT WE NOW ARE, EVEN IF WE'RE CLINICALLY IN EQUIPOISE AS AN INSTITUTION, INDIVIDUALLY AS A PHYSICIAN, PERHAPS YOU'RE NOT IN EQUIPOISE, SO THERE'S A DOUBLE CONFLICT FOR ME THERE. >> >> ROBERT TRUOG: DO YOU THINK THAT ALL CONTROL PATIENTS SHOULD BE GIVEN A CHOICE OF GETTING THE EXPERIMENTAL TREATMENT? >> AGAIN, I CAN'T -- IT'S DIFFICULT FOR ME TO MAKE A DECISION SO QUICKLY ON THIS ISSUE, BUT I THINK IT DOES CHALLENGE THAT RELATIONSHIP WITH THE PHYSICIAN AND THE PATIENT, AND IN THIS CASE WE'RE NOT ACTUALLY SEEKING CONSENT FROM THE ACTUAL PATIENT, WE'RE SEEKING CONSENT FROM THEIR AUTHORIZED PERSON, THEIR PARENT, WHO IS IN A VERY DELICATE SITUATION, EMOTIONALLY WROUGHT. >> >> ROBERT TRUOG: GOOD POINT. THANK YOU VERY MUCH. YES, PLEASE. >> I HAVE MORE OF A QUESTION, WHICH IS IF THE BARTLETT STUDY HAS ALREADY BEEN DONE, WAS IT PUBLISHED, AND I MEAN, I CAN'T IMAGINE TAMMYING TO EXPLAIN THE -- I CAN'T IMAGINE ATTEMPTING TO EXPLAIN THE STATISTICS TO THE FAMILY, BUT IF THERE IS PUBLISHED DATA SHOWING THAT IT MAY ALREADY BE EFFECTIVE, IT DOESN'T SEEM ETHICAL NOT TO PRESENT THAT DATA IF YOU'RE DOING A STUDY. >> >> ROBERT TRUOG: YOU MEAN TO -- WELL, OKAY. GRANTED, NOW REMEMBER, THE BOSTON PEOPLE LOOKED AT THAT BARTLETT DATA AND SAID, OH, ONLY ONE PATIENT DIDN'T GET ECMO, WE'RE NOT CONVINCED SOMETHING ELSE NEEDED TO BE DONE. SO -- >> I KNOW EXACTLY WHAT YOU'RE SAYING, BUT WHEN I SEE THE PLAY FOR WINNER VERSUS THE WARE APPROACH, I MEAN, I'M NOT -- YOU KNOW, WHY IS ONE BETTER THAN THE OTHER? >> >> ROBERT TRUOG: BASICALLY THEY'RE THE SAME IS WHAT YOU'RE SAYING. >> IT LOOKS LIKE, YEAH. >> >> ROBERT TRUOG: OKAY. FAIR ENOUGH. OKAY. ANOTHER COMMENT ABOUT THIS? GREAT. THANK YOU. >> I JUST HAVE A MAJOR PROBLEM THAT THERE'S NOT CONSENT FOR THE CONTROL ARM BECAUSE ESSENTIALLY YOU ARE IN THE STUDY, YOU JUST DON'T KNOW YOU'RE IN THE STUDY, AND YOU DON'T KNOW THAT THERE ACTUALLY ARE THE OPTION THAT YOU COULD HAVE BEEN IN, BUT THIS DETERMINATION WAS DONE WITHOUT YOUR KNOWLEDGE, THAT'S WHAT I HAVE A PROBLEM WITH TO BEGIN WITH. >> >> ROBERT TRUOG: I'M SO GLAD YOU BROUGHT THAT UP. SO LET ME RESPOND A LITTLE BIT TO THAT. THE ONLY INFORMATION THAT WE WERE REALLY TAKING ON THOSE PATIENTS WAS INFORMATION THAT WE GOT FROM THE CHART, AND YOU CAN ROUTINELY GET A WAIVER OF IRB -- A WAIVER OF CONSENT FROM THE IRB IF ALL YOU'RE DOING IS COLLECTING ANONYMIZED DATA. SO HOW IS THIS ANY DIFFERENT? THESE BABIES WERE GETTING EXACTLY THE SAME TREATMENT THEY WOULD HAVE HAD IF THERE HAD BEEN NO STUDY AND THE ONLY THING THAT ANYBODY WAS DOING WAS LOOKING IN THEIR CHART AND RECORDING WHETHER THEY SURVIVED OR DIED OR MAYBE OTHER NUMBERS TOO, BUT THINGS THAT WE ROUTINELY DO WITHOUT GETTING THE CONSENT OF FAMILIES. ALL RIGHT. WELL, LET ME GO ON HERE. BUT MAYBE JUST ONE MORE TIME BEFORE WE DO GO ON, AFTER THIS LITTLE BIT OF A DISCUSSION, HOW ABOUT I JUST ASK YOU, YOU'RE ON THE IRB, YOU'RE GOING TO HAVE TO SAY YES/NO, HOW MANY OF YOU WOULD APPROVE THE STUDY? AND HOW MANY OF YOU WOULD NOT? I THINK IT'S REALLY PRETTY 50/50. OKAY. AM SO THE STUDY GETS PUBLISHED. I CAN REMEMBER THE MORNING THAT I CAME DOWNSTAIRS FOR BREAKFAST WITH MY AT THAT TIME YOUNG CHILDREN AND GOT THE BOSTON GLOBE AND THERE IN THE LOWER LEFT-HAND CORNER IS A STORY ABOUT THE STUDY, RICHARD KNOX WAS THE BOSTON GLOBE REPORTER, HE NOW DOES WORK FOR NPR, AND I WAS, OH, MY GOODNESS, I WAS A FELLOW, I WAS KIND OF PROUD OF THE STUDY, APPARENTLY SOMEBODY ELSE READ IT AND CLIPPED IT OUT AND SENT IT IN TO THE NIH. THIS WAS BEFORE WE SENT THINGS BY INTERNET, WE ACTUALLY USED THE MAIL. SO THEY SENT IT TO THE OFFICE OF PROTECTION FOR RESEARCH SUBJECTS HERE AT THE NIH AND THEY WENT, WOW, THEY DID A STUDY WITHOUT INFORMED CONSENT? SO THEY ASKED THE CHILDREN'S HOSPITAL IRB TO EXPLAIN WHY. SO THESE WERE THE THREE EXPLANATIONS THAT WERE GIVEN. THE FIRST WAS THE ARGUMENT THAT THE CONTROL PATIENTS WERE NOT REALLY RESEARCH SUBJECTS, IN THE WAY THAT I JUST TRIED TO DEFEND. THEY GOT EXACTLY THE SAME TREATMENT THAT THEY WOULD HAVE GOTTEN IF THERE HAD BEEN NO STUDY, WE WERE ONLY CLEKING DATA FROM THE CHART, THEY WERE NOT RESEARCH SUBJECTS. SECONDLY THE PARENTS OF THE CONTROL PATIENTS WERE NOT REALLY BEING OFFERED A CHOICE. SO WHY SUBJECT THEM TO STRESS? I MEAN, I CAN REMEMBER AT THE TIME, EVEN IF ONE OF THE KENNEDY CHILDREN CAME IN AT THIS TIME, THEY WERE GOING TO BE RANDOMIZED, THERE WERE GOING TO BE NO EXCEPTIONS MADE FOR ANYBODY. SO, YOU KNOW, FOR A BABY TO SAY, WELL, YOUR CHILD HAS HEY LIFE-THREATENING CONDITION, WE'RE DOING THIS STUDY, DONE THE TRADITIONAL WAY, DO YOU AGREE TO BE RANDOMIZED, THEN THE ANSWER IS I'M SORRY BUT YOU'RE NOT GOING TO GET ECMO, WHAT'S THE VALUE OF HAVING THAT CONVERSATION WITH THE FAMILY? IT'S ONLY GOING TO MAKE THEM STREMSED, RIGHT? -- STRESSED. RIGHT? THAT WAS ARGUMENT NUMBER TWO. THE THIRD IS THAT THE PRESSURE TO CROSS OVER FROM CONVENTIONAL THERAPY TO ECMO WOULD HAVE BEEN UNBEARABLE AND THE PROBLEM IS WHEN YOU DIE ON ECMO, IT'S KIND OF A LONG SLOW DEATH AND 90% OF THE WAY THROUGH THAT DYING PROCESS IF SOMEHOW THE FAMILIES WOULD PRESSURE US TO PUTTING THE CHILD ON ECMO, NUMBER ONE, IT PROBABLY WOULDN'T HAVE WORKED, AND IT WOULD HAVE JUST BEEN A MESS. THESE WERE THE THREE REASONS THAT WERE PROPOSED. YEAH, COMMENT? >> I THINK ONE OF THE BIGGEST PROBLEMS WITH THIS STUDY THAT HASN'T BEEN DISCUSSED IS THAT THERE WASN'T JUST THE DIFFERENCE BETWEEN THE IDEA OF ECMO OR CONVENTIONAL THERAPY. IT WAS THE ENTIRE SORT OF TREATMENT PARADIGM AND THE TREATMENT LOCATION AND WHO WAS PROVIDING THOSE CARE WERE VERY, AS YOU SAID INITIALLY, VERY PRO ECMO, VERY ANTI-ECMO, AND THE PEOPLE PROVIDING THOSE CARE WERE VERY DIFFERENT, THE LOCATIONS OF THOSE WERE VERY DIFFERENT. SO OBVIOUSLY THERE'S OTHER FACTORS THAT ARE CONFOUNDERS FOR THE STUDY, BUT I THINK THE FACT THAT THE PEOPLE WHO WERE GETTING CONVENTIONAL THERAPY WERE GOING TO A PLACE WHERE THEY WOULD NEVER BE OFFERED ECMO, EVEN THEY WOULDN'T BE ALLOWED IN THE STUDY BECAUSE AT THAT INSTITUTION THEY WOULDN'T, BUT THEY MAY HAVE BEEN OFFERED THE OPPORTUNITY TO PURSUE IT ELSZ WHERE THAT IT WAS MAYBE OFFERED AS A STANDARD OF CARE, IF SOMEONE SAID TO THEM, YOU KNOW, THIS IS A REALLY BAD SITUATION, 85% CHANCE OF DYING OR 60% OR WHATEVER, 40%, WHATEVER NUMBER YOU WANT TO, THERE'S THIS NEW THERAPY THAT, YOU KNOW, WHATEVER HOSPITAL DOWN THE ROAD COULD GIVE YOU, WE'RE DOING A STUDY HERE, AND YOU MAY OR MAY NOT GET IT DEPENDING ON THAT, DO YOU WANT TO PARTICIPATE, AND I THINK THAT'S THE BIGGEST PROBLEM THAT IF IT WAS NOT OFFERED ANYWHERE ELSE IN THE WORLD AND IT WAS THE FIRST TIME IT WAS BEING EWED, I THINK -- BEING USED, I THINK IT WOULD BE A MORE ETHICAL THING, BUT WHEN YOU HAVE OTHER DATA PARTICULARLY PRIOR RANDOMIZED DATA WHETHER WE BELIEVE OR NOT, I THINK THAT'S THE BIGGEST ETHICAL DILEMMA HERE. >> >> ROBERT TRUOG: YOU RAISED ALE NUMBER OF ETHICAL POINTS. I ADMITTED A IMPORTANT DETAIL IN MY DISCUSSION. AT THIS TIME THE NEAREST ECMO CENTER WAS AT PHILADELPHIA, CHILDREN'S HOSPITAL OF PHILADELPHIA, AND THERE WAS GENERAL AGREEMENT THAT THESE CHILDREN NEVER WOULD HAVE SURVIVED A TRANSPORT TO THAT HOSPITAL. SO I MEAN, I THINK YOUR POINT WOULD HAVE BEEN ABSOLUTELY DETERMINATIVE IF MASS GENERAL TEN MINUTES AWAY HAD BEEN OFFERING ECMO AND IF YOU WEREN'T IN THE STUDY, YOU COULD HAVE GOTTEN IT AT MASS GENERAL, I THINK THAT WOULD HAVE BEEN HANDS DOWN A SOLID REASON WHY EVERYBODY HAD TO KNOW ABOUT IT. BUT THAT WAS THOUGHT NOT TO BE THE CASE BECAUSE AN ALTERNATIVE CENTER WAS THOUGHT NOT TO BE A POSSIBILITY. SO THANK YOU FOR LETTING ME CLARIFY THAT. OKAY. SO THIS INFORMATION GOES TBOOK THE N -- GOES BACK TO THE NIH, THEY DIDN'T BUY IT, THEY REPRESENT MANNED THE HOSPITAL, WHICH AS YOU KNOW IS A PRETTY SERIOUS THING, CHARLES McCARTHY, DIRECTOR OF OPRR AT THE TIME THE HOSPITAL IRB MADE DECISIONS THAT RIGHTFULLY BELONGED TO THE PARENT, THEY REALLY BLEW IT, GEORGE ANNIS, WELL-KNOWN ATTORNEY AT BOSTON UNIVERSITY, THE DOCTORS WERE DOING EXACTLY WHAT PHYSICIANS DID BEFORE WE HAD A DOCTRINE OF INFORMED CONSENT, MAKING DECISIONS FOR PARENTS. NOW, ACTUALLY, I THINK BOTH OF THESE KIND OF MIPS THE -- MICHES THE POINT. -- MIPS THE POINT. I DON'T THINK THAT THE STUDY INVOLVED MAKING DECISIONS FOR THE PARENTS. IN A SENSE RGS THE PARENTS REALLY DIDN'T HAVE ANY DECISIONAL AUTHORITY, EITHER WAY IT WOULD HAVE COME N AT MOST THEY COULD HAVE DONE IS SAY WE DON'T WANT TO BE A PART OF THE STUDY, IN WHICH CASE THEY WOULD HAVE GOTTEN CONVENTIONAL THERAPY AND THE ONLY DIFFERENCE WOULD HAVE BEEN THAT THE DATA FROM THE CHART WOULDN'T HAVE BEEN USED, SO I'M SURE THIS IS IT, BUT I'VE THOUGHT ABOUT THIS FOR MANY YEARS, AND I DO THINK IT'S A GOOD ARGUMENT TO BE MADE FOR DOING THE STATEMENT RANDOMIZATION, BUT THERE JUST SEEMED TO BE A CERTAIN LACK OF TRANSPARENCY HERE AND I OFTEN WONDER IN READING THAT ARTICLE IN THE BOSTON GLOBE WHAT IF SOME COUPLE HAD SAID GOD, YOU KNOW, OUR BABY WAS IN THE HOSPITAL WHEN THEY WERE DOING THAT STUDY AND WE WERE ON THE 7TH FLOOR AND HAD PPHN AND OUR BABY DIDN'T SURVIVE, I WONDER IF WE WERE IN THAT STUDY. I THINK THAT WOULD JUST BE A HORRIBLE THING TO HAVE THEM GO BACK AND FIND OUT THAT THEY WERE PART OF A STUDY AND THEIR CHILD DIED AND JUST A LACK OF TRANSPARENCY ABOUT IT. SO WE CAN GO BACK AND FORTH A LOT, BUT THERE IS AN ELEMENT I THINK OF SORT OF FUNDAMENTAL RESPECT FOR PERSONS THAT MAKES ME FEEL THIS PROBABLY WASN'T AN APPROPRIATE THING TO DO. IN CLOSING, LET'S TOUCH ON THIS LAST POINT HERE, ARE RCT'S THE ONLY WAY TO LEARN. SO, YOU KNOW, WE ALL LEARN THAT THERE IS A LOT OF DIFFERENT STUDIES THAT CAN BE DONE. THIS CAME UP IN ONE OF THE NICE COMMENTS EARLIER ON. YOU DON'T HAVE TO DO AN RCT. YOU CAN DO CASE SERIES WITH HISTORICAL CONTROLS, CASE CONTROL OBSERVATIONAL STUDIES. THE POINT IS THAT ALL OF THESE ARE VALID IN CERTAIN SITUATIONS, THEY JUST HAVE VARYING LEVELS OF CONFIDENCE. YOU KNOW, THERE'S NO SUCH THING AS A FACT IN MEDICINE. ALL OF OUR INFORMATION IS CONTINGENT AND COMES WITH VARYING DEGREES OF CONFIDENCE. BUT I WOULD SAY THAT FOR A NUMBER OF REASONS, RANDOMIZED CONTROL TRIALS HAVE BEEN SOMEWHAT IDOLIZED AS BEING THE STANDARD AND WE DON'T KNOW ANYTHING UNTIL THE RCT HAS BEEN DONE. PEOPLE HAVE TALKED ABOUT THIS, THE BRILLIANT SUCCESS OF THE RCT HAS NOW BECOME A FORM OF INTELLECTUAL TYRANNY, WE SHOULD NOT PROCEED THAT IN THE ASSUMPTION THAT WHERE THERE IS NO RANDOMIZATION, THERE IS NO TRUTH, AND INDEED STUDIES LIKE THIS CAN ARE TELLING, WE FOUND LITTLE EVIDENCE THAT ESTIMATES OF TREATMENT EFFECTS IN OBSERVATIONAL STUDIES REPORTED AFTER 19LY 4 ARE EITHER CONSISTENTLY LARGER THAN OR QUALITATIVELY DIFFERENT FROM THOSE OBTAINED IN RANDOMIZED, CONTROLLED TRIALS. SO AS OBSERVATIONAL STUDIES HAVE GOTTEN BETTER ACCIDENT THE QUAWLTD OF THAT INFORMATION HAS GOTTEN BETTER. NOW, FURTHERMORE, IF WE GO BACK AND LOOK AT DATA PUBLISHED IN 1988, THERE WAS AN ECMO DATABASE OF 7 NEWBORNS MOSTLY -- OF 715 NEWBORNS MOSTLY AT BOB BARTLETT'S CAN HOSPITAL THAT HAD BEEN TREATED WITH ECMO, NO CONTROLS, JUST ECMO PATIENTS, THEY HAD AN 81% SURVIVAL AND IF YOU DO THE MATH YOU WOULD SAY THAT ECMO WAS STATISTICALLY SUPERIOR THAN TO ANY OTHER TREATMENT WITH A SURVIVAL RATE OF LESS THAN 78.4% AND MANY PEOPLE HAVE POINTED OUT, INCLUDING REFLECTING SOME OF YOUR COMMENTS, THAT IF YOU LOOK AT HOW SICK THESE BABIES WERE, NOBODY COULD PLAUSIBLY SAY THAT THEY WOULD HAVE HAD ANYTHING CLOSE TO A 78% SURVIVAL IN THE ABSENCE OF ECMO. SO IT SHOULD HAVE BEEN OBVIOUS TO ANYONE THAT THIS WAS TRUE. NOW, I DON'T THINK THESE DATA WERE ACTUALLY PUBLISHED AT THE TIME THESE TRIALS WERE DESIGNED, BUT AT LEAST SOME OF THEM WERE PROBABLY AVAILABLE TO THE INVESTIGATORS, BUT WE TYPICALLY DON'T ACCEPT JUST DATABASE DATA WITHOUT ANY CONTROLS. WE NORMALLY DON'T THINK THAT THAT'S ACCEPTABLE. LET ME JUST PAUSE HERE. IS THERE ANYBODY IN THE ROOM WHO AT THIS POINT WITH ALL THAT YOU'VE SEEN WOULD SAY THAT YOU STILL HAVE SIGNIFICANT DOUBT ABOUT THE EFFICACY OF ECMO FOR PPHN IN NEWBORNS? I'M NOT SEEING ANY HANDS UP. SO IN CLOSING HERE, GIVEN ALL YOU'VE SEEN, ARE YOU NOW CONVINCED THAT ECMO IS SUPERIOR, YOUR ANSWER WAS YES, SO A FEW YEARS LATER IN THE MIDDLE '90S THEY'RE LOOKING AT WHETHER TO ADOPT ECMO IN THE UNITED KINGDOM, THEY LOOKED AT ALL THE SAME DATA THAT YOU'VE SEEN, AND THEY WERE NOT CONVINCED. THEY SAID THE EXISTING RCT'S SUGGESTED REDUCTIONS IN MORTALITY BUT WERE NOT CONCLUSIVE, AND WHY, BECAUSE THEY USED ATAPTIVE DESIGNS, WHICH MAY HAVE INTRODUCED BIAS. SO THEY SAID WE'RE GOING TO DO IT RIGHT. WE'RE GOING TO DO THE REAL RCT AND PUT THIS ISSUE TO REST ONCE AND FOR ALL. SO THEY ENROLLED 185 NEONATAL STRAIGHT UP RANDOMIZED TO ECMO VERSUS CONVENTIONAL THERAPY, TRIAL STOPPED EARLY BY THE DATA SAFETY MONITORING BOARD WITH ALE 65% SURVIVAL IN THE ECMO GROUP, 41% SURVIVAL IN THE CONVENTIONAL GROUP, AND, YOU KNOW, YOU ARE MIGHT SAY, WELL, THAT NUMBER IS KIND OF SMALL, BUT REMEMBER THAT THESE WERE ALL ECMO CENTERS THAT HAD NO EXPERIENCE DOING ECMO, SO THEY WERE ALL LEARNING HOW TO DO ECMO AT THE SAME TIME THAT THIS STUDY WAS GOING ON, NEVERTHELESS, IT STALE CAME OUT SIGNIFICANT -- IT STILL CAME OUT SIGNIFICANTLY BETTER. NOW, THIS WAS SORT OF TRIUMPHANTLY PUBLISHED AS WELL, OKAY, WE FINALLY DID IT RIGHT, BUT BIOETHICIST JOHN LANTOS ASKED THE QUESTION IN A POINTED LETTER TO THE EDITOR WHY WAS THIS STUDY DONE AT ALL? AND WERE 22 BABIES WHO WOULD HAVE STATISTICALLY SURVIVED WITHOUT THIS STUDY, WERE THEY SACRIFICED IN ORDER JUST TO SERVE THE GOD OF THE RCT AND SAY THAT WE FINALLY HAVE DONE THE GOOD STUDY? THE INVESTIGATORS DISAGREED AND EVERYTHING ELSE, AND I THINK IN OUR CUNLT CLIMATE WHERE RC -- IN OUR CURRENT CLIMATE WHERE RCT'S ARE HELD UP ARMS ABSOLUTELY THE WAY TO GET NEW INFORMATION, YOU COULD UNDERSTAND WHY THEY DID THE TRIAL, BUT IT DOES LEAVE QUESTIONS IN ANY MIND AS TO WHETHER THIS WAS SOMETHING THAT SHOULD HAVE BEEN DONE. SO IN CONCLUSION HERE, I CERTAINLY DON'T WANT YOU TO LEAVE HERE SAYING THAT I'M OPPOSED TO RCT'S, BECAUSE I'M NOT. I WANT TO EMPHATICALLY SAY THEY'RE USUALLY AM THE BESES APPROACH FOR EE -- BEST APPROACH FOR EVALUATING NEWLY THERAPIES, BUT THE CONFLICT BETWEEN CLINICIAN AND INVESTIGATOR IS PROFOUND, GOES ALL THE WAY TO THE BONE, AND CAN NEVER BE ENTIRELY ELIMINATED. IF EMERGING AS A POWERFUL NEW TECHNIQUE. ZELEN RAFN DOMMIZATION DOES REDUCE THE PSYCHOLOGICAL BURDENS OF THE INVESTIGATORS BUT IS PROBABLY UNACCEPTABLE. I WOULD HATE FOR ANY OF YOU TO PUT YOUR FUTURE CAREERS INTO A TRIAL THAT THE NIH HAS STRONGLY CRITICIZED. SO AGAIN RG THE LATE BENJAMIN FRIEDMAN WO GAVE US THE CONCEPT OF CLINICAL EQUIPOISE HAS WRITTEN THAT THE USES OF STATISTICS IN MEDICAL RESEARCH HAS BEEN COMPARED TO A RELIGION, IT HAS ITS HIGH PRIESTS, THE STATISTICIAN, SUM CAN'TS, JOURNAL -- S YOU PPLICANTS, JOURNAL EDITORS AND RESEARCHERS, AND/OR THOUGH DOCKS EXI, FOR EXAMPLE, THAT P LESS THAN .05 IS SIGNIFICANT. ALSO ONE OF THE ORTHO DOCKS EXIS -- ORTH - - AND HE WOULD ADMONISH US TO RESIST THOSE ORTHODOXIES OR THOSE WHO WOULD TELL US TO NEVER EVER THINK OUTSIDE THE BOX. I THINK WE'RE ALREADY PROBABLY OVER, ARE WE? >> WE ARE, BUT IF THERE'S A BURNING QUESTION OR TWORKS WE'LL TAKE IT. DO WE HAVE QUESTIONS FOR BOB OR COMMENTS? >> WHEN THEY DID WHEN -- WHEN THEY DW THE PHASE II AND OFFERED THE ECMO DID THEY SWITCH TO THE OTHER UNIT? >> >> ROBERT TRUOG: THEY ALL CAME TO THE UNIT WHO DID THE ECMO. >> SO THERE WAS NO TRAINING OF THE STAFF? >> >> ROBERT TRUOG: NO, TO THIS DAY ALL THE YEARS LATER ALL THE BABIES WHO NEED ECMO STILL COME TO THAT SAME ICU. YEAH. >> I WAS THINKING ABOUT WHAT YOU WERE SAYING ABOUT CHOICES AND THE FACT THAT THE CONTROL PARENTS KIND OF DIDN'T HAVE ANY CHOICES AND THAT WAS PART OF THE JUSTIFICATION. I WAS ORIGINALLY LIKE MORE FOR THE ZELEN RANDOMIZATION BUT AS I WAS THINKING ABOUT THOSE CHOICES, I WAS WON DOARG LIKE ISN'T THE CHOICE TO -- I WAS WONDERING LIKE ISN'T THE CHOICE TO REMOVE YOUR INFORMATION FROM THAT TRIAL STILL A CHOICE, AS A PROVOST PROTEST CHOICE? ISN'T WE INFORM THE VIEW CON SEN AS KIND OF LIKE THE LAST PROTECTION, THE KIND OF FINAL BARRIER TO MAKE SURE THAT, YOU KNOW, THE PEOPLE WHO ARE ACTUALLY INVOLVED IN THIS TRIAL AGREE THAT IT'S ETHICAL. SO ISN'T THAT REMOVING THAT PROTECTION AND THAT CHOICE TO SAY NO I THINK THIS TRIAL IS NOT ETHICAL, I DON'T WANT TO BE INVOLVED, I DON'T WANT TO BE ANYWHERE NEAR IT, EVEN IF THAT STILL MEANS I'M NOT GETTING THE GOOD TREATMENT? >> >> ROBERT TRUOG: I THINK THAT'S A COMPELLING ARGUMENT. MY ONLY RESPONSE WOULD BE IS THAT IRB'S ROUTINELY ALLOW US TO LOOK INTO CHARTS IN THIS WAY WITHOUT PATIENTS OR FAMILIES KNOWING. BUT I'M PERSUADED BY YOUR POINT AS WELL. SO THANK YOU. >> ANY OTHERS? JOIN ME IN THANKING BOB SCOTT KIM FROM OUR DEPARTMENT OF BIOETHICS, WHO YOU MET LAST WEEK, WILL TALK ABOUT THE PRAGMATICS OF TRIALS. INTERESTINGLY, THIS FOLLOW ON THE TWO LECTURES IN WAYS THAT ARE IMPORTANT. MOST PRAGMATIC TRIALS ARE IN FACT RCTs SO THEY RAISE SOME OF THE SAME QUESTIONS OTHER RCTs RAISE. SO SCOTT WILL GIVE YOU BOTH THE LAY OF THE LAND AND LOTS OF EXAMPLES AS WELL. SO THANK YOU FOR COMING BACK AND YOUR ATTENTION. >> GREAT. CAN YOU HEAR ME? CAN YOU HEAR ME AND I STEP OVER HERE TOO? GREAT. I KNOW PEOPLE ARE STILL WALKING IN THIS IS MY THIRD YEAR AND THOUGH AT ONE LEVEL IT SEEMS LIKE A SIMPLE TOPIC AND THEY'RE COMMONLY PERCEIVED AS LOW RISK AND THEY RAISE COMPLICATED ETHICAL ISSUES. INSTEAD OF MY TRYING TO TELL YOU WHAT I THINK. THE BULK OF THE TIME THIS MORNING I HOPE WILL BE WALKING THROUGH EXAMPLES OF STUDIES THAT WE CAN PERHAPS THINK THROUGH TOGETHER OR AT LEAST HEAR YOUR COMMENTS AND THOUGHTS ABOUT THEM. I'LL START BY TALKING ABOUT WHAT PRAGMATIC TRIALS ARE. MOST MAY KNOW BUT WE'LL GET EVERYBODY ON THE SAME PAGE THEN I'LL DESCRIBE WHAT I WOULD CALL THE CENTRAL ETHICAL TENSION AT ANALYZING THE TRIALS. THE FIRST TWO PARTS WILL END WITH A BRIEF FRAMEWORK IN ING THE ETHICS OF THE TRIALS. SO PRAGMATIC RANDOMIZED TRIALS ARE IMPORTANT. THEY ATTEMPT TO MEASURE WHAT PEOPLE CALL IN THE REAL WORLD SETTING TO ATTEMPT THE EFFECTIVENESS OF AN INTERVENTION THAT COULD BE CLINICAL OR POLICY OR WHATEVER. IS THE IDEA IF WE DO A WELL SELECTED GROUP OF PEOPLE EF EFFICACY TRIAL WE MAY QUESTION WHETHER IT WILL WORK IN THE REAL WORLD. THAT'S WHY ISSUES OF PRACTICE AND POLICY DECISIONS COME INTO PLAY. SO THESE TRIALS, NOW EVEN HAVE TOOLS TO TELL YOU THE DEGREE TO WHICH YOUR TRIAL CAN BE CALLED PRAGMATIC. A TOOL DEVELOPED BY PEOPLE IN CANADA LOOKS AT THE RECRUITMENT OF SUBJECTS, INTERVENTIONS THAT ARE USED. THERE'S FLEXIBLE INTERVENTIONS AND THE OUTCOMES THAT ARE CLINICALLY RELEVANT AND MEASURED IN THE REAL WORLD WAY INSTEAD OF DOING EXTENSIVE MEASUREMENT AT THE END. IT INVOLVES RESEARCH PROCEDURES THAT MIMIC THE CLINICAL OPERATIONS OF THE CLINIC OR HOSPITAL OR A HEALTH SYSTEM IN FACT. THERE'S BLURRING OF RESEARCH AND USUAL CARE. SOME PEOPLE HAVE CALLED ATTENTION TO THE FACT. THOUGH THEY ALL FALL UNDER THE RUBRIC OF PRAGMATIC AND EFFECTIVENESS TRIAL COMPARING TWO INTERVENTIONS, TWO PRACTICES OR TWO OR THREE, IT DOESN'T HAVE TO BE JUST TWO. IT COULD BE INDIVIDUAL RANDOMIZED TRIAL WITH CONSENT OBTAINED PRIOR TO RANDOMIZATION IF CONSENT IS REQUIRED OR HAVE CLUSTER RANDOMIZED TRIALS WHERE THERE'S TYPES OF CLUSTERS. INDIVIDUAL CLUSTER AND GROUPED. PROFESSIONAL CLUSTERS IS IF THE POINT OF INTERVENTION IS STAFFING DECISIONS ON IN AN ICU. THERE'S NO WAY TO DELIVER THAT BY AN INDIVIDUALIZED WAY AND THAT'S BY PROFESSIONAL RULE AND CERTAIN INTERVENTIONS YOU CAN ONLY DO BY CLUSTERS LIKE A HOSPITAL ADOPTING POLICY THAT'S HOSPITAL WIDE. THERE'S A GROUP OF RANDOMIZED DESIGNED THAT FALL UNDER THE RUBRIC OF POST-RANDOMIZATION CONSENT DESIGNS. WHAT THAT MEANS IS INSTEAD OF FIRST SELECTING PEOPLE GETTING CONSENT AND THEN RANDOMIZING AND YOU HEARD ABOUT THE KIND OF TRIAL BRIEFLY. I UNDERSTAND THERE WERE SOME TECHNICAL DIFFICULTIES EARLIER BUT THAT'S WHAT THIS IS TALKING ABOUT WHERE YOU FIRST IDENTIFY THE FOCUS, RANDOMIZE AND OBTAIN REAL-TIME CONSENT. THE GROUP IN WHICH YOU DO THE ACTUAL INTERVENTION. THERE ARE MANY VARIATIONS IN WHICH THIS CAN OCCUR. FOR EXAMPLE, THERE MAY BE BROAD CONSENT AT THE VERY BEGINNING THAT WARNS THEM OF THIS HAPPENING. SO IN SOME SENSE THE CONTROL ARM THAT IS NOT APPROACHED FOR EXPLICIT CONSENT HAVE GIVEN BROAD CONSENT AHEAD OF TIME FOR WHAT TURNS OUT TO BE SERVING AS A PROSPECTIVE OBSERVATIONAL COHORT. THERE'S MANY VARIATIONS I WON'T GO INTO. IT'S A TOPIC ONTO ITSELF BUT THERE'S LOTS OF ATTRACTIVE FEATURES ABOUT THE DESIGN AND IT'S BECOMING QUITE A FOCUS. THESE CAN BE DRUGS, PROCEDURES OR POLICIES AND THERE'S ACCEPTED PRACTICES. THIS IS REALLY IMPORTANT TO DO BECAUSE FOR EXAMPLE, B CAN BE A NEW DRUG AND 100 TIMES MORE EXPENSIVE. PEOPLE MAY QUESTION IS IT THAT MUCH BETTER OR BETTER AT YOU WILL? IT COULD BE COMPARED TO A PLACEBO AND B DATA COULD SUGGEST IT'S SOMEWHAT BETTER. YOU HAVE TO DECIDE WHETHER THAT'S ACTUALLY TRUE OR THERE MAY BE SITUATIONS WHERE YOU HAVE MUCH MORE RIGOROUS CLINICAL TRIALS DATA FOR B BUT THE COMPANY THAT SELLS A WHICH IS VERY LIKE B IS BETTER AT MARKETING. SO IT JUST DOMINATES THE MARKET. YOU CREATE THE SITUATION WHERE DOCTORS ARE FORCED TO USE A DRUG THAT KIND OF HAS PIGGYBACKED ON THE SUCCESS OF ANOTHER DRUG THAT'S NOT AS MARKETED AS WELL. WE SEE THIS HAPPENS. OR YOU COULD HAVE A AND B THAT ARE COMMONLY USED PROCEDURES. PROCEDURES ARE NOT REGULATED UNLESS IT INVOLVES A MEDICAL DEVICE OR SOMETHING LIKE THAT. THIS COMMONLY HAPPENS. YOU DON'T KNOW WHICH PROCEDURE TO USE WHICH IS BETTER OR A AND B COULD BE TWO HEALTH SYSTEM POLICIES OR PRACTICES. OR OPTION B HAS EVOLVED BASED ON AN OLD STUDY. MAYBE NOT EVEN A RANDOMIZED CONTROL TRIAL AND THERE'S EARTH OPTION A LESS OFTEN USED AND PEOPLE FEEL IT'S JUST AS GOOD. THERE'S A NEED TO TEST IT HEAD-TO-HEAD. THESE SITUATIONS COVER FOR WHICH WE NEED MORE ACTUAL SCIENTIFIC DATA THAN OTHER TRIALS WE CONDUCT. WHAT'S THE RESEARCH RISK TO THE SUBJECTS? THERE'S RESEARCH SPECIFIC PROCEDURES THAT ARE NOT ABSOLUTELY NECESSARY. WHAT IS NECESSARY FOR A CONTROLLED TRIAL IS RANDOMIZATION. YOU CAN HAVE SOME TRIALS WHERE THE ONLY REAL TECHNICAL RESEARCH COMPONENT IS RANDOMIZATION. EVERYTHING COULD BE PART OF REGULAR PRACTICE. THE ONLY RESEARCH RISK WOULD BE IF ANY FROM THE POTENTIAL DIFFERENCE OF THE TWO ARMS YOU WOULD BE PUT INTO. ON THE OTHER HAND, THEY'RE BOTH ACCEPTED PRACTICES, RIGHT? SO PEOPLE ASK WHAT'S THE PROBLEM. IT SEEMS LIKE FROM THE START THE PREMISES ARE SUCH WE SHOULDN'T GET TOO WORKED UP OR OVER ABOUT THE ETHICS OF THE TRIALS BECAUSE IT'S FORTUNATELY A SITUATION WHERE WE DON'T NEED TO WORRY GIVEN THE FEATURES I JUST WENT OVER. HERE'S THE PROBLEM. EVEN THOUGH IT SEEMS THERE'S NOT A LOT OF RISK BUT OVERSEEING THE TRIALS IS STILL THE SAME IRB AND REGULATIONS. PEOPLE ARE CONCERNED ABOUT THIS. YOU MAY HAVE HEARD THE CONCEPT IN WHICH PEOPLE TRY TO INTEGRATE AN ENTIRE SYSTEM WITH THESE KINDS OF TRIALS AND STUDIES. YOU MAY HAVE STUDIES IN WHICH PEOPLE ATTEMPT TO DO THE TRIALS WE HAVE. IF YOU HAVE TO GET ADDITIONAL INFORMED CONSENT THAT TAKES TIME WITH EVERY PATIENT THAT COMES INTO A PRIMARY CARE CLINIC IT IS NOT REALISTIC TO HAVE SUCH A SYSTEM. THERE'S THIS CONSIDERABLE CONCERN THAT GIVEN THE PROMISE OF THESE TRIALS BUT THE CURRENT REGULATORY APPARATUS, HOW DO THEY MEET. OKAY. NOW, ONE SCHOOL OF THOUGHT SAYS THE FOLLOWING. THESE ARE ETHICALLY SPECIAL. THEY'RE NOT REALLY DIFFERENT FROM USUAL CLINICAL PRACTICE THEREFORE WE NEED TO RELAX THE OVERSIGHT RULES. I'LL GIVE EXAMPLES OF WHAT THAT MEANS. THERE'S ANOTHER GROUP OF PEOPLE THAT THINK, WELL, YES. OVERALL IT IS TRUE THESE ARE SOMEWHAT SPECIAL TRIALS. BUT THESE SPECIAL FEATURES MAKE THE ETHICAL ANALYSIS DIFFICULT AND YOU REALLY HAVE TO DO A CASE BY CASE ANALYSIS NOT JUST GROUP THEM ALTOGETHER. I HAVE TO CONFESS THIS IS FAIR WARNING -- I FALL INTO THAT CAMP. SO WHAT ARE PEOPLE SAYING ABOUT RELAXING SOME OF THE REGULATORY PRINCIPLES. FOR SOME PRAGMATIC RCPs, PEOPLE ARGUE YOU DON'T NEED INFORMED CONSENT. ONE ARTICLE SAYS THEY MAY NOT ONLY BE ETHICALLY NECESSARY BUT YOU CAN'T CHANGE THE RESEARCH. YOU NEED TO BROADEN SITUATIONS IN WHICH CONSENT COULD BE WAVED. SO THIS IS A VERY COMMONLY ESPOUSED VIEW IN THE LITERATURE. THE BASIS UPON WHICH THIS IS DONE AND THERE'S SOME QUOTES SO YOU SEE THE REASONING USED BEHIND THIS. I'LL READ THROUGH THIS. THIS IS REFERRING TO THE SUPPORT TRIAL YOU MAY HAVE HEARD OF. IT WAS AN NICU TRIAL BUT A COMPARATIVE EFFECTIVENESS TRIAL. THIS IS WHAT ONE OF THE COMMENTATORS SAYS. SINCE ALL THE STUDY PARTICIPANTS WOULD RECEIVE TREATMENT WITHIN THE PREVAILING STANDARD OF CARE THERE WAS NO ADDITIONAL RISK TO BEING ENROLLED IN THE TRIAL. THEY FURTHER SAY THERE'S NO BASIS FOR CLAIMING RISK VERSUS RECEIVING STANDARD CARE. THESE ARE THE EDITORS OF THE NEW ENGLAND JOURNAL WHO SAY THE SAME THING. IRBs NEED TO DETERMINE WHETHER EQUIPOISE EXITS. HEARD ABOUT EQUIPOISE TODAY, RIGHT? THEY'RE SAYING IF THERE'S EQUIPOISE THERE'S NO INCREASED RISK. AND OTHER ARTICLES EXPLICITLY MAKE LINKS OF EQUIPOISE THEREFORE THERE'S NO INCREASED RESEARCH RISK. SO THAT'S THE BACKGROUND. I WANT TO SEE IF THERE'S ANY QUESTIONS ABOUT WHAT I'VE SAID SO FAR. I DON'T KNOW HOW YOU PRONOUNCE THE NAME OF THIS TRIAL. MIGHT BE CALLED MI3 OR SOMETHING. THIS IS BE AN INTERESTING TRIAL. DOES ELIMINATING THE MEDICATION IMPROVE OUTCOME FOR PEOPLE WITH CARDIAC ILLNESS. PEOPLE WITH RECENT MYO CARDIAL INFARCTION PART OF THIS VAST INSURANCE NETWORK RANDOMIZED PEOPLE BY CLUSTERS ACCORDING TO WHO THE SPONSOR OF THE INSURANCE IS. . IT COULD BE NIH, SUBURBAN HOSPITAL, IDM. THEY RANDOMIZE HEAD TO GROUPS THAT RECEIVED NO COVERAGE AND THOSE WHO GOT WHAT THEY SIGNED UP FOR ALREADY CO-PAYMENTS. THAT WAS THE RANDOMIZED TRIAL. PRIMARY OUTCOME WAS COMPOSITE OF RIYADH MISSION FOR CARDIAC EVENTS AND RIVAS REVASCULARIZATION. IS IT RISKY OR NOT RISKY? YOU'RE NOT CHANGING YOUR MEDICAL CARE. HOW MANY PEOPLE THINK YOU NEED TO GET INFORMED CONSENT FROM THE INDIVIDUALS ENROLLED IN THIS? MAYBE A THIRD. HOW MANY THINK DEFINITELY NO, YOU DON'T NEED INFORMED CONSENT? THAT THE A MINORITY. OKAY. THEY GOT CONSENT BECAUSE ALL PATIENTS GOT THEIR USUAL LEVEL AND NO UNUSUAL CONSENT WAS SOUGHT. THIS IS INTERESTING. THEY GAVE THE USUAL CARE RATIONALE. THIS WAS APPROVED BY THE IRB AT THE BRIGHAM. IT'S TRUE EVERYBODY RECEIVED AT LEAST THE USUAL COVERAGE HERE'S A QUESTION, DIT HAVE TO BE CLUS CLUSTER RANDOMIZATION OR COULD IT HAVE BEEN INDIVIDUAL RANDOMIZATION? YOU CAN'T REALLY DO STUDY OF ICU INTERVENTIONS IN ONE WHERE YOU'RE CONSTANTLY -- IT'S HARDER. PEOPLE INTEREST TRIED BUT IF YOU'RE UNBLIND TO STUDY YOU CAN'T ARGUE. IT'S AN INTERESTING QUESTION TO ASK. DOES THE FACT THAT THERE ARE SEVERAL CAUSAL LINKS TO THE FINAL OUTCOME MATTER? FOR INSTANCE, IT'S NOT LIKE A DOCTOR INSERTING SOMETHING INTO YOUR ARTERY AND CHECKING TO SEE WHAT HAPPENED VERSUS YOU LET PEOPLE MAKE A DECISION AND SOMEWHERE DOWN THE LINE THEY MAKE AN EFFECT. DOES IT MATTER? I DON'T KNOW. OKAY. THIS IS ANOTHER EXAMPLE. I CHOSE THIS ONE BECAUSE LAST WEEK IN THE NEW ENGLAND JOURNAL DAVID ASH FROM PEN WROTE AN EDITORIAL CRITICIZING OUR CURRENT SYSTEM OF OBTAINING INFORMED CONSENT PRECISELY FOR THE KIND OF TRIALS I'M TALKING ABOUT. YOU CAN ARGUE THE ARTICLE FALLS THERE ARE THE RUBRIC OF CRITIQUE OF THE REGULATORY SYSTEM GIVEN THE NEED FOR THESE KINDS OF TRIALS. OKAY. SO THIS IS WHAT HE IMAGINED. QRS HELD SYSTEM WANTS TO SEE IF TWO INTERVENTIONS WILL INCREASE OCCURRENCE TO COLONOSCOPIES. THERE'S A LOT OF YOUNG PEOPLE IN HERE YOU MAY NOT KNOW BUT WHEN YOU OLDER YOU HAVE TO SUBMIT YOURSELF TO THIS IN DIGNITY COLONOSCOPY AND IT'S BEEN SHOWN TO DETECT EARLIER TO DO SOMETHING ABOUT IT, COLON CANCER. THIS IS BEING PROPOSED IN THE IMAGINATION OF DAVID ASHE. AND YOUR 50th BIRTHDAY YOUR HEALTH PLAN SENDS YOU A WHIMSICAL CARD REMINDING YOU OF COLONOSCOPY SCREENING WITH SOME QUOTE, CLEANSING SUPPLIES. I'LL LET YOU FIND OUT FOR THOSE DELIGHTS WHEN YOU REACH AGE 50. A CARD WITH A DEFAULT APPOINTMENT. IT SAYS CONGRATULATIONS, YOU MADE IT TO 50. COME TO MAKE YOUR APPOINTMENT FOR YOUR COLONOSCOPY ON THIS DATE. THE IDEA IS TO CREATE A DEFAULT YOU CAN CALL AND CHANGE THE APPOINTMENT. C IS USUAL, YOU MAY GET A BORING FORM LETTER. SO YOU TURNED 50, IT'S THE PROCEDURE TO DO X, Y, Z. PLEASE CALL YOUR DOCTOR, WHATEVER. PRIMARY OUTCOME IN THIS CASE IS A SCREENING RATE WHAT'S THE RESEARCH RISK? IS INFORMED CONSENT MEDICALLY NECESSARY FOR ALL THREE ARMS? [COMMENT OFF-MIC] . >> IT'S A COMBINATION OF RESPECT FOR PERSONS AND P.R. ISSUE ALMOST. TRUST IS VERY IMPORTANT. IT IS TRUE IN ARMS A AND B THEY MAY OR MAY NOT BE TOLD ABOUT A STUDY BEING DONE BUT YOU CAN GET A SLIDE THAT SAYS YOU'VE BEEN VECTED IN A STUDY. THAT'S AN INTERESTING STUDY. I WANT YOU TO THINK ABOUT WHY THERE ISN'T THAT MUCH RISK AND WHY YOU THINK. THIS TRIAL HAS BEEN CRITICIZED BY CERTAIN PUBLIC ADVOCACY GROUPS AND IT'S ABOUT MYOCARDIAL INFARCTION PATIENTS. THEY'RE RECRUITING PEOPLE HOSPITALIZED WITH LOW BLOOD COUNTS. HEMOGLOBIN OF LESS THAN 10 AND RANDOMIZED THE TWO ARMS. YOU MUST TRANSFUSE WHEN IT FALLS BELOW 10 GRAM PER DECILITER OR PERMIT TO FIT FALLS BELOW EIGHT AND HIGHLY RECOMMENDED IF IT GETS TO SEVEN OR BELOW. >> THERE'S A MORBIDITY IN 30 DAYS. ONE PERSON BRAVELY RAISED THEIR HAND. AN EQUAL NUMBER. IT'S HARD TO SAY BECAUSE YOU'RE WONDERING, WELL, WHAT'S THE DATA. IF I TOLD YOU, YOU KNOW, THEY'VE DONE TWO TRIALS AND ONE SHOWED GREAT BENEFIT FOR HIGH AND ONE SHOWED GREAT BENEFIT FOR LOW BEING YOU MAY HAVE DIFFERENT VIEWS, CORRECT? IS THERE SIMILAR CONSENT NEEDED NOR TRIAL? YES? HOW MANY PEOPLE SAY KNOW YOU DON'T NEED IT. SUPPOSE I SAID TO YOU, YOU KNOW, PEOPLE HAVE BEEN TRYING TO ANSWER THIS QUESTION AND EVERYBODY AGREES SCIENTIFICALLY THE CURRENT DATA THOUGH THEY'VE DONE OBSERVATIONAL STUDIES. SOME PEOPLE SAY IT'S BETTER IF YOU GO LOW OR HIGH. THERE'S COMPLICATIONS OF GIVING PEOPLE BLOOD. IF I SAID THAT, HOW MANY PEOPLE SAID, MAYBE YOU CAN BYPASS INFORMED CONSENT. OKAY. INTERESTING. IN THAT CASE THE EVIDENCE-BASED DISCUSSION DOESN'T SWAY YOU ABOUT INFORMED CONSENT. THE INTUITION DIDN'T ENGAGE. ALL RIGHT. IN THIS STUDY THEY HAVE TO GET INFORMED CONSENT. AND THIS IS THE CONSENT DESCRIPTION SECTION. IT'S A LONG PARAGRAPH. BUT WHAT'S INTERESTING IS THIS ALMOST ENTIRELY RISK SECTION IS A DESCRIPTION OF THE CLINICAL RISKS OF RECEIVING BLOOD TRANSFUSION. SOME PEOPLE WHO WOULDN'T HAVE GOTTEN IT OTHERWISE EXCEPT THE FACT THEY WERE IN THE STUDY IN THAT SENSE BUT IT IS MOSTLY A CLINICAL DESCRIPTION AND THE DESCRIPTION IS THERE MAY BE DISCOMFORT FROM HAVING TRANSFUSIONS OR TRANSFUSIONS DELAYED NOT YET KNOWN. OKAY. HERE'S THE QUESTION, IS THAT A TRUE STATEMENT? YES? IT'S OBVIOUSLY A TRUE STATEMENT, RIGHT? IF THEY DIDN'T KNOW FOR SURE THEY WOULDN'T BE DOING THE STUDY. FAIR? IS THAT A GOOD DESCRIPTION OF THE RISKS INVOLVED? IN OTHER WORDS, WHEN YOU CONVEY THE RISKS OF THE PROS AND CONS OF THE INTERVENTION, IS IT THE KNOWNESS OF THE EFFECTSES OF EFFECTS THAT SHOULD BE INCLUDED IN THE RISK? I DON'T KNOW. IT'S A COMPLICATED QUESTION. I'LL TRY TO ADDRESS THAT BRIEFLY AT THE END. . HOW MANY THINK IT'S SUFFICIENT OF THE RISK IN ENTERING THE STUDY? HOW MANY THINK I THINK INTEREST SHOULD BE MORE? THIS ONE CAN CREATIVELY NAMED HEAD POST. I TRY TO PICK TRIALS THAT ARE PUBLISHED IN PROMINENT JOURNALS GIVE YOU A SENSE WE'RE NOT TALKING ABOUT A SMALL OBSCURE THINK BUT IT'S A MAJOR MOVEMENT ABOUT WHICH WE HAVE TO DO THESE ETHICAL ANALYSIS. WE ALL KNOW YOU HAVE HAD EXPERIENCES OF STANDING UP AND FEELING LIGHT HEADED. IT'S GRAVITY. IT MAKES SENSE AFTER YOU HAVE A STROKE SO IF YOU LIE FLAT YOU MAY GET GREATER PROFUSION OF THE BRAIN. SOME STUDIES SHOW THAT MAY BE THE CASE. PEOPLE MAY SHOW IT MAY INCREASE THE BLEED IN SOME PEOPLE BUT IT'S ENOUGH OF A QUESTION THEY DECIDE TO DO THE STUDY. THIS IS WHAT THEY DID. THEY RANDOMIZED BY CLUSTER, BY HOSPITAL BUT IT'S AN INDIVIDUAL INTERVENTION. SUPINE, FLAT, VERSUS LETTING PEOPLE SIT UP 30 DEGREES. PRIMARY OUTCOME, 90 DAY DISABILITY RATING. WHAT'S THE RISK OF THE STUDY? TRIVIAL? WHY DO YOU THINK IT'S TRIVIAL? >> DO YOU THINK--SORRY. THERE MAY BE MANY OTHER VARIABLES INVOLVED. WOULD THAT SUMMARIZE WHAT YOU SAID? SOME SAID IT'S REALLY LOW RISK. DO YOU WANT TO SPEAK UP? HOW MANY THINK THERE'S SIGNIFICANT RISK? AN ANDFUL. HOW MANY AREN'T SURE? THAT'S THE MAJORITY? . IS INFORMED CONSENT REQUIRED? YES? MOST PEOPLE. HOW MANY THINK INFORMED CONSENT, NO. CONSENT WINS IN THAT ONE. A PROTOCOL WAS APPROVED AT THE PARTICIPATING CENTERS. A SENIOR EXECUTIVE OFFICER AT EACH HOSPITAL ACTED AS -- THE EXACT WORD IS GUARDIAN AS PART OF THE CLUSTER RANDOMIZED CLUSTER AND PROVIDED HEAD POSITIONS TO BE IMPLEMENTED AS A LOW-RISK INTERVENTION TO CLUSTERS PATIENTS AS PART OF ROUTINE CARE. WRITTEN INFORMED CONSENT WAS FROM PATIENTS AND APPROVED SURROGATES FOR THE COLLECTION OF DATA AND FOLLOW-UP ASSESSMENT. IN OTHER WORDS, THEY DID THE INTERVENTION BASED ON A HOSPITAL HEAD SAYING THIS IS FINE FOR OUR PATIENTS. THEY RANDOMIZED. THEY WERE RANDOMIZED BY HOSPITAL AND THEN ONLY AFTERWARDS THEY GO TO THE PATIENTS INDIVIDUALLY AND ASK FOR PERMISSION TO USE THEIR DATA. OKAY. THIS IS THE RATIONALE WHY IT WAS LOW RISK. THERE'S LEVEL 1 EVIDENCE SPECIFYING THE BENEFITS FOR PATIENTS WITH ACUTE STROKE. I'LL ACCEPT THAT AS TRUE. THEY'RE THE EXPERTS. ONE WOULD THINK IF YOU MADE THAT A REQUIREMENT YOU WOULDN'T NEED TO DO THE STUDY, RIGHT? IT'S ODD REASONING AND WITHIN ROUTINE DAILY LIFE IT HAPPENS ALL THE TIME. THEY THINK THE INTERVENTION ITSELF IS BENIGN. IT'S NOT LIKE WE'RE DOING MAJOR SURGERY, BASICALLY. AND PATIENT CARE WOULD NOT BE COMPROMISED BY EITHER INTERVENTION. I THINK WHAT THEY MEAN IS THIS IS WITHIN THE STANDARD OF CARE ACROSS HOSPITAL. SO THAT WAS THE RATIONALE. I'LL MOVE TO ANOTHER ONE. WHICH IS BETTER THAN ACUTE M.I., HEPARIN OR A NEW DRUG THAT'S SUPPOSED TO BE BETTER THAN HEPARIN. WHEN PEOPLE COME IN THE EMERGENCY ROOM WITH HEART ATTACKS THEY THIN THE BLOOD TO TREAT THE PATIENT. ALL RIGHT. SO WHAT DO THEY DO? THESE ARE PEOPLE WHO CAME IN THE HOSPITAL WITH HEART ATTACKS AND RANDOMIZED ON AN INDIVIDUAL BASIS TO THE TWO INTERVENTIONS. THE TWO OUTCOMES INCLUDED MORTALITY AND HAD A PRIMARY SAFETY OUTCOME WHICH WITH WAS BLEEDING BECAUSE THIS IS A BIG ISSUE. WHEN YOU THIN THE BLOOD YOU WORRY ABOUT THAT. AND THERE'S DELAYED CONSENT IS SIMILAR TO THE PREVIOUS ONE. AND THEY USUALLY SIGN CONSENT FOR THEIR REVASCULARIZATION. PATIENTS WERE RANDOMLY ALLOCATED AND NO ATTEMPT WAS MADE TO DISCUSS THE TRAILER SEEK CONSENT. SURVIVING PATIENTS FOR APPROACHED TO FOLLOW THEIR DATA. NOW, THE REASON WHY THEY DID THIS IS REMEMBER OUR FIRST SLIDE ABOUT PRAGMATIC IMPERATIVE. IF YOU ONLY SELECT PEOPLE WHO CAN GIVE FULL CONSENT FOR THIS STUDY YOU'RE ONLY GOING TO GET PEOPLE WHO ARE ACTUALLY MIGHT HAVE NOT BEEN EFFECTED BY WHATEVER. BY DOING IT THIS WAY THEY CAPTURE EVERYBODY ANYWAY M.I. THAT WAS THE RATIONALE FOR DOING THIS. WHAT'S THE RISK LEVEL OF THE STUDY? HIGH, MEDIUM, LOW? HIGH? MEDIUM. LOW? I DON'T KNOW. IT'S ABOUT EVENLY DIVIDED AMONG THE FOUR OPTIONS. THIS IS A VERY HONEST GROUP OF I DON'T KNOWS. WHAT DUE THINK ABOUT INFORMED CONSENT AND YOU CAN SEE IT AS JUSTIFIED? MY LAST EXAMPLE IS IN THE NEONATE SITUATION. THIS WITH US DONE IN LATE 1990s. HERE'S THE QUESTION. IS SECTIONING AND INTUBATION BETTER IN THE DELIVERY TO KEEP MECONIUM ASPIRATION. MECONIUM IS WHEN BABIES HAVE A BOWEL MOVEMENT -- I'M HAVING A MENTAL BLOCK. A SENIOR MOMENT. THAT'S BAD. WHEN THEY ASPIRATE THAT IT'S NOT GOOD. AND SHOULD WE INTUBATE AND BE AGGRESSIVE OR WAIT TO SEE WHAT HAPPENS WITH THESE BABIES? THAT THE THE QUESTION. THIS IS THE PROCEDURE. IT'S NOT FDA REGULATED. IT'S A PRACTICE THAT'S DEVELOP OVER THE YEARS ACROSS THE WORLD IN THE DELIVERY ROOMS. PRIMARY OUTCOME HOW OFTEN THEY GET THE SYNDROMES. WHAT'S THE RISK OF THE STUDY? A MINIMAL RISK OR LOW-RISK STUDY. IS THIS WELL, THERE'S SIGNIFICANT RISK. OKAY. IS INFORMED CONSENT FROM THE MOM REQUIRED? I'LL GIVE YOU AN EXAMPLE. NOW, THIS IS IN THE DELIVERY ROOM. I THINK IT'S CRUEL AND UNUSUAL PUNISHMENT WHILE YOU'RE GIVING BIRTH TO ASK THEN TO SIGN THIS. YOU CAN'T DO THAT. USUALLY IF THEY DO THESE TRIALS WHAT THEY HAVE TO DO IS TO GET ALL INTO A CLINIC PRENATALLY AND TALK ABOUT IT WITH TIME AND THEN GET CONSENT. SO SHOULD THEY HAVE DONE THAT KIND OF CONSENT OR NOT? YES. MOST SAY YES. THIS WAS A NO-INFORMED CONSENT PROTOCOL. THE RATIONALE WAS INCLUDED AND THE MANAGEMENT STRATEGIES. GET THE THEME. IT'S A RECURRING THEME. THEY'RE BOTH STANDARD OF CARE SO THIS SITUATION ISN'T NOTED UNTIL MOMENTS BEFORE DELIVERY. WE CAN'T GET CONSENT AT THE TIME. INHERENT DIFFICULTIES OBTAINING CONTENT FROM A MOTHER UNDERGOING PAIN OF LABOR. WE ESTIMATED IF WE WERE TO ATTEMPT TO OBTAIN INFORMED CONTENT AT MOST WE CAN ENROLL 70%. IT'S INTERESTING. MAY VIEW IS 70% IS PRETTY DARN GOOD BUT HEY, THEY WEREN'T SATISFIED BECAUSE OF THE PRAGMATIC IMPERATIVE. THEY WANT TO BE ABLE TO GENERALIZE FROM THEIR STUDY. FROM A SCIENTIFIC POINT OF VIEW THEY WANT THE BEST DATA CLINICIANS CAN USE. pCONCEPT AND THEN YOU HAVE TO ASK, IT WORKED THERE BUT WILL IT WORK HERE? THAT'S WHY THEY DID THAT? THE POPULATION OF ENROLLED NEONATES WOULD NOT BE REPRESENTATIVE. SAME THING. LET'S GO TO THIS. WHAT DO YOU THINK ABOUT THE FACT THERE WAS NO INFORMED CONSENT FOR THIS? SO YOU KNOW, WHEN THE SUPPORT STUDY WAS DONE ALSO IN NEONATES IN THE NICU, WHERE THEY WOULD HAVE HAD MORE TIME TO OBTAIN CONSENT THEY CHOSE PRENATAL CONSENT. IT TURNED OUT THEY WERE ABLE TO ENROLL ABOUT THIS NUMBER OF ELIGIBLE PEOPLE. THE CONCERNS WERE BORN OUT IF YOU COMPARE THE OUTCOMES OF PEOPLE ENROLLED VERSUS NOT ENROLLED THE OUTCOMES WERE DIFFERENT BY THAT FACT. PEOPLE WHO WERE NOT ENROLLED DID WORSE. THE REASON, IS IT BECAUSE BEING IN RESEARCH IS BETTER FOR YOU? NO. THEY'RE CONFOUNDING FACTORS. PEOPLE WHO ARE NOT ENROLLED MAY HAVE HAD MAY HAVE BEEN MOMS WHO LIVED MORE DIFFICULT PSYCHO SOCIAL CIRCUMSTANCES. THE LUXURY OF BEING ABLE TO CONSENT GOING TO THE PRENATAL VISITS WAS LESS AND INDEED THAT'S WHAT YOU FIND OUT. THEIR CONCERN WIZ RIGHT AND IT'S BEEN WAS RIGHT AND IT'S BEEN BORN OUT. NOW I'D SAY THE MODERN IDEA HAS SHIFTED TO TRYING GET PRENATAL CONCEPT. EVEN AS HEALTH CARE TRIES TO COME UP WITH WAYS OF NOT HAVING TO FOLLOW THE FULL INFORMED CONSENT PROCEDURES BECAUSE THEY CAN GET IN THE WAY OF THE PRAGMATIC IMPERATIVE. SO I HOPE THOSE STUDIES GIVES I A FEEL FOR THE FACT THAT THERE AREN'T MANY STUDIES THAT INTUITIVELY WE THINK, WOW, REALLY, NO CONSENT? OR OH YEAH, NO CONSENT SEEMS OKAY. THEY ALL FALL UNDER THE SAME RUBRIC OF THE PRAGMATIC TRIALS. IF THERE'S ONE MESSAGE I CAN LEAVE YOU WITH AND I'LL FEEL GOOD ABOUT HAVING GIVEN THE LECTURE IF YOU WALK AWAY FROM THE TALK WITH ONE CONCLUSION WHICH IS THE FOLLOWING, YES, THERE ARE THESE STUD YES THAT NEED TO BE DONE AND IT'S REALLY IMPORTANT BUT THE FACT THEY'RE COMPARING TWO ACCEPTED OR STANDARD OF CARE OR WIDELY USED OR PEOPLE ARE SEEN AS COMPARABLE, THAT FACT BY ITSELF DOESN'T DO A WHOLE LOT OF WORK WHEN WE HAVE TO DO THE ANALYSIS OF THE ETHICS OF THESE STUDIES. ANY QUESTIONS THAT? DOES THAT MAKE SENSE? ALREADY. NOW I'M GOING TO BRIEFLY GO THROUGH HOW YOU GO THROUGH THE RESEARCH RISKS AND OTHER ISSUES -- SUPPOSE YOU'RE IN THE IRB OR A RESEARCHER HAVING TO DESIGN STUDIES AND YOU WANT TO ANTICIPATE THESE ISSUES. IF THE STUDY IS A STANDARD OF TEST TREATMENTS, BY DEFINITION IT'S IN CLINICAL EQUIPOISE. YOU HEARD A TALK ABOUT CLINICAL EQUIPOISE AND A ROUGH AND READY WAY OF THINKING ABOUT CLINICAL EQUIPOISE IS, YOU KNOW, IF THESE PATIENTS ENROLL IN THIS TRIAL THEY'RE NOT GOING TO BE KNOWINGLY THIS ADVANTAGED. THAT'S A CONCERN BEHIND CLINICAL EQUIPOISE. WHEN TWO STANDARDS OF CARE TREATMENTS REPUBLIC COMPARED, WE CAN'T HONESTLY SAYING WE'RE NOT KNOWINGLY DISADVANTAGING ONE GROUP OR ANOTHER OR ANYBODY. THAT'S FAIR. YOU STILL HAVE TO ASK WHETHER THE ECT HAS CLINICAL EQUIPOISE IS THE FACT THAT IT STILL HAS TO BE SUBSTANTIATED. STUDIES THAT LOOKED AT NON RELATED INTERVENTIONS LIKE PRACTICES, PROCEDURES IN DELIVERY ROOMS, ICUs, HOSPITALS, HOW DO YOU KNOW WHEN YOU SAY WELL, THESE ARE STANDARD PRACTICE. WHAT'S THE EVIDENCE GAVE OR THE LEVEL OF RIGOR WITH WHICH WE ACCEPT THE FACT IT'S STANDARD PRACTICE? SO ISSUE OF CLINICAL EQUIPOISE SURPRISINGLY IS STILL A LIVE ISSUE WHEN WE ASK THIS QUESTION ABOUT PCTs. NOW, I WILL SUBMIT IF YOU'RE COMPARING TWO DRUGS BOTH FDA APPROVED, WIDELIZED WIDELY USED FOR THAT INDICATION IT'S EASIER. THERE IT'S EASIER TO MAKE THE ARGUMENT THERE'S CLINICAL EQUIPOISE. PROCEDURES, PRACTICES, HARDER. LET'S ACCEPT WE LOOKED AT THE PROTOCOL AND IT'S IN CLINICAL EQUIPOISE. YOU HAVE TO ASK THE RESEARCH RESEARCH. CLINICAL EQUIPOISE MAY JUSTIFY A STUDY BUT IT DOESN'T DIRECTLY PROVIDE A SENSE OF WHAT'S AT STAKE FOR THE PARTICIPANTS. WHY? I GAVE SIX OR SEVEN EXAMPLES AND WE CAN ASSUME WHETHER THEY'RE CLINICAL EQUIPOISE. GIVEN OUR LEVEL OF EXPERTISE IN THE FIELDS WE'LL JUST TAKE THE P.I.s WORD FOR IT, THEY'RE IN EQUIPOISE. THOUGH THEY WERE ALL IN EQUIPOISE DID YOU THINK THEY WERE IN SIMILAR RISK LEVEL. CLINICAL EQUIPOISE CAN'T TELL WHAT YOU THE RESEARCH RISK IS IN THE TRIALS. NOW, EVERY PCP MUST MEET TWO CONDITIONS IF THEY'RE WORTH DOING. ONE, IT HAS TO BE UNCERTAIN THAT WE DON'T ALREADY KNOW ONE IS SUPERIOR TO THE OTHER. IF WE KNEW WE SHOULDN'T DO THE STUDY, WHY WASTE THE MONEY. IT'S NECESSARY FOR EQUIPOISE. BUT THERE'S A SECOND CONDITION IT HAS TO MEET. IT HAS TO BE UNCERTAIN THE TWO ARE EQUIVALENT. IT HAS TO BE -- YOU DON'T KNOW. YOU DON'T KNOW FOR SURE THEY ARE EQUIVALENT. IF THEY WERE KNOWN TO BE EQUIVALENT YOU WOULDN'T NEED TO DO THE TRIAL EITHER. WHY IS THE SECOND CONDITION IMPORTANT? BECAUSE IF ITS UNCERTAIN A IS EQUAL TO B, THERE'S A REAL PROSPECT THAT ONE MIGHT BE BETTER THAN THE OTHER. THAT IS THE PRECISE REASON WHY YOU DO THE TRIALS. THERE'S PRIOR EVIDENCE THAT SAYS, YOU KNOW, WE'RE TREATING THESE LIKE EQUALS MAYBE IN PRACTICE BECAUSE WE DON'T KNOW BETTER BUT THERE'S EVIDENCE THAT SUGGESTS WE SHOULD TEST IT. THAT'S WHAT CREATES THE UNCERTAINTY. THIS LEADS TO THE PROSPECT SHE COULD RECEIVE A INSTEAD. SINCE EVERY PCT HAS TO HAVE SUCH A PROSPECT BECAUSE IF IT DIDN'T HAVE THE PROSPECT IT'S NOT WORTH DOING THE STUDY. IF THAT'S THE CASE THERE'S A RISK IN EVERY PCT THIS COULD HAPPEN. I WANT TO NOTE FOR SOME INDIVIDUALS ENTERING THE STUDY, THERE'S SOME CHANCE THEY COULD FARE BETTER. THERE'S A PROSPECT OF THAT. IT SAYS IT COULD BE BETTER AND X AND T RISK IS KIENGD OF BETTER FOR THAT PERSON. NOT A KNOWN RISK. GIVEN THIS WE CAN USE THE NATURE OF THE MAIN OUTCOMES AS GAUGING THE RISK LEVEL. THAT'S WHAT YOU ALL INTUITIVELY DID TODAY WHICH IS WHEN YOU LOOKED AT THE MAIN OUTCOMES BEING MEASURED YOU THOUGHT, OOH, WOW. THERE'S CEPTIONS AND THE BASELINE AND THERE'S AN EXTRA BENIGN BASELINE. SO EVERYBODY GOT WHAT THEY WOULD HAVE GOTTEN OTHERWISE. SO THAT IS THE WAY I SUGGEST WE LOOK AT THE RESEARCH RISK. THE LAST IS THERE REASON TO WAVE OR MODIFY INFORMED CONSENT. THAT THE THE THIRD QUESTION. IN THE UNITED STATES WE HAVE A SET OF CRITERIA YOU SAY THERE'S MINIMAL RISK TO QUALIFY EVEN AS A CANDIDATE FOR WAIVER OR MODIFICATION OF THE USUAL INFORMED CONSENT PROCESS. AND IT HAS TO MEET THREE OTHER CRITERIA OR OTHER CRITERIA. RESEARCH WOULD BE IMPRACTABILITY AND IT CAN'T AFFECT THE RIGHTS OR WELFARE OF PARTICIPANTS. A CRYSTAL CLEAR STATEMENT. THAT WAS A JOKE. BUT YOU HAVE TO DEBRIEF AFTER THE FACT. I WANT TO SAY ONE THING ABOUT THE IDEA OF IMPRACTICABILITY AND THE CLAIMS OF IMPRACTICABILITY PEOPLE WILL MAKE. SO WHAT'S RELEVANT TO SAY IT'S NOT PRACTICABLE TO DO THE RESEARCH. YOU HAVE TO SAY IF I FOLLOW THE PROCEDURES IT'S IMPRACTICABLE. DOES THAT MEAN YOU DON'T HAVE THE MONEY TO DO THAT KIND OF STUDY? OR I'LL HAVE TO USE CLUSTER DESIGN AND THE CLUSTER DESIGN REQUIRES I CAN'T DO THE INDIVIDUAL CONSENT. THAT SEEMS LIKE A PRETTY GOOD REASON. IMPINGEMENT ON THE STUDY. WE SAW THAT IN THE JUSTIFICATIONS GIVEN IN THE PAPERS WE SAW EARLIER. AND THE REGULATIONS ARE WRITTEN IN A WAY IT'S BLACK OR WHITE. COWL YOU COMPROMISE SO YOU SORT OF SACRIFICE A LITTLE BIT OF THE PRAGMATIC NATURE BUT MEET SOME OF THE INFORMED CONSENT REQUIREMENTS SO IT'S AT LEAST TRANSPARENT WITHOUT HAVING A FULL INFORMED CONSENT FOR INSTANCE. I SUGGESTED THAT OPTION FOR CERTAIN STUDIES. I THINK THAT'S REASONABLE. IF THE STUDY IS MINIMAL RISK WHY YOU NEED TO DO THIS ELABORATE KIND OF CONSENT. OKAY. ONE OF THE REASONS WE ALL FELT UNEASY ABOUT BYPASSING CONSENT IN THE TRIALS IS IS THE FOLLOWING. THE CLINICAL DECISION IN GOING FOR A OR B WHICH IS DRIVING THE RESEARCH, THEY'RE HETROGENEOUS. THERE'S A TRADE-OFF INVOLVED AND THEY'RE PRECISELY THE KIND OF SITUATIONS WE HAVE NOW AN ENTIRE FIELD CALLED SHARED DECISION MAKING AND DECISION AIDS. THE SITUATIONS WHERE YOU BYPASS INFORMED CONSENT SEEMS TO GO AGAINST A TREND DEVELOPED OVER DECADES. I'LL LEAVE TIME TO ANSWER QUESTIONS AND FULFILL THE PROPOSE OF QUESTIONS. AND THERE'S USUAL CASE BY CASE SCRUTINY. YOU CAN THROW OUT EVERYTHING ELSE I SAID JUST REMEMBER THIS, WHETHER IT'S CONSISTENT WITH EQUIPOISE FOR NON-REGULATED INTERVENTIONS. EQUIPOISE ANSWERS WHETHER IT'S GOOD TO ENROLL BUT THE CONCEPT DOESN'T DIRECTLY POINT YOU TO THE RISK. SO IT CAN'T ANSWER THE QUESTIONS LIKE WHAT KIND OF RISK DO I NEED TO COMMUNICATE OR IS THIS MINIMAL RISK OR IS WAIVER OF CONSENT PERMISSIBLE. THEY ALL HAVE TO BE SEPARATE EVEN AFTER YOU DETERMINE THAT THERE'S CLINICAL EQUIPOISE. THANK YOU VERY MUCH. >> EVERYBODY WANTS TO LEAVE EARLIER. I UNDERSTAND. >> I HAVE A QUESTION FOR THE CLUSTER RANDOMIZATION. THERE CAN BE A LOT OF BIAS IF YOU TAKE THE EXAMPLE FOR THE CO-PAYMENT. IF YOU TAKE THE EXAMPLE OF THE CO-PAYMENT IF YOU'RE IN AN LOW EXPECT AREA YOU PROBABLY BENEFIT VERY MUCH AND YOU PROBABLY ARE MUCH MORE INCLINED TO FOLLOW THROUGH WHERE IN AN AREA LIKE OURS WHERE YOU HAVE THE MAJORITY OF PEOPLE THAT HAVE GOOD HEALTH INSURANCE DOESN'T THE DATA GET SKEWED? >> THESE ARE PRETTY SOPHISTICATED PEOPLE WHO DID IT STUDY. I WO WOULD THINK THE LOOKED AT THE CLUSTERS AND RANDOMIZED THEM AND TOOK THAT INTO ACCOUNT IS MY GUESS. YOU'RE SAYING IN SOME SENSE INDIVIDUAL RANDOMIZATION WOULD HAVE BEEN BETTER FROM THAT POINT OF VIEW. IF HAVE ENOUGH CLUSTERS YOU CAN RANDOMIZE ACROSS THAT TOO. >> I HAVE A QUESTION ON INFORMED CONSENT WAIVERS. I KNOW YOU THINK TOO MANY OF THESE WOULD BE IN TRIALS. I WONDER IF YOU AGREE IN SOME OF THESE TRIALS IT MAY SEEM PERMISSIBLE BUT AN OBJECTION MIGHT BE -- THE IDEA THERE SHOULD BE ANY TRIALS WHERE INFORMED CONSENT IS WAVED EXCEPT FOR AN EMERGENCY TRIAL. SO A NUMBER OF TRIALS ESPECIALLY THOSE THAT INVOLVED SOME PHYSICIAN-PATIENT INTERACTION. MAYBE THE CO-PAYMENT ONE IS EXEMPTED ISN'T IT IMPORTANT SOMEONE DISCLOSES TO ME AND WHAT THEY'RE DOING TO MY BODY. >> THANK YOU. I'LL SPEND 60 SECONDS OR MORE TALKING ABOUT THE ISSUE BECAUSE IT'S SO IMPORTANT. TOO BAD BOB WASN'T HERE FOR THE PREVIOUS. THIS IS WHERE I'LL TALK ABOUT THE ECMO STUDY YOU GUYS SAW IN THE VIDEO. THAT WAS A STUDY WHERE PEOPLE WERE STUDYING IF THERE WAS NOVEL INTERVENTION AT THE TIME FOR THE HEART LUNG MACHINE FOR NEONATES AND DECIDE TO CLUSTER AND THEN THEY WANTED TO DO A POST RANDOMIZATION CONSENT ONLY WITH THE ACTIVE ARM. PEOPLE WHO WERE NOT RANDOMIZED TO ECMO WERE SENT TO THE PICU. ALL THE NURSES KNEW IT WAS GOING ON. EVERY DAY THEY HAD TO FACE THE FAMILIES AND KNEW IN THE NICU ALL THE BABIES WERE GETTING THE ECMO. THERE WAS IN MY MIND, CONCERN WHETHER THAT WAS EQUIPOISE. SAY TECHNICALLY IT WAS EQUIPOISE THAT IF YOU SURVEYED THE SPECIALISTS YOU WOULDN'T HAVE GOTTEN THE ANSWER. ON THE OTHER HAND IF YOU PUT YOUR CHILD INTO IT BECAUSE OF PREFERENCE, I BELIEVE MOST PEOPLE WOULD HAVE SAID, NO, I'D BET ON THIS. IMAGINE HAVING SOME PRIOR EVIDENCE WHICH TELLS YOU AS THE SOMETHING LEADING IN THIS WAY BUT HAVING TO ACTIVELY NOT DISCLOSE THAT DAY IT DAY IN THE HEAD POST STUDY OF PEOPLE LYING DOWN VERSUS STANDING UP. ONE STRIKING FINDING IS THE COMPLIANCE RATE. PEOPLE SITTING UP THERE WAS LIKE 96% COMPLIANCE RATE. EVERYBODY WAS HAPPY TO SIT UP 30 DEGREES. ONLY 86% OF THE PEOPLE COULD MAINTAIN ENOUGH TIME LYING FLAG DURING THE 4 -- 24 HOURS OF THE INTERVENTION. THE NURSES HAD TO CONSTANTLY REMIND THEM. BUT THEY COULDN'T DISCLOSE TO THE PATIENT THAT THE REASON WHY I'M REALLY PRESSURING YOU TO DO THIS IS BECAUSE EVEN THOUGH LAST MONTH BEFORE THE TRIAL STARTED WE USED TO LET PATIENT DO WHATEVER, I'VE BEEN TOLD EVERYBODY WHO COMES IN WIN YOUR CONDITION HAS TO LIE FLAT. THAT ASPECT IS DIFFICULT AND NEEDS TO BE THOUGHT THROUGH. I THINK IF BOB WERE HERE HE'D SCRIBE THE KIND OF STRESS THIS COSTS PEOPLE WORKING IN A CHILDREN'S HOSPITAL AT THE TIME. >> VERY INTERESTING TALK. PERHAPS TAKING IT TO ANOTHER LEVEL ON HUMAN STUDY AND SOCIAL MEDIA AND HUMAN SUBJECT RESEARCH AND WHETHER THERE'S CONSENT AND I WONDERED YOUR THOUGHTS ON POTENTIAL EXPERIMENTS THAT CAN BE DONE BY SOCIAL MEDIA OR COMPANY ADVERTISING THAT MAY NOT BE IN THE BENEFIT OF THE GROUP BEING STUDIED AND WHAT YOU THOUGHT ABOUT THE NEXT GENERATION OF HUMAN SUBJECT RESEARCH. IT'S A TOPIC FOR AN ENTIRE SESSION. THERE WAS OUTCRY ON THE FACEBOOK STUDY. IN FACT THE PECK -- THE PECULIARITY IS IF YOU DO IT FOR STUDY IT MAY BE OKAY BUT -- THERE'S A CYNICAL OVER SIMPLIFICATION. I DON'T KNOW -- I THINK IT'S A HUGE AREA AND INTERESTING. ONE THING I DIDN'T GO OVER IN ONE OF THE SLIDES IS THE ISSUE OF EVOLVING EXPECTATIONS OF PEOPLE AND HOW THAT PLAYS INTO HOW WE ANALYZE THE ETHICAL ISSUES. I THINK THAT IS GOING TO BE A REAL IMPORTANT FACTOR. >> THANK YOU. SO WHAT DO YOU SEE AS THE FUTURE FOR THESE PROSPECTIVE PRAGMATIC TRIALS WHEN WE FACE OPPORTUNITIES WITH THE ADVENT OF ELECTRONIC HEALTH REGISTRIES AND COORDINATION FOR ANSWERING MANY QUESTIONS, PERHAPS. >> I'LL GIVE YOU AN EXAMPLE OF POST RANDOM CONSENT. FOR WIDE INTERVENTIONS LIKE THE COLONOSCOPY EXAMPLE, THEY MAKE THE MOST SENSE TO DO AS RANDOMIZE FIRST AND THEN YOU THINK ABOUT THE DISCLOSURE YOU PROVIDE TO PEOPLE WHO ARE GETTING SOMETHING NEW. THAT'S ONE WAY OF APPROACHING IT. THE OTHER IS IN THAT SITUATION IT'S CLEAR WE NEED TO DEVELOP MORE MEANINGFUL WAYS OF COMMUNICATING TO PEOPLE WHEN THEY ENTER HEALTH SYSTEMS AND PLANS AND SO FORTH. WHAT THEY'RE SIGNING UP FOR IS MOR MORAN -- MORE THAN JUST DATA. NOT JUST AS RETROSPECTIVE DATA REVIEW BUT USED AS A COMPARISON GROUP AT THESE KINDS OF CLINICAL TRIALS, FOR INSTANCE. I THINK WE NEED TO CHANGE THE EXPECTATIONS IN SUCH A WAY THAT IT BECOMES MORE OF A PART OF WHAT WE THINK. FOR A LOT OF THE BIG SYSTEM-WIDE TRIALS THEY'RE MOST PRACTICAL TO DO IT WITH POST-RANDOMIZATION AND IN THE ACTIVE ARM TO DO A MODIFIED CONSENT. AND IN A WAY THAT'S SUFFICIENT AND TRANSPARENT BUT WITHOUT PULLING OUT THE BIG CANNON OF 20-PAGE CONSENT. SO THAT'S EFFICIENT. THEN ON THE CONTROL SIDE WE NEED TO DEVELOP A METHOD OF DOING EARLY EFFECTIVE BROAD CONSENT THAT LAWS PEOPLE TO PARTICIPATE BUT PARTICIPATE ESSENTIALLY AS PERSPECTIVE COHORT WHO'S DATA SERVES AS COMPARISON GROUPS. WHEN WE PUT THE POST HAD-RANDOMIZATION STUDIES AS RCTs WE IMMEDIATELY THINK THE PEOPLE IN THE CONTROL ARM ARE BEING HARMED OR PUT AT RISK. ACTUALLY, AFTER RANDOMIZATION THE CONTROL ARM, WHAT YOU'RE DOING IN THE POST RANDOMIZATION DESIGN REALLY ISN'T HOW WE'LL ASSIGN THE TREATMENT. IT'S A SUBJECT AT DIFFERENT BUT I THINK IT'S IMPORTANT. YOU LOOK AT WHICH GROUP WILL YOU PERTURB IN THEIR ORDER NARY COURSE OF LIFE AND WHICH PEOPLE ARE WE JUST GOING TO LEAVE AS THEY ARE? THAT THE THE RANDOMIZATION. AND MY VIEW IS THAT THE SECOND GROUP SHOULD NOT BE SEEN AS IDENTICAL TO THE CONTROL ARM AND THE USUAL RCT WHERE WE'RE CONTROLLING WHAT THEY GET. IN SOME SENSE WE'RE CONTROLLING IT BUT IT'S NO MORE CONTROLLING THAN IT IS WHEN A DOOR TO DOOR SURVEY PERSON RANDOMLY DECIDES NOT TO SELECT -- OR DECIDES NOT TO SELECT THIS DOOR AND THEN BEING OBLIGATED TO TELL THEM THEY WERE BEING SELECTED. I THINK THERE'S WAYS MUCH DOING THIS. WHAT I WORRY ABOUT IS THIS IDEA JUST BECAUSE THERE'S STANDARD OF CARE THERE'S NO RISK THEREFORE WE CAN DO WHATEVER WE WANT. THAT WILL BACKFIRE. I BELIEVE SOME OF THE TRIALS HAD THERE BEEN HUGE DISCREPANCIES IN EFFECT AND PEOPLE FOUND OUT I THINK IT COULD HAVE HAD NEGATIVE CONSEQUENCES AND GETTING BACK TO THIS GENTLEMEN'S POINT IT WOULD HAVE BEEN A BAD THING FOR THE ENTIRE PRAGMATIC RESEARCH ENTERPRISE. 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