>> WELCOME TO OUR THIRD SESSION OF THIS COURSE. TODAY WE'RE GOING TO TALK ABOUT A DIFFERENT CLINICAL -- DIFFERENT DESIGNS NOT ALL CLINICAL TRIALS BUT DIFFERENT DESIGNS OF CLINICAL RESEARCH. WE HAVE THREE VERY INTERESTING SESSIONS, STARTING WITH THIS MORNING PRAGMATIC TRIALS, THE MIDDLE SESSION WILL BE ABOUT RANDOMIZED CONTROL TRIALS, AND THE THIRD SESSION WILL BE ABOUT VACCINE TRIALS. SO IT SHOULD BE VERY INTERESTING MORNING. TO START US OFF WE HAVE DR. SCOTT KIM WHO IS SENIOR INVESTIGATOR IN THE NIH CLINICAL CENTER DEPARTMENT OF BIOETHICS AND HE TALK TO YOU ABOUT THE ETHICS OF PRAGMATIC TRIALS. THANK YOU, SCOTT. >> GREAT. IS THIS ON NOW? CAN YOU HEAR ME? GREAT. SO IF I GET QUIET, SCREAM OUT. SO I'LL BRIEFLY DESCRIBE WHAT A PRAGMATIC TRIAL IS, IT'S IMPORTANT, HOT, IT'S A HUGE PUSH TO DO MORE OF THESE TRIALS. I'M GOING TO SPEND THE FIRST THIRD OF THE TALK DESCRIBING WHAT THE ETHICAL ISSUES ARE BUT MOSTLY I WOULD LIKE TO SPEND SOME TIME GOING THROUGH SOME CASES, TRIALS, SO WE ALL GET A FEEL FOR WHAT THESE ISSUES MIGHT BE. THEN I WILL RUN THROUGH SOME THOUGHTS ABOUT GIVEN WHAT I HOPE WE WILL LEARN TOGETHER BY GOING THE EXAMPLES HOW WE SHOULD ANALYZE THE ETHICAL ISSUES IN PRAGMATIC TRIALS. SO THE PRAGMATIC -- THE TERM PRAGMATIC OBVIOUSLY IS WHAT IT SOUNDS LIKE. IT'S -- THE IDEA IS TO DO RESEARCH TO ADDRESS PRACTICAL QUESTIONS LIKE POLICY QUESTIONS OR ACTUAL CLINICAL PRACTICE QUESTIONS THAT COME UP, SOMETHING AS CONCRETE AS WELL, I HAD DRUG A AND DRUG B THAT I USE FOR SAY DEPRESSION F. I WANT TO FIND OUT WHICH IS BETTER. LET'S SAY MAYBE A IS MORE EXPENSIVE THAN B, THINGS LIKE THAT AS I'LL TALK ABOUT. EFFECTIVENESS. REAL WORLD EVIDENCE IS NOW A TECHNICAL TERM PEOPLE USE. THE IDEA IS TO DESIGN A TRIAL THAT MIMICS WHAT IT REALLY LOOKS LIKE AT POINT OF DELIVERING THAT PIECE OF CARE OR IN TERMS OF POLICY IMPLEMENTATION. SO THAT YOU ARE DOING IT IN THE SETTING WHICH YOU'RE GOING TO USE THE INFORMATION. SO I THINK THAT'S BRIEFLY THAT'S THE BEST WAY TO PUT IT. THIS IS SUCH A BIG DEAL, THERE IS A SECOND VERSION OF A TOOL YOU CAN USE TO GO THROUGH DESIGN OF YOUR TRIAL TO SEE HOW PRAGMATIC YOUR TRIAL IS, THAT'S WHAT -- IS. THE IDEA IS TO MIMIC THE USUAL CLINICAL OPERATIONS OF A CLINICAL OR HOSPITAL OR HEALTH SYSTEM ACTUALLY AS YOU WILL SEE. THEY COMPARE TWO OR MORE INTERVENTIONS, DRUGS, PROCEDURES, POLICIES, CAN INVOLVE THINGS LIKE ELECTRONIC HEALTH RECORD ALERTS TO DOCTORS WHEN SOMETHING HAPPENS TO SEE IF THAT MAKES A DIFFERENCE IN HOW PEOPLE ARE TREATED. SO IT CAN BE A VARIETY OF THINGS O. WE USE THE TERMS LIKE STANDARD OF CARE, USUAL, ACCEPTED CARE, WIDELY USED, ACCEPTABLE PRACTICE, IT'S A WHOLE RANGE OF TERMS WE USE, THEY DON'T ALL MEAN THE SAME THING BUT FOR PURPOSES I WILL PRETEND THEY ARE OVERLAPPING AND SIMILAR. THE IDEA BEING THESE ARE ACCEPTABLE OR WHAT WE ACCEPT A HOSPITAL SYSTEM OR DOCTOR TO USE AND WE WILL SAY YES THAT'S FINE, THAT'S WITHIN WHAT WE ACCEPT AS A PRETTY STANDARD THING TO DO. SO WHY IS THIS IMPORTANT? BECAUSE THERE'S SO MANY QUESTIONS IN MEDICINE THAT ARE BASED ON CONVENTION HABIT AND NOT REALLY EVIDENCE. FOR EXAMPLE, THERE IS A NEW DRUG FOR THE SAME TREATMENT, TREATMENT OF THE SAME CONDITION, SAY A AND B ARE TWO INTERVENTIONS, B IS NEW. AND IT'S HUNDRED TIMES MORE EXPENSIVE. THOSE OF YOU WHO FOLLOW THE NEWS AT ALL YOU KNOW THIS IS ACTUALLY TRUE. IT COULD BE MORE THAN A HUNDRED TIMES EXPENSIVE GIVEN HOW EXPENSIVE SOME OF THE MODERN INTERVENTIONS ARE. B COULD BE I'M USING B AS THE NEW THINGS. MORE BURDENSOME TO USE BUT THERE'S LIMITED DATA SUGGESTING IT MIGHT BE MORE EFFECTIVE SO THIS MIGHT BE A TRADE OFF IMPORTANT TO FIND OUT. OR IT COULD BE THERE'S A LOT MORE DATA SUPPORTING USE OF B, SAY IT WAS USED IN ALL THESE LARGE CLINICAL TRIALS. IN FACT THE COMPANY THAT MANUFACTURES A IS MUCH BETTER AT MARKETING A THAN B. SO EVERYBODY USES B THOUGH IT'S THE SAME FAMILY OF DRUG, VERY SIMILAR. BUT IT DOESN'T HAVE DIRECT EVIDENCE. ARE THEY EQUIVALENT? VERY IMPORTANT QUESTION. A AND B ARE COMMONLY USED PROCEDURES. PROCEDURES UNLESS IT INVOLVES A DEVICE IS NOT REGULATED. IN FACT, DOCTORS HAVE LOTS OF FREEDOM TO IMPLEMENT DIFFERENT PROCEDURES FOR DOING THINGS. THERE'S NO STRICT WAY OF REGULATING THAT. SO WE OFTEN DON'T KNOW WHICH IS BETTER. IFIF THERE'S DISCREPANCY IN PRACTICE. OR THERE COULD BE HEALTH SYSTEM LEVEL POLICIES OR PRACTICES. FINALLY THIS SITUATION STILL EXISTS WHERE EVERYBODY USES A CERTAIN DRUG FOR A CONDITION BASED ON ONE STUDY DONE IN 1935 AND NO ONE HAS GOTTEN OFF OF THAT TRAIN. PEOPLE THINK, WELL, IS THIS THE RIGHT THING TO DO? YOU MIGHT TEST THAT. I CAN COME UP WITH OTHER EXAMPLES, BUT THE BASIC IDEA IS A LOT OF THESE PRACTICES ARE THERE BECAUSE THAT'S HOW WE DO IT. SOMETIMES IT COULD BE HARMFUL. WE DON'T KNOW OR SOMETIMES MORE EXPENSIVE THAN IT NEEDS TO BE. SO YOU MIGHT ASK WHEN A AND B ARE COMPARED IN A CLINICAL TRIAL WE CALL THEM PRAGMATIC CLINICAL TRIALS, WHAT'S THE RESEARCH RISK TO THE SUBJECTS WHO ARE ROLLED? THESE TRIALS ARE DESIGNED IN SUCH A WAY THAT YOU MIGHT HAVE VERY LITTLE RESEARCH-SPECIFIC MEASURES OR PROCEDURES. IN FACT, YOU MIGHT USE ELECTRONIC MEDICAL RECORDS TO TO MEASURE OUTCOMES OR CLAIMS DATA OR WHATEVER. SO YOU DON'T HAVE TO ACTUALLY SIT DOWN WITH THEM OR DO SPECIAL BIOPSIES OR INTERVIEWS EVEN, THINGS LIKE THAT. SOMETIMES THE ONLY RESEARCH THING THAT'S DONE IS YOU RANDOMIZE PEOPLE BETWEEN A AND B. EVERYTHING ELSE YOU SORT OF TRACK BY FOLLOWING THE RECORDS, LET'S SAY MEDICAL RECORDS. SO THE ONLY RESEARCH RISK WOULD BE IF THERE'S ANY WOULD BE WHATEVER IMPLICATIONS THERE ARE, WHEN YOU RANDOMIZE A PERSON TO STANDARD TREATMENT A VERSUS STANDARD TREATMENT B T. IT CAN ALSO BE SAID THAT EVERY SINGLE PERSON IN SUCH A TRIAL RECEIVES AN ACCEPTED LEVEL OF TREATMENT. WHAT'S THE PROBLEM? SEEMS LIKE IF -- THE WAY I DESCRIBED IT TO YOU, IT SEEMS LIKE WELL, WHAT'S THE WIG DEAL? IT'S LIKE YOU CAN HAVE THE BEST OF BOTH WORLDS, YOU CAN DO RESEARCH AND YOU CAN SAY YOU ARE GIVING THE BEST CARE POSSIBLE SO THERE'S NO RESEARCH RISK, WE DON'T HAVE TO WORRY ABOUT IT. IF ONLY IT WERE THAT SIMPLE. HERE IS THE PART WHERE THE ETHICAL DISPUTE START TO ARISE. IT'S THIS. THE MIMIC REAL WORLD PRACTICE, SEEMS INCOMPATIBLE WITH THE VERY HEAVY APPARATUS WE HAVE CONSTRUCTED TO REGULATE CLINICAL TRIALS. ESPECIALLY -- TO SHOW YOU THE TENSION I'M GOING TO BRING IN CONCEPT CALLED LEARNING HEALTH SYSTEMS. THE IDEA IS LIKE ASPIRATIONAL GOAL WHERE IF YOU HAVE A HEALTH SYSTEM IN WHICH YOU HAVE DEVELOPED YOUR INFRASTRUCTURE IN SUCH A WAY THAT YOU CAN ACTUALLY TEST ALL SORTS OF QUESTIONS REAL TIME IN YOUR PATIENTS BY RAN TOMMIZING DIFFERENT -- RANDOMIZING THE DIFFERENT TREATMENTS AND THIS IS A CONTINUAL CYCLE OF IMPROVEMENT, SUPPOSE THAT'S THE IDEA. NOW YOU CAN SEE HOW IF YOU ARE GOING TO A VERY BUSY PRIMARY CARE CLINIC AND YOU WANT TO DO THESE TRIALS, THE REGULAR DELIVERY OF CARE WHICH IS THE PLACE IN WHICH YOU WANT TO DO THESE TRIALS, AND YOU WANT EVERYTHING FROM THE OUTSIDE TO LOOK LIKE THEY ARE JUST DOING REGULAR PRACTICE, IF THEY START SPEND 30 MINUTES DOING INFORMED CONSENT IN BUSY PRIMARY CARE CLINIC THERE'S NO WAY TO DO THESE TRIALS IF THAT WERE LIKE NO WAY THEY CAN DO THE TRIALS IN THE WAY THEY WANTED TO DO IT. RIGHT? IF THAT WERE THE REQUIREMENTS. SO IT CREATE THIS TENSION AND BECAUSE OF THIS PEOPLE HAVE COME UP WITH ACTUALLY LITERALLY A DIFFERENT FRAMEWORK, THE ASSERTION IS, FOR ANALYZING THE ETHICS OF THESE. SO THIS IS A STATEMENT FROM ONE OF THOSE PAPERS WHERE THE WRITERS SAY THE FRAMEWORK WE PROPOSE REJECT THE A SIMILAR SHUN THAT CLINICAL RESEARCH AND PRACTICE ARE FROM ETHICS STANDPOINT FUNDAMENTALLY DIFFERENT ENTERPRISES. IT SHOULDN'T BE SURPRISING TO YOU SINCE YOU ARE IN THIS HUMAN SUBJECT RESEARCH COURSE, THIS IS ALL PREMISED ON THIS IDEA THAT CLINICAL RESEARCH DOING RESEARCH AND PROVIDING TREATMENT ARE FUNDAMENTALLY DIFFERENT GOALS AND ASPIRATIONS AND THERE'S ATTENTION BUT HOAR THEY ARE PROPOSING A FRAMEWORK WHERE THEY REJECT THAT DISTINCTION. ANOTHER WAY PUTTING IT DRAWING A SHORT DISTINCTION BETWEEN RESEARCH AND THERAPY CAN BE APPEAL BUG A GROWING NUMBER OF ACTIVITIES AND HEALTHCARE CANNOT BE COMFORTABLY CLASSIFIED AS EITHER RESEARCH OR THERAPY. SO BECAUSE OF THIS, YOU SAY LOOK SYSTEM OF THESE TRIALS WE SHOULD NOT NEED EXPRESS INFORMED CONSENT. OBTAINING CONVENTIONAL WRITTEN INFORMED CONSENT MAYBE NOT ONLY ETHICALLY UNNECESSARY OR MAY RENDER SUCH RESEARCH IMPRACTICABLE. WE NEED CHANGE IN SITUATIONS WHICH BROADEN SITUATIONS WHERE INFORMED CONSENT IS NOT REQUIRED OR COULD BE WAIVED. IN ORDER PEOPLE WOULDN'T KNOW THESE TRIALS ARE BEING DONE. USUALLY THESE STATEMENTS ARE MADE IN CONTEXT OF THE CURRENT REGULATIONS WHICH REQUIRE THAT YOU CAN ONLY WAIVE CONSENT IF IRB DETERMINES RESEARCH TO BE MINIMAL RISK. I WANT TO BE VERY CLEAR WHAT THAT MEANS. IT MEANS IT HAS TO BE MINIMAL RISK AS A NECESSARY CONDITION. IT DOESN'T MEAN IT'S SUFFICIENT FOR WAIVING CONSENT BUT IT GETS YOU INTO THE DOOR OF BEING A CANDIDATE FOR AN ANALYSIS TO SEE IF YOU CAN WAIVE CONSENT. SO THEREFORE PEOPLE HAVE SAID THINGS LIKE THIS: THIS IS REGARDING A VERY CONTROVERSIAL CLINICAL TRIAL CALLED SUPPORT DONE IN NICU. THE AUTHORS WHO ARE PROMINENT BIOETHICISTS IN THIS COUNTRY SAY THE FOLLOWING, SINCE ALL THE STUDY PARTICIPANTS THIS COMPARED TO WHAT THEY THOUGHT WERE TWO PROCEDURES THAT WERE DONE, WITHIN STANDARD OF CARE IN NICU, THEY SAY SINCE ALL STUDY PARTICIPANTS RECEIVE TREATMENTS WITHIN PREVAILING STANDARD OF CARE, THERE WAS NO ADDITIONAL RSK TO BEING ENROLLED IN THE TRIAL. THERE WAS NO BASIS FOR CLAIMING AN INCREASE IN RISK FROM ENROLLING A TRIAL VERSUS RECEIVING STANDARD CLINICAL CARE. SO IT JUST RECAPITULATES WHAT I SAID EARLIER. THIS IS A VERY POPULAR VIEW. I CAN SHOW YOU LOTS OF ARTICLES SUPPORTING THIS. IN FACT PEOPLE HAVE NOT PROPOSED EVEN IF YOU ARE GOING TO DO THESE PRAGMATIC TRIALS FOR USING DRUGS AND DEVICES THAT FDA REGULATE THEY CAN -- THEY ASSERT THAT THEY CAN BE MINIMAL RISK IF THE FOLLOWING CONDITIONS ARE MET. THIS IS PAPER WHICH THEY SAY THAT. AND IT COULD BE ELIGIBLE FOR WARE OF CONSENT FOR EXAM -- WAIVER OF CONSENT FOR EXAMPLE. NUMBER ONE. IF THE PRODUCTS BEING COMPARED ARE USED ACCORDING TO APPROVED LABEL. SO THIS IS A DRUG THAT WAS APPROVED FOR DEPRESSION, THIS IS FOR USE IN DEPRESSION, IF YOU ARE GOING TO USE IT JUST THE WAY YOU USE IT IN THE CLINICAL PRACTICE AS APPROVED MARKETING APPROVAL, THEN THAT'S STUDY BY DEFINITION SHOULD BE CONSIDERED MINIMAL RISK. EVEN IF IT'S NOT APPROVED, THEY FEEL THESE AUTHORS FEEL IF THERE'S CLINICAL GUIDELINES THAT SAY YES, YOU SHOULD USE THIS DRUG TO TREAT THIS, IF THAT IS IN PLACE IT SHOULD BE MINIMAL RISK SO IT'S A PRETTY BROAD-SWEEPING STATEMENT. OKAY? ALL RIGHT. SO THAT IS THE BACKGROUND. WHAT I'M GOING TO DO NOW IS TO GO THROUGH SOME CLINICAL TRIALS AND WE ARE GOING TO KIND OF THINK THROUGH SOME OF THESE TRIALS TOGETHER. MOST ARE ACTUAL TRIALS, THERE'S ONE THAT IS A HYPOTHETICAL ONE THAT WAS POSED IN NEW ENGLAND JOURNAL, THAT WAS INTERESTING, SO THIS IS AN ACTUAL TRIAL. QUESTION WAS, DOES ELIMINATING CO-PAYMENT FOR PRESCRIPTION DRUGS TIM PROVE MEDICATION ADHERENCE AND OUTCOMES IN PEOPLE WHO HAVE HAD A RECENT MYOCARDIAL INFARCTION OR HEART ATTACKS? SO WHAT THEY DID WAS THIS. THEY CLUSTER RANDOM ICED AND THE CLUSTER WAS THE EMPLOYER. PEOPLE COVERED BY INSURANCE SCHEME, THE COVERAGE VARIOUS INSTITUTIONS AND THOSE INSTITUTIONS WERE RANDOMIZED SO IF YOU WORK FOR NIH YOU MIGHT GET ONE ARM. IF YOU WORK FOR MASS GENERAL YOU MIGHT GET SOMETHING ELSE. AND THE TWO ARMS WERE FULL COVERAGE SO YOU ARE LUCKY, UNLIKE EVERYBODY ELSE YOU DON'T HAVE TO PAY NICO PAYMENTS FOR YOUR CARDIAC DRUGS AFTER A HEART ATTACK. -- ANY, CO-PAYMENTS. AND OTHER Z RANDOMIZED TO REGULAR COVERAGE WHERE YOU PAY CO-PAYS DEPENDING ON YOUR PLAN. THE PRIMARY OUTCOME WAS COMPOSITE OF WHETHER OR NOT HOW SOON THEY WERE ADMITTED TO THE HOSPITAL IF ANY OR THEY NEEDED PROCEDURE TO REOPEN THEIR CLOGGED VESSELS THAT CAUSED HEART ATTACK. SO WHAT WAS THE STUDY RESEARCH RISK? HOW MANY PEOPLE -- I HOPE I CAN SEE YOU. I'LL STAND HERE. HOW MANY PEOPLE THINK THIS STUDY IS MINUTE MINNESOTA MALL RISK? RAISE YOUR HAND. MORE THAN HALF. HOW MANY THINK IT WAS MORE THAN MINIMAL RISK? FEW. HOW MANY DON'T KNOW? SOME HONEST PEOPLE. DO WE NEED INFORMED CONSENT FOR THIS TRIAL? HOW MANY PEEP THINK WE HAVE TO HAVE UNFORMED CONSENT FOR THIS TRIAL, RAISE YOUR HAND? FEW, I WOULD SAY SMALL MINORITY. HOW MANY THINK WE CAN WAIVE CONSENT IN A TRIAL LIKE THIS. ALL RIGHT. MAJORITY. OKAY. SO HERE IS MY TAKE ON THIS. I DON'T THINK THERE'S ANY INTERVENTION RELATED BURDENS ON SUBJECTS. BECAUSE INTERVENTION IS ESSENTIALLY SOME PEOPLE DON'T PAY A CO-PAY. SO BUT WHAT WAS THE RISK CAUSED BY DOING THAT? IN THE CO-PAY GROUP REALLY NO DIFFERENCE BETWEEN USUAL VERSUS RESEARCH BECAUSE I'M JUST PAYING, THEY TONE EVEN KNOW THEY'RE IN -- THEY DON'T EVEN KNOW THEY'RE IN RESEARCH. THE NO CO-PAY GROUP, IT'S REASONABLE TO SAY THAT IT'S PRETTY DIFFICULT TO IMAGINE THAT COULD CAUSE HARM IN PEOPLE. I THINK THAT'S A JUDGMENT CALL THE IRB CAN MAKE AND IF IRB SAID LOOK WE DON'T THINK PAYING NO CO-PAY IS A RISKY THING TO DO TO A PERSON. SO THAT'S THE CASE. SEEMS TO ME THAT THIS MIGHT BE CONSIDERED A REALLY NO PROSPECT OF RISK ABOVE MINIMAL. THIS WAS JUST INTUITIVE ANALYSIS, WE CAN LOOK AT THE REGULATIONS AND USE EXACT WORDING AND GO THROUGH IT BUT I DON'T THINK THAT WOULD BE DIFFERENT IN MY CASE BUT LET'S MOVE ON TO A SECOND EXAMPLE. SOME OF YOU IN THE ROOM WILL HAVE HAD THE INDIGNITY LIKE I HAVE OF PREPPING FOR COLONOSCOPY WHEN YOU TURN 50. 'S NOT FUN,'S PROBABLY THE WORST PART OF GETTING THE THING DONE BECAUSE IT TAKES A WHOLE DAY FROM YOUR LIFE. OR AN EVENING ANYWAY. SO THIS IS A HYPOTHETICAL TRIAL THOUGHT UP COOKED UP BY DAVID ASH FROM PENN. HE SAYS QRS HEALTH SYSTEM WANTS TO SEE IF TWO INTERVENTIONS COMPARED TO USUAL WILL INCREASE ADHERENCE TO COLONOSCOPIES BECAUSE IT'S A SCREENING TOOL AND MORE PEOPLE DO IT MORE EFFECTIVE IN TERMS OF POPULATION HEALTH. RIGHT? SO HE IMAGINES A THREE ARM STUDY. A WHIMSICAL CARD ON 50th BIRTHDAY REMINDING PERSON OF COLONOSCOPY SCREENING WITH SOME CLEANSING SUPPLIES. SECOND INTERVENTION SYSTEM DEFAULT APPOINTMENT, SAY LOOK YOU TURN 50, WE HAVE SET A TIME FOR YOU TO COME IN FOR THIS. BUT IF YOU CAN'T MAKE IT, CALL THIS NUMBER. THIRD IS USUAL. WE INFORM YOU THAT UNITED STATES PREVENTIVE TASK FORCE HAS DETERMINED THAT BLAH BLAH BLAH BLAH BLAH. THE KIND OF THING YOU LOCK READ THE FIRST LINE AND THROW AWAY. RIGHT? SO THE PRIMARY OUTCOME IS HOW MANY PEOPLE ACTUALLY ADHERE TO THE SCREENING? WHAT'S THE RESEARCH RISK OF THIS STUDY? HOW MANY THINK THAT'S MORE THAN MINIMAL RISK TO THIS STUDY? SOME BRAVE SOULS. COUPLE. HOW MANY THINK MORE THAN MINIMAL RISK? JUST DON'T KNOW. HOW MANY DON'T CARE? INFORMED CONSENT NECESSARY, RAISE YOUR HAND. COMFORTABLE WITH NO INFORMED CONSENT? MOST PEOPLE. SO I KIND OF AGREE WITH THAT. SEEMS TO ME AGAIN WE END UP USING THE SAME ANALYSIS WE DID FOR THE FIRST EXAMPLE. THE INTERVENTIONS THEMSELVES AROUND HARMFUL. THERE ISN'T REALLY AN OUTCOME THAT YOU CAN IMAGINE REASONABLY IMAGINE TO BE HARM TO THE PEOPLE. IT IS A COMPARISON BETWEEN STATUS QUO VERSUS IS IT GOING TO HELP OR NOT. SO I THINK IN THAT CASE I DIDN'T DO INFORMED CONSENT ANALYSIS BECAUSE THAT REQUIRES VARIOUS OTHER THINGS SO WE'LL PUT IT ASIDE. BUT IN TERMS OF RISK I'M IN AGREEMENT WITH MOST OF YOU I THINK. IF YOU DISAGREE WITH ME YOU CAN EMAIL ME. THIS IS ANOTHER STUDY CALLED A HEAD POST STUDY. YOU WILL SEE PEOPLE COME UP WITH THESE CLEVER NAMES. THE QUESTION HERE WAS DOES LYING FLAT AFTER ACUTE ISCHEMIC STROKE IMPROVE OUTCOMES? SO META ANALYSIS HAD SHOWN THAT THERE SEEMED TO BE BETTER BLOOD FLOW IN THE AFFECTED HEMISPHERE OF YOUR BRAIN WHEN YOU ARE SUPINE OR FLAT ON YOUR BACK, THE IDEA BEING'S LOWER, YOU HAVE MORE BLOOD FLOW. HOWEVER, IN PRACTICE, IN HOSPITALS WHEN PEOPLE COME IN PEOPLE ARE SOME PLACES SAY YOU CAN SIT UP DO WHATEVER YOU WANT, SOME PLACE IT IS DOCTORS GO OH, WE THINK IT'S BETTER YOU LIE DOWN. PERFECT QUESTION TO TEST IN THE PRAGMATIC TRIAL. SO WHAT THEY DID WAS AGAIN, CLUSTER RANDOMIZATION, BY HOSPITAL. HOSPITALS RANDOMIZE, SOME HOSPITALS THEY TOLD THEIR PATIENTS LIE FLAT, SOME HOSPITALS SIT UP 30-DEGREES. THEY DID IT FOR FIRST 24 HOURS. NOTICE THAT THE RANDOMIZATION WAS CLUSTER BUT THE INTERVENTION WAS INDIVIDUAL. THAT'S IMPORTANT. SOME CLUSTER TRIALS ARE CLUSTER INTERVENTION WHERE YOU REALLY CAN'T INDIVIDUALLY CONTROL THE INTERVENTION. FOR EXAMPLE, IF YOU WERE GOING TO CHANGE STAFFING ON A FLOOR AS AN INTERVENTION, THE INDIVIDUAL PATIENTS CAN'T DETERMINE WHETHER THE STAFFING IS INDIVIDUALIZED OR NOT, IT'S FOR THE ENTIRE FLOOR. SO YOU HAVE TO MAKE IN THE SAME POSITION FOR EATING DRINKING AND TOILETING. ANIMAL THAT, LET THAT SOAK IN. SO THE PRIMARY OUTCOME WAS 90 DAYS AFTER STROKE HOW MUCH DISABILITY WAS THERE IN PEOPLE? HOW MANY PEOPLE THINK THIS WAS MINIMAL RISK? RAISE YOUR HAND. A HANDFUL, HOW MANY PEOPLE FEEL THIS IS NOT MINIMAL RISK. I'M PRETTY SURE IT'S NOT MINIMAL RISK, RAISE YOUR HAND. MAJORITY. CAN WE WAIVE CONSENT SO THEY HAVE NO -- THE PATIENTS HAVE NO IDEA THAT YOU ARE DOING THIS TRIAL? HOW MANY THINK THAT WOULD BE OKAY? ONE OR TWO. ALL RIGHT IN FACT THIS WAS A REAL TRIAL PUBLISHED IN NEW ENGLAND JOURNAL AS I SHOWED YOU. THIS IS WHAT THEY SAID. THE PROTOCOL WAS APPROVE BY ALL REGULATORY AUTHORITIES AND ETHICS COMMITTEES AT THE PARTICIPATING CENTERS. A SENIOR EXECUTIVE OFFICER AT EACH HOSPITAL ACTED AS QUOD GUARDIAN AS PART OF THE CLUSTER DESIGN AND PROVIDED CONSENT. THIS IS THE ACTUAL WORDS THEY USE. AT INSTITUTIONAL LEVEL FOR HEAD POSITION TO BE IMPLEMENTED AS A LOW RISK INTERVENTION TO CLUSTER PATIENTS AS PART OF ROUTINE CARE. WRITTEN INFORMED CONSENT WAS SUBSEQUENTLY OBTAINED FROM THE PATIENTS FOR USE OF THE DATA. SO CONSENT WAS FOR THE DATA. NOT FOR ACTUAL INTERVENTION. SINCE SO FAB TIME ONLY GOES IN ONE DIRECTION YOU CAN'T GET RETROSPECTIVE CONSENT, THAT'S REAL CONSENT, RIGHT? SO THERE WAS TROUBLESOME READERS ON THE NEW ENGLAND JOURNAL WHO WROTE A LETTER, YES. HOLLY HAS A QUESTION. (OFF MIC) I WAS THINKING ABOUT MYSELF AS A NURSE ON THE FLOOR WHO HAS A PARTICULAR PREFERENCE. I MIGHT FEEL MAYBE BURDENED BY HAVING TO FOLLOW TELLING ALL MY PATIENTS TO LIE DOWN. I DON'T KNOW IF THAT'S -- >> CAN YOU REPEAT THE QUESTION? >> YES. IF YOU WERE A NURSE WORK, AT A HOSPITAL, HE OR SHE MIGHT THINK I CHOUGH YOU WILY THINK IT'S BETTER FOR YOU THE LIE DOWN WHEN ACTUALLY WE ARE ASKED TO SIT UP OR VICE VERSA. THEY MIGHT HAVE SOME QUALMS ABOUT THAT. SO I'M GOING TO ADDRESS THAT LATER. YOU SHOULD ACTUALLY -- IS BOB TALKING TODAY, CHRISTINE? BOB TRUOG WILL WALK YOU THROUGH THAT BECAUSE THAT'S A RELEVANT POINT FOR HIS TALK. >> IT'S DIFFERENT THAN EQUIPOISE >> IT'S NOT EQUIPOISE. I WILL TALK -- WE CAN TALK MORE. SO SOME TROUBLESOME READERS WROTE A LETTER TO THE EDITOR SAYING YOU KNOW, WE ARE KIND OF UNCOMFORTABLE, SEEMS LIKE THERE IS NOT ENOUGH JUSTIFICATION WHAT THEY DID FROM ETHICAL POINT OF VIEW. THIS WAS THEIR REPLY. THE INSUFFICIENT -- THERE WAS INSUFFICIENT AMOUNT, THE REASON THEY THOUGHT THERE WAS LOW RISK INSUFFICIENT OF LEVEL 1 EVIDENCE, LEVEL 1 EVIDENCE BEING CLINICAL GUIDELINES, LIKE THEY SORT OF RANK THE LEVELS OF EVIDENCE ONE BEING HIGHEST SOMETIMES THEY SAY LEVEL A, LEVEL ONE, WHATEVER. SPECIFYING BENEFIT HARMS OF POSITION OF PATIENTS WITH ACUTE STROKE. BASICALLY WHAT THEY ARE SAYING IS WE THOUGHT THERE WAS EQUIPOISE. THE FACT PEOPLE CHANGE HEAD POSITION WITHOUT -- WITHIN THE RANGES BEING TESTED DURING ROUTINE HOSPITAL CARE HAPPENS ALL THE TIME. JUST CAN'T BE RISKY. THE VIEW THAT PATIENT CARE WOULD NOT BE COMPROMISED BY EITHER THE INTERVENTION. SO BASICALLY THEY ARE SAYING DAY PRACTICE THIS CAN'T BE RISKY. IS THAT -- HOW MANY PEOPLE ARE CONVINCED BY THAT RESPONSE THAT YOU WHO THOUGHT IT WAS GREATER THAN MINIMAL RISK. OKAY. DIDN'T CONVINCE ANYBODY. IT DIDN'T CONVINCE US. WE WERE THE TROUBLESOME LETTER WRITERS. I SHOULD SAY. HERE IS ANOTHER TRIAL. YOU CAN TELL WE ARE GOING UP ON THE SCALE OF INTERVENTIONS A& LITTLE BIT. WHAT'S BETTER IN ACUTE HEART ATTACK SITUATION? HEPARIN, AN OLD STAND BY, OR BIVALIRUDIN (PHONETIC) WHICH IS A NEW PANT COAGULANT IN THE -- ANTI-COAGULANT IN SETING IS OF ACUTE THROMBOSIS, A LOT MORE EXPENSIVE. THE PRIMARY OUTCOME IS COME PRIDESSED OF SEVERAL FACTORS INCLUDING MORTALITY AND THEY ALSO HAVE AS AN OUTCOME BLEEDING BECAUSE THEY WERE REALLY WANTED TO KNOW WHICH CAUSED MORE BLEEDING AS A SIDE EFFECT. THEIR CONSENT PROCEDURES WERE AS FOLLOWS, FULL ETHICAL APPROVAL GRANTED FOR USE OF DELAYED CONSENT. THE PATIENTS RANDOMLY ALLOCATED WENT THROUGH THE PROCEDURE OF ANGIOGRAPHY IN AN EMERGENCY SETTING AND NO ATTEMPT WAS MADE TO DISCUSS TRIAL OR SEEK CONSENT DURING THIS PHASE. SURVIVING PATIENTS OR THEIR APPROPRIATE REPRESENTATIVES WERE APPROACHED LATER TO ASK THEM IF WE CAN USE THEIR DATA. THERE WAS AN ACCOMPANYING ETHICS COMMENTARY BY A BIOETHICIST.& THIS IS WHAT THE BIOETHICIST SAID. HE SAID FAR FROM BEING UNETHICAL THE STUDY SETS A HIGH STANDARD FOR CONSENT IN PRAGMATIC TRIALS. DESPITE TRADITION OF OBTAINING INFORMED CONSENT FOR ALMOST ALL RESEARCH DEBATE SURROUND WHETHER PATIENT CONSENT SHOULD BE SOUGHT. WHEN BOTH TREATMENTS ARE LICENSED, LICENSED APPROVED LABELS, CONSENSUS SAY IS PRESENT REGARDING EQUIPOISE. WE DON'T KNOW AHEAD OF TIME WHICH IS BETTER. AND RANDOMIZATION DOES NOT POSE ANY ADDED RISK. SO THERE'S ASSUMPTION THAT RANDOMIZATION DOES NOT POSE ANY ADDED RISK. YOU MAY OR MAY NOT AGREE WITH THIS. I HAD COLLEAGUES THAT DIDN'T AGREE WITH THIS AND WROTE AN ARTICLE CRITIQUING THIS PROCEDURES. HOW MANY PEOPLE THINK THIS WAS A MINIMAL RISK STUDY? OKAY. HOW MANY PEOPLE THINK IT WAS DEFINITELY GREATER THAN MINIMAL RISK? HOW MANY DON'T KNOW? OKAY. NO UNIFORM VIEW. I WILL SKIP OVER THIS ONE. THIS IS A PEDIATRIC EXAMPLE. BUT BASICALLY MAKES THE SAME POINT. I HOPE FOR SOME OF YOU ANYWAY, WHERE WE ARE NOW IS THE FOLLOWING. WE NOW KNOW WHAT A PRAGMATIC TRIAL IS, HOW IT'S DESIGNED, WE SAW EXAMPLES. WE KNOW MANY PEOPLE THINK IF YOU ARE COMPARING TWO STANDARD OF CARE INTERVENTIONS, THAT AUTOMATICALLY MEANS IT'S MINIMAL RISK AND CANDIDATE FOR WAIVER. I THINK IT'S FAIR TO SAY FOR -- I WOULD SAY MAJORITY OF PEOPLE IN THE ROOM FELT THAT WELL MAYBE THAT DEFINITION BY ITSELF DOESN'T SAY IT'S MINIMAL RISK, WE HAVE THE LOOK AT THE ACTUAL TRIAL. I'M GOING TO TAKE IT AS A GIVEN THAT'S WHERE WE ARE AT. AND I'M GOING TO JUST GO THROUGH COUPLE OF WAYS IN WHICH WE -- I THINK WE SHOULD BE THINKING ABOUT THESE TRIALS. THE FIRST PART OF IN THE REMAINING I THINK 13 -- EIGHT MINUTES OR SO I HOPE I WILL GO THROUGH WITHIN CURRENT REGULATIONS HOW WE THINK ABOUT CERTAIN THINGS AND I'M GOING TO SAY SOME THINGS THAT ARE OUTSIDE OF THE CURRENT REGULATIONS AS SUGGESTIONS. WE DIDN'T SPEND TOO MUCH TIME TALKING ABOUT EQUIPOISE TODAY BECAUSE I KNOW BOB TRUOG H TALK ABOUT IT MANY MORE DETAIL. ESPECIALLY FOR TRIALS WHICH PROCEDURES PREVAILING PRACTICES WITHIN ICUs AND SO FORTH ARE DONE THERE IS SOME DISPUTE T IN FACT THERE ARE RESEARCHERS WITHIN NIH WHO BELIEVE A LOT OF THESE LARGE SCALE ICU TRIALS OFTEN COMPARE TWO INTERVENTIONS THAT ARE SEEN BY THE EXPERTS WHEN THEY DESIGNED IT AS WITHIN THE STANDARD OF CARE BUT IN ORDER TO DETECT DIFFERENCE SOMETIMES THEY TAKE THE EXTREMES OF THE PRACTICES AND THEY THINK THAT DOESN'T REPRESENT EQUIPOISE BECAUSE THAT'S NOT WHAT PEOPLE ACTUALLY DO. SO I THINK NUMBER ONE THING THAT WE SHOULD THINK ABOUT IS SHOULD CLAIM OF STANDARD PRACTICE OR WHY YOU USE BE VERIFIED? IS IT THE CASE THESE ARE STANDARD ACCEPTED PRACTICES AS DESIGNED IN THE TRIAL. THAT'S AN IMPORTANT POINT TO THINK ABOUT AT THE START FOR AN IRB. ESPECIALLY IMPORTANT FOR NON-REGULATED INTERVENTIONS. SECOND POINT IS HOW DO WE THINK ABOUT DETERMINING WHAT IS RESEARCH RISK AND HOW DO YOU PINPOINT THE FACT WHAT WE INTUITIVELY SAW IN THESE EXAMPLES AS WELL, THE IDEA IF THEY ARE IN STANDARD OF CARE YOU USE A OR B STANDARD PRACTICE AND COMPARE IT, THERE'S NO RISKER IT SOUNDS REALLY GOOD BUT WHEN WE LOOK AT EXAMPLES THERE ARE SOME EXAMPLES THAT MAKE YOU PAUSE EVEN IF YOU SAID MINIMAL RISK I'M SURE IT MADE YOU THINK IS IT THE CASE. HOW DO WE SYSTEMATICALLY GO THROUGH THAT? I'M GOING TO SPEND COUPLE OF MINUTES GIVING YOU RATIONALE AS TO WHY SOME OF THOSE STUDIES WERE NOT MINIMAL RISK IN MY MY OINION. IT'S THE FOLLOWING. CLINICAL EQUIPOISE MAY JUSTIFY A STUDY, IT'S A SCIENTIFICALLY WORTHY STUDY TO DO, BECAUSE IT'S AN OPEN QUESTION WHICH IS BETTER. BUT IT DOESN'T DIRECTLY PROVIDE A SENSE OF WHAT IS AT STAKE FOR THE PARTICIPANTS. WHAT DO I MEAN BY THAT, I'M GOING TO FLUSH THAT OUT. IF YOU ARE WILLING TO JUSTIFY DOING A PRAGMATIC TRIAL THE FOLLOWING TWO CONDITIONS HAVE TO BE MET. ONE, IT HAS TO BE UNCERTAIN THAT A IS BETTER THAN B OR B IS BETTER THAN A. BECAUSE IF YOU KNEW WITH SUFFICIENT LEVEL CERTAINTY ONE IS BETTER THAN THE OTHER YOU DON'T HAVE A BASIS FOR DOING THE STUDY. BUT REMEMBER ALSO IT HAS TO BE UNCERTAIN THAT A IS EQUIVALENT TO B BECAUSE IF THERE WAS SUFFICIENT INFORMATION WITH LOW ENOUGH ERROR RATE IN YOUR MIND THEY WERE EQUIVALENT THEN WHY DO THE STUDY. THAT HAS TO BE A GENUINE UNCERTAINTY IN BOTH OF THOSE SENSES. THE POINT IS THESE ARE -- COMPATIBLE WITH EQUIPOISE IF IT'S UNCERTAIN THAT A IS EQUIVALENT TO B SO YOU DON'T KNOW IF THEY'RE THE SAME IN TERMS OF THEIR MERITS, THEIR MERITS THERE IS A REAL PROSPECT THAT A COULD BE BETTER THAN B OR P COULD BE BETTER THAN A, DEPENDING ON THE PRIOR EVIDENCE OF THOSE TWO INTERVENTIONS. THIS PROSPECT TRANSLATES INTO THE PROSPECT THAT SOMEONE RECEIVING B IN ORDINARY CARE COULD FACE A DIFFERENT WELFARE OUTCOME BY ENTERING THE TRIAL. THERE IS A 50, 50 CHANCE SHE COULD GET A INSTEAD T. SINCE EVERY TRIAL WILL HAVE PROSPECT EVERY TRIAL HAS SOME RISK OF DIFFERENT WELFARE OUTCOME, BETTER OR WORSE FOR THAN INDIVIDUAL. THAT'S WHAT WE CALL RESEARCH RISK BECAUSE IT'S BY VIRTUE OF ENTERING THE TRIAL, PARTICIPATING RESEARCH THAT YOU INKER THAT RISK. THEREFORE, FROM IS RESEARCH RISK EVEN WHEN TWO TREATMENTS ARE BOTH CONSIDERED WITHIN STANDARD OF CARE. AS A RULE OF THUMB I THINK IT'S IMPORTANT TO LOOK AT THE OUTCOME, PRIMARY END POINT, IF IT'S MORTALITY MORBIDITY, SIGNIFICANT WHATEVER, AND THERE IS A PROSPECT THAT ENTERING THAT TRIAL YOU COULD FACE SOMETHING DIFFERENT FROM OUTSIDE, THEN THAT'S MORE THAN MINIMAL RISK. THE OTHER THING IS THAT WHICH I HOPE I WILL TALK ABOUT IN A MINUTE IS THAT IN THE HEAD POST TRIAL FOR INSTANCE EVEN WITHOUT UNDERSTANDING WHAT THE OUTCOME WOULD BE IN TERMS OF CIRCULATION SO FORTH, WHICH ONE IS BETTER THAN THE OTHER, THE IDEA OF ASKING A PERSON TO LIE DOWN, EAT, SLEEP AND TOILET LYING DOWN FOR 24 HOURS I WOULD SAY IS NOT A MONEY MALL BURDEN ON PERSON IF THAT IS CHOSEN FOR THE SAKE OF THE RESEARCH. THERE ARE CERTAIN BURDENS THAT YOU KNOW BEFORE YOU GO INTO THE TRIAL THAT ASSOCIATED ONE ARM OF THE INTERVENTION THAN NOT THAT YOU HAVE TO REALLY TAKE INTO ACCOUNT BECAUSE YOU DON'T -- THAT COULD CONSTITUTE, IN FACT BE SUFFICIENT TO SAY THIS IS NOT MINIMAL RISK BECAUSE RISK, BROADLY TAKING ADS DIFFERENCE IN WELFARE INCLUDING THE BURDENS OF BEING IN THE STUDY. I'M GOING TO SKIP MY DISCUSSION OF WAIVER AND MODIFICATION OF INFORMED CONSENT. INSTEAD JUMP TO SOME SUGGESTIONS I HAVE REGARDING THESE TRIALS. THE FIRST SUGGESTION IS THAT I WOULD SUBMIT NO INDIVIDUAL INTERVENTION, MEANING IF IT'S CLUSTER RANDOMIZED, IF YOU ARE DOING THE INTERVENTION INDIVIDUALLY, AND THIS SPEAKS TO HOLLY'S POINT TOO I THINK, SHOULD RECEIVE A COMPLETE WAIVER OF CONSENT. I'M MAKING A DISTINCTION BETWEEN A COMPLETE WAIVER AND ALTERING THE CONSENT PROCESS. MEANING I DON'T BELIEVE THAT APPROXIMATE INDIVIDUAL INTERVENTION CLINICAL RESEARCH SHOULD BE ALLOWED TO PROCEED WITH COMPLETE LACK OF TRANSPARENCY. WHY? THAT JUST ISN'T -- THAT DOESN'T PASS MUSTER IN TERMS OF CLINICAL ETHICS. THE IDEA THAT YOU WOULD DO SOMETHING AND CHOOSE SOMETHING THAT THE REASON FOR CHOOSING BETWEEN A AND B AS MOTIVATE BY SOME OTHER CONSIDERATION THAN WHAT IS BEST FOR THE PATIENT. THAT ELEMENT IS NOT TRANSPARENT TO THE PATIENT. I THINK IS AN IMPORTANT ETHICAL ISSUE. THIS IS ONE OF THE REASONS WHY WE HAVE SO MUCH DISCUSSION ABOUT CONFLICT OF INTEREST AND DOCTORS WHO MIGHT GET PAYMENTS FOR DOING THIS AND NOT -- WHERE INCREASE -- IT CREATES ANOTHER INCENTIVE FOR CHOOSING BETWEEN DIFFERENT TREATMENTS. I THINK THIS IS AN IMPORTANT POINT, IF IT'S AN INDIVIDUAL INTERVENTION WHERE YOU HAVE LIKE 24 HOURS INTERACTING WITH THIS PERSON AND YOU ARE INTENTIONALLY I THINK WITHHOLDING A CERTAIN PIECE OF INFORMATION, I THINK IT'S RELEVANTTOR THE PERSON. SUGGESTION TWO, FOR THESE STANDARD OF CARE CLINICAL TRIALS, LET'S STEP BACK AND THINK ABOUT WHY WE STARTED HAVING THIS DISCUSSION IN THE FIRST PLACE. IT REALLY IS A TRIAL COMPARING TWO ACCEPTED TREATMENTS. FROM THAT STANDPOINT, IT IS A DIFFERENT KIND OF TRIAL. I CAN TELL YOU THAT IF IT IS A NOVEL INTERVENTION AN IRB SHOULD DO THE FOLLOWING QUESTION. SHOULD WE OFFER THIS TO PEOPLE? IS IT SAFE ENOUGH TO OFFER? IF A PRAGMATIC TRIAL WAS WELL DESIGNED WITH A GOOD QUESTION, KNOWING THAT THEY ARE BOTH STANDARD OF CARE I THINK YOU HAVE YOUR ANSWER WHETHER OR NOT IT'S SAFE ENOUGH TO OFFER TO PEOPLE. IT IS. WE USE IT ALL THE TIME. THAT'S A MOOT QUESTION. I THINK PEOPLE CONFUSE THE ANSWER TO THAT QUESTION WHETHER OR NOT YOU SHOULD GET CONSENT BECAUSE IN THIS CASE WHAT WE SHOULD BE DOING IS TRYING TO MIMIC AS MUCH AS POSSIBLE GIVEN INTERACTION IS VERY CLOSE TO WHAT YOU DO IN CLINICAL PRACTICE MEET YOUR CLINICAL ETHICS OBLIGATIONS OF TRANSPARENCY AND THEN CONSIDER WHAT ADDITIONAL RESEARCH ETHICS TRANSPARENCY YOU NEED. I WOULD SUBMIT THIS IS WHAT WE SHOULD DO. THE TRULY IMPORTANT ELEMENTS OF INFORMED CONSENT FOR A TRIAL LIKE THIS, IS THE FOLLOWING: TUSHED DISCUSSION TWO ALTERNATIVE TREATMENTS AT THE LEVEL YOU OFFER TO PATIENTS IN A CLINICAL SETTING. I DON'T THINK YOU NEED TO DO ANY MORE THAN THAT, A OR B YOU DISCUSS USUAL AMOUNT OF DETAIL& ABOUT THAT TREATMENT. YOU DON'T NEED MORE BECAUSE THIS IS RESEARCH IN MY VIEW. THE REREALLY IMPORTANT THING IS TO TELL THEM LOOK, WE WANT TO BE TRANSPARENT HOW WE SELECT BETWEEN A AND B AND THIS RANDOMIZATION BECAUSE THAT'S DIFFERENT FROM HOW WE DO IT ORDINARILY CLINICALLY. TO ME THAT IS THE ESSENCE OF WHAT YOU NEED TO CONVEY, BECAUSE EVERYTHING ELSE IS WHAT YOU WOULD DO CLINICALLY. THAT NEEDS TO BE TRANSPARENT. ALL THE OTHER STUFF WE PILE ON THROUGH INFORMED CONSENT REQUIREMENTS WE SHOULD DO IT BRIEFLY OR I THINK WE SHOULD BE ABLE TO ALTER THE CONSENT. DOING THIS SHOULD TAKE A LITTLE EXTRA TIME THAN WHAT YOU DO FOR REGULAR CLINICAL CONSENT. MY FINAL SUGGESTION IS THAT THE REGULATIONS NEED THE SEPARATE OUT WAIVERS OF CONSENT FROM ALTERATIONS OF CONSENT. CURRENTLY THEY ARE TREATED COMPLETELY EQUIVALENTLY IN TERMS OF WHAT CONDITIONS HAVE TO BE IN PLACE BEFORE YOU ALLOW ONE OR THE OTHER. THEY ARE SEEN AS THE SAME THING. WHICH IS NOT ETHICALLY REALISTIC OR JUSTIFIED BECAUSE NOT BEING TRANSPARENT AT ALL VERSUS BEING COMPLETELY TRANSPARENT BUT DELETING SOME THINGS THAT YOU DON'T NEED TO REALLY TALK ABOUT IN A CLINICAL SETTING. LIKE IF YOU ARE IN A DOCTOR'S OFF IF IS AND YOU ARE TALKING ABOUT TREATMENT OPTIONS YOU DON'T NEED TO SAY WE ARE GOING TO MAINTAIN CONFIDENTIALITY IN ALL THIS, THAT'S IMPLICIT IN YOUR ENCOUNTER. SO I THINK THAT YOU SHOULD BE ALLOWED TO HAVE A MODIFIED CONSENT THAT ACCOMMODATES THE NEEDS OF PRAGMATIC TRIALS EVEN IF THE RISK ANALYSIS SHOWS THAT IT'S GREATER THAN MINIMAL RISK. IN SUMMARY, THE FACT THAT STANDARD OF CARE PCP IS COMPARING TWO STANDARD OF CARE INTERVENTIONS DOES NOT BY ITSELF CREATE A SPECIAL ETHICAL CATEGORY OF MINIMAL RISK OR NO RISK. INSTEAD WE NEED TO DO A CAREFUL CASE BY CASE ANALYSIS. SOME OF THIS WILL TURN OUT TO BE MNIMAL RISK AS WE SAW, SOME WILL NOT. WE NEED TO RECOGNIZE THAT UNIQUENESS OF SOME OF THESE PCTs WITH FLEXIBLE BUT STILL REQUIRED CONSENT PROCEDURES. THANK YOU. [APPLAUSE] WE CAN TURN THE LIGHT UP OR THAT LIGHT DOWN, I DON'T KNOW. QUESTIONS? YOU CAN ASK QUESTIONS ABOUT WHAT WASN'T CLEAR EITHER. FAIR GAME. KEVIN. >> HI, SCOTT. I COME FROM SOCIAL SCIENCE BACK GROUND. AND IRBs PUT SOCIAL SCIENTISTS THROUGH THE RINGER. AND LOTS OF DIFFERENT SOCIAL INTERVENTIONS THAT THEY TRY TO DO WITH THAT IN LIFE THEY WOULD HAVE NOT NEED INFORM CONSENT EVEN FOR LOW RISK TRIALS. CAN YOU WALK THROUGH KIND OF THE LOGIC BETWEEN THE CONSENT WAIVERS AND WHEN YOU CAN USE THEM VERSUS NOT? >> KEVIN, SO YOU CAN CORRECT ME IF I'M WRONG, I THINK YOU WANTED ME TO TALK ABOUT HOW WOULD THIS TRANSLATE INTO SOCIAL SCIENCE RESEARCH WHERE ISSUES COME UP WHERE THEY OFTEN REQUIRE >> I'M >> I'M CON >> I'M >> I'M >> I'M I'M #-SZ #-Z PROO >> I'M >> I'M >> I'M #-Z >> I'M K40EU6R7B8G9SDZS ABILITIES K3R50EU6R7B8G9SDZ -- >> I'M TROUBLED BY THE FACT THAT YOU WOULD HAVED CON SCENE >> I'M SPLURGE WAIVERS. >> YOU ARE TALKING ABOUT DISCREPANCY. >> I'M TIER, THAT'S MORE A SOCIOLOGICAL QUESTION RATHER RATHER THAN AN ETHICAL ONE. USED TO BE -- I'LL USE THIS EXAMPLE TO FLESH OUT. USED TO BE FDA WOULD NOT CATEGORIZE ANY CLINICAL TRIALS AS MINIMAL RISK. NOW THEY DO. THAT'S BECAUSE OF LARGELY THE MOVEMENT TO MOVE TOWARD ALLOWING SOME OF THESE TRIALS AS MINIMAL RISK WITHOUT -- AND WITH ALTERED OR MAYBE NO CONSENT. WHY DOES THAT HAPPEN? WAS THAT DONE THROUGH CAREFUL PUBLIC ETHICAL ANALYSIS? I DON'T THINK SO. I THINK THAT -- AND THE FLIP SIDE OF IT IS I DO ACTUALLY THINK THERE'S OVER-REGULATION OF SOCIAL BEHAVIORAL SCIENCE RESEARCH AND I'LL SEND YOU A PAPER IN WHICH I TRY TO FLESH THAT OUT. SO THERE IS A CERTAIN AMOUNT OF LACK OF INTERACTION BETWEEN ACROSS THESE DIFFERENT TYPES OF RESEARCH AND REALLY DOING THE ASSESSMENT OF RISK THAT'S RELEVANT. I HOPE THAT ANSWERS THAT. >> I WAS GOING TO ASK YOU TO SAY MORE AT THE THRESHOLD OF JUSTIFYING A PCT BUT NOT ENOUGH TO TALK ABOUT WHICH IS BETTER ALREADY. YOU TALK ABOUT META ANALYSIS WHERE SUPINE IS BETTER POST STROKE. SEEMS LIKE AT WHAT POINT WOULD THAT PRELIMINARY EVIDENCE HAVE BEEN SO MUCH THAT A PCT WASN'T WARRANTED IN THE FIRST PLACE? BECAUSE YOU ALREADY KNEW. >> THAT'S A GREAT QUESTION. THAT TRIAL TURNED OUT TO BE NEGATIVE SO THERE WAS NO DIFFERENCE BETWEEN THE TWO GROUPS. THE HEAD POST TRIAL. YOUR QUESTION IS WHAT JUSTIFY -- AT WHAT POINT IS IT A -- IS EVIDENCE SUFFICIENT TO SAY. AND THE QUESTION IS DEEMED IMPORTANT THAT YOU CAN SPEND THE MONEY DOING THE TRIAL, I BELIEVE. THAT'S A GENERAL QUESTION. AND THERE IS NO SYSTEMATIC WAY IN WHICH PEOPLE DO THAT. YOU SUBMIT GRANTS LET CEASE SAY AND YOU HAVE PEER REVIEW AND THEY SAY OH YES YOU JUSTIFIED THIS TRIAL AS IMPORTANT. YOU HAVE PEOPLE FOR WHOM THIS QUESTION IS IMPORTANT, THAT THEY MIGHT DECIDE TO TEST IT. SO IT IS A AREA THAT REQUIRES A LOT MORE ATTENTION BECAUSE THAT HAPPENS EVEN IN NOVEL TREATMENT DEVELOPMENT. RIGHT? THERE IS TREMENDOUS AMOUNT OF CRITICISM THESE DAYS ABOUT WHETHER OR NOT WE HAVE A TRULY SCIENTIFIC AND RATIONAL BASIS TO MOVE TO HUMAN STUDIES. BASED ON ANIMAL STUDIES AND OTHER THEORETICAL CONSIDERATIONS. BECAUSE LOT OF THE QUALITY OF THE RESEARCH DONE PRIOR TO THE CLINICAL, A LOT OF PEOPLE FEEL IS NOT VERY GOOD. PRONE TO LOTS OF FALSE POSITIVES. THAT'S WHY WE HAVE A REPLICATION CRISIS IN CLINICAL RESEARCH. SO THAT'S A GENERAL QUESTION. AND THE ANSWER OF COURSE IS A -- THERE IS NOT A SET WAY OF DOING IT. BUT WE NEED MORE. >> HI. I WAS WONDERING IF YOU COULD TALK A BIT MORE ABOUT TRIALS THAT DON'T INVOLVE A DIRECT CLINICAL INTERVENTION LIKE THE FRST TWO YOU MENTIONED? >> YES. >> HOW DO YOU THINK OR HOW MIGHT YOU GO ABOUT GETTING CONSENT FOR THAT KIND OF TRIAL WHEN THERE'S NOT A CLINICIAN PATIENT INTERACTION BEFOREHAND? LIKE WITH THE AND WHETHER YOU STILL THINK IT'S IMPORTANT IN THOSE CASES? >> I SORT OF THE GLOSSED OVER THE HOW YOU DETERMINE STUDY THAT'S BEEN DETERMINED TO BE MINIMAL RISK. THEN IT BECOMES A CANDIDATE FOR A WAIVER ALTERATION OF CONSENT AND THERE'S CERTAIN CRITERIA SUPPOSED TO MEET. I THINK THAT YOU CAN MAKE -- WE CAN GO THROUGH THOSE SO YOU WOULD TO HAVE TO DO THAT ANALYSIS TO SHOW WHY YOU WAIVE CONSENT IN THOSE TRIALS. THOSE PROBABLY YOU COULD DO THAT. BUT IT WOULD BE A JUDGMENT CALL HOW YOU FLESH THAT OUT AND EXPLAIN IT. SO MY ANSWER TO YOUR QUESTION WOULD BE SOME OF THOSE TRIALS, IF LOW RISK, AND YOU CAN MAKE A STRONG ENOUGH ARGUMENT THAT IT MEETS CRITERIA FOR WAIVER, THEN YOU WOULD DO IT WITH THE WAIVER. SO MY POSITION ISN'T THAT YOU HAVE TO DO EVERY SINGLE HOW SHOULD PUT IT -- MAYBE MODIFY THAT. WHEN YOU HAVE A FACE TO FACENT COUNTER WITH CLINICIAN, THIS SPEAKS TO HOLLY'S POINT WHERE YOU ARE ASKING SOMEBODY TO DO SOMETHING FOR SAKE OF RESEARCH AND YOU ARE IN A POSITION OF WITHHOLDING THE INFORMATION THAT HAS RESEARCH WE SHOULD TRY TO AVOID THAT. >> OTHER QUESTIONS? >> ALL RIGHT. GREAT. WE ARE VERY PRIVILEDGED TO HAVE WITH US DR. ROBERT TRUOG, A FRANCIS GLASSNER PROFESSOR OF LEGAL MEDICINE AND PROFESSOR OF ANESTHESIA AND PEDIATRICS, HARVARD MEDICAL SCHOOL. THANKS TO BOB, HE'S BEEN TEACHING IN THIS CLASS I THINK SINCE WE STARTED IT SO IT'S NOW MORE THAN 20 YEARS. IT MAKES THE TREK FROM BOSTON SPECIFICALLY TO SHARE HIS WISDOM WITH YOU. SO WE APPRECIATE HIM BEING HERE, THANK YOU. >> THANKS, CHRISTINE. [APPLAUSE] >> THANK YOU, EVERYBODY. I WAS ACTUALLY LOOKING AT MY RECORD, THIS IS THE 21st TIME I HAVE BEEN DOWN TO DO THIS, I MISSED ONE YEAR WHEN I HAD SURGERY AND FRANK MILLER DID THE LECTURE FOR ME BUT I'M STARTING TO GET THE TALK DOWN AND I HOPE THAT'S SOMETHING VALUABLE HERE. AS OLD IT IS THE CASE IS A LITTLE DATED BUT I WOULD SAY THAT THE ISSUES THAT WE'RE GOING TO TALK ABOUT ARE AS CURRENT AS EVER AND INDEED IN SOME CASES BUT I'LL EXPLAIN PERHAPS EVEN MORE CURRENT. I DO SOME WORK WITH DATA SAFETY MONITORING BOARDS, NONE OF IT RELATED TO THE CONTENT OF THIS TALK. HERE IS A PAPER WE ARE GOING TO TALK ABOUT. A MANUSCRIPT PUBLISH IN PEDIATRICS IN 1989, EXTRA MEMBRANE OXYGENATION AND CONVENTIONAL THERAPY IN NEONATES WITH PERSISTENT HYPERTENSION OF NEWBORN PROSPECTIVE RANDOMIZED STUDY. I KNOW THE CASE WELL BECAUSE I WAS A FELLOW AND CRITICAL CARE MEDICINE AT THE TIME THIS WORK WAS BEING DONE SO FOLLOW THAT PROCESS ALONG, I WASN'T ONE OF THE INSIDERS BUT I HAVE HAD MANY CONVERSATIONS ABOUT THE CASE WITH THOSE WHO WERE AND GOT AN LOT OF INSIGHT FROM THAT WHICH I WILL SHARE WITH YOU. HOW MANY OF YOU ARE FAMILIAR WITH ECMO AS A TECHNOLGY? SO NOT ACTUALLY THE MAJORITY I WOULD SAY SO LET ME EXPLAIN IT TO YOU A LITTLE BIT. IT'S SOMETHING WE USE AS FORM OF CARDIO PULMONARY BY PASS WE USE FOR PATIENTS -- BYPASS WE USE FOR PATIENTS WITH LIFE THREATENING CARDIAC OR PULMONARY FAILURE. I WILL EXPLAIN WHY THE PICTURE IS OF A BYE-BYE IN A MOMENT BUT LET ME GO THROUGH HOW IT WORKS. -- A BABY. BUT TO PUT SOMEBODY ON ECMO AN INCISION IS MADE IN THE NECK AND TWO CANNELLA ARE PASS TO THE HEART. ONE INTO THE RIGHT ATRIUM, AND THEN ONE INTO THE AORTIC ARCH, VENUS BLOOD IS DRAINED FROM THE ATRIUM TO A RESERVOIR WHERE WE ADD MEDICATION, MOST NOTABLY HEPARIN TO KEEP THE BLOOD FROM CLOTTING WHICH LEADS TO MAJOR RISK OF ECMO WHICH IS BLEEDING. THEN IT GOES TO A PURPOSE WHICH IS THE ARTIFICIAL HEART AND UP THROUGH THIS MEMBRANE OX GENEITYTOR. YOU CAN THINK ABOUT THIS AS A SILICON ENVELOPE ROLLED UP INTO A CYLINDER, BLOOD IS PASS THROUGH THE INSIDE OF THE ENVELOPE IN ONE DIRECTION AND FRESH GAS IS PASSED IN THE OUTSIDE OF THE ENVELOPE IN THE OTHER DIRECTION AND YOU GET GAS EXCHANGE OCCURRING ACROSS A SILICON MEMBRANE WHICH ADDS OXYGEN AND REMOVES CARBON DIOXIDE FROM THE BLOOD. FROM THERE, THE BLOOD GOES THROUGH A HEAT EXCHANGE TO WARM BACK UP TO BODY TEMPERATURE AND THEN BACK INTO THE BABY. AND THESE CHILDREN ARE TWO SICK TO GO TO THE OPERATING ROOM TO BE PUT ON ECMO SO WE BRING THE OPERATING ROOM UP TO THE ICU, WE CREATE THIS STERILE ENVIRONMENT AND YOU CAN SEE SURGEONS HERE PLACING THE CANNELLA. THIS IS WHAT IT LOOKS LIKE WHEN A BABY IS ON ECMO THOUGH THIS PICTURE WAS TAKEN YEARS AGO IT LOOKS ALMOST EXACTLY THE SAME TODAY. THIS IS OF COURSE THE PATIENT. BLOOD BEING DRAINED DOWN HERE TO THE BLADDER OR RESERVOIR WHERE MEDICATIONS ARE ADDED, UP THROUGH THE PUMP HERE, THE ARTIFICIAL HEART, THEN THROUGH THE MEMBRANE OX GENEITYTOR THE ARTIFICIAL LUNG. THROUGH THE HEAT EXCHANGE THROUGH THIS CYLINDER HERE TO WARM THE BLOOD BACK UP AND BACK INTO THE PAY BY. -- BABY. 24, 7 WE HAVE A NURSE THAT TAKES CARE OF THE BABY AND ECMO SPECIALIST THAT TAKES CARE OF THE PUMP. THIS IS WHAT A BABY LOOKS LIKE ON ECMO. IF YOU USE YOUR IMAGINATION YOU MIGHT CONVINCE YOURSELF THE BLOOD HERE IS A LITTLE DARKER THAN THE BLOOD HERE. SO THIS IS THE VENUS BLOOD THAT IS COMING OUT, THIS IS THE ARTERIALIZED BLOOD BACK IN. AND THE LIGHTS ARE AWKWARD BUT I WANT TO ASK SOME QUESTIONS. SO I CAN'T SEE YOU VERY WELL. BUT AT SEVERAL POINTS WE WILL PAUSE FOR A FEW COMMENTS. ONE FOR ANY OF YOU WHO HAVE EXPERIENCE WORKING IN AN ICU WHAT STRIKES YOU AS UNUSUAL ABOUT THIS PICTURE OTHER THAN THE FACT THE BABY IS ON ECMO? ANYTHING RELATED TO THE ENDOTRACHEAL TUBE? SPEAK UP. ANYBODY? OKAY. WELL, IT'S WHAT? IT IS LARGE TUBE THAT'S CONNECTED THERE. WHAT'S UNUSUAL IS THAT WE USUALLY HAVE THAT TUBE CONNECTED TO A VENTILATOR. TUBE FOR THE PATIENT, IT DRAMATICALLY MAKES THE POINT WHEN YOU ARE ON ECMO YOU DON'T NEED TO BREATHE. THE MACHINE IS DOING IT FOR YOU. IN TRUTH WE TOOK THE BABY OFF THE VENTILATOR TO DO THE PICTURE BECAUSE WE USUALLY KEEP THE VENTILATOR ATTACHED BUT NOT TO BREATHE FOR THE PATIENT RATHER PROVIDE POSITIVE PRESSURE TO KEEP RUNGS INFLATED. AND TO HEAL MORE QUICKLY. SO LET ME GIVE YOU BACKGROUND TO THE HARVARD TRIAL THAT I'M GOING TO DISCUSS. THEY ARE GOING TO RANDOMIZE CONTROL TRIAL MULTI-CENTER TRIAL PERFORM IN THE 1970s THAT SHOWN ECMO WAS NOT EFFECTIVE FOR THE ADULT RESPIRATORY SYNDROME IN ADULTS. ONE OF THE SURGEONS WAS INVOLVED IN THAT STUDY, HIS NAME WAS BOB BARTLETT, MASS GENERAL AT THE TIME, HE LOOKED BACK AT THE FAILURE OF THIS TRIAL AND HE THOUGHT MAYBE THE REASON IT FAILED WAS BECAUSE THESE PATIENTS ALREADY HAD IRREVERSIBLE LUNG FAILURE. IN OTHER WORDS ECMO CAN KEEP YOU ALIVE BUT IT DOESN'T DO ANYTHING PURETIVE. SO YOUR LUNGS HAVE TO BE ABLE TO HEAL WHILE ECMO IS WORKING AND IF YOUR LUNG DISEASE IS ALREADY IRREVERSIBLE IT'S NOT GOING TO, WHO. SO WE THOUGHT IT'S KIND OF A TECHNOLOGY INSERTION DISEASE WE THOUGHT CAN YOU FIND A DISEASE THAT IS REVERSIBLE AND REVERSIBLE IN A RELATIVELY SHORT PERIOD OF TIME LIKE A COUPLE OF WEEKS. THEN ECMO MIGHT BE USEFUL, THOUGH HE WASN'T A PEDIATRIC SURGEON, HE CAME ACROSS A PEDIATRIC DISEASE CALLED PPHN OR PERSISTENT PULMONARY HYPERTENSION OF NEWBORN. THE MOST COMMON CAUSE OF THIS IS WHEN A BABY IS BEING BORN, IF THE BABY INHAILS MICONIUM DURING THE PROCESS, IT IS IRRITATING TO THE LUNGS AND CAUSE IT IS PULMONARY ARTERIES TO GO INTO SPASM, IF THEY ARE IN SPASM AND YOU DON'T GET BLOOD FLOW TO THE LUNGS IT'S LIFE THREATENING. BUT IF YOU CAN KEEP THE BABY ALIVE FOR A WEEK OR SO, THAT'S SPASM RELAXES, BLOOD FLOW RETURNS TO THE LUNG AND YOU SAVE THE PATIENT'S LIFE. SO HE MOVED FROM BOSTON TO ANN ARBOR, MICHIGAN IN THE 1980s AND BEGAN TO USE ECMO TO TREAT BABIES WITH THIS DISEASE PPHM. HIS RESULTS WERE IMPRESSIVE. IN FACT, A LOT OF PEOPLE THOUGHT THEY WERE MIRACULOUS. THAT THERE WAS JUST THIS AMAZING ABILITY TO SAVE THE LIVES OF NEWBORNS THAT EVERYBODY WAS SURE OTHERWISE WOULD HAVE DIED. BUT HE FACED A DILEMMA, PEDIATRICIANS AROUND THE COUNTRY WERE RELUCTANT TO ADOPT THIS INVASIVE SURGICAL PROCEDURE WITHOUT CONVINCING DATA FROM A RANDOMIZED CONTROL TRIAL. SO I WOULD LIKE TO TO ASK YOU QUESTIONS, HOPEFULLY AGAIN, HOW DOES THIS WORK IN TERMS OF STUFF, CHRISTINE? SHOULD THEY COME TO THE MICROPHONE OR -- YES? (OFF MIC) YOU HAVE A ROVING MIC. MENT OKAY. HERE IS AN IMPORTANT QUESTION. IMAGINE YOU WERE BOB BARTLETT, YOU HAVE THIS NEW TREATMENT THAT YOU THINK IS LIFE SAVING. YOU CAN'T CONVINE OTHER PEOPLE TO USE IT. SO WOULD YOU HAVE SOUGHT TO PERFORM A RANDOMIZED CONTROL TRIAL TO DEMONSTRATE SUPERIORITY OF ECMO TO CONVENTIONAL MEDICAL THERAPY, IF YOU WERE IN HIS POSITION. THAT'S THE QUESTION. COUPLE OF PEOPLE WHO MIGHT BE WILLING TO SHARE THOUGHTS ABOUT THAT. YES OR NO? HOW ABOUT THIS. LET'S DO A VOTE HERE. KEVIN. OKAY. HERE WE GO. ALL RIGHT. SO I WOULD BE HESITANT IF MY MOTIVATION WAS TO GET PATIENTS QUICKLY YOUR DEALING WITH SMALL CHILDREN. WE ARE GOING (INDISCERNIBLE) EVEN ONCE YOU GET THROUGH THE TRIALS THAT TAKE A LONG TIME WHATEVER BABIES THAT AREN'T GIVEN THIS MEDICAL TREATMENT. SO IF -- HELP ME OUT, IF I DIDN'T GET ALL THAT RIGHT, YOU WERE SAYING BE HESITANT BECAUSE THESE ARE SMALL BABIES. SO THAT WOULD BE A REASON NOT TO DO THE TRIAL THAT WE REALLY HAVE A PRIMARY OBLIGATION TO TREAT THEM CLINICALLY. BUT THEN YOU ALSO AT END MENTIONED THE TRIAL WOULD TAKE A LONG TIME AND WHILE THE TRIAL IS GOING ON THERE'S GOING TO BE OTHER CHILDREN WITH THIS DISEASE. WHO ARE GOING TO DIE BECAUSE THEY DON'T GET THIS THERAPY. YEAH. SO I GOT YOU. AND YET WE HAVE THIS DILEMMA THAT OTHER PEDIATRICIANS AREN'T GOING TO ADOPT THE THERAPY UNLESS THEY HAVE THIS RANDOMIZED TRIAL. SO I THINK YOU SEE THE DILEMMA HERE IF HE DOES THE TRIAL TYPICALLY BABIES WOULD GET RANDOMIZED TO ECMO OR CONVENTIONAL THERAPY. IF E C,MO IS THAT GOOD SOME MR. BAYHI: S WHO DON'T GET THE THERAPY -- BABIES WHO DON'T GET THE THERAPY WHO WON'T SURVIVE WHO OTHERWISE WOULD HAVE. ON THE OTHER HAND, IF YOU DON'T DO THE TRIAL, THEN THE ONLY BABIES YOU ARE SAFING ARE THE ONES IN ANN ARBOR, AND YOU ARE DEPRIVING CHILDREN AROUND THE COUNTRY AND POTENTIALLY AROUND THE WORLD OF SOMETHING THAT COULD IN THE LONG RUN SAVE MANY MORE LIVES. SO I SHOULD HAVE DONE THIS FIRST, WITH THAT BACKGROUND HOW MANY OF YOU WOULD SAY NO, YOU SHOULD DO A RANDOMIZED TRIAL AT THIS POINT FOR THE GREATER GOOD OF CHILDREN AROUND THE WORLD. I WOULD SAY THAT'S MOST OF YOU. HOW MANY WOULD SAY NO HE HAS AN OBLIGATION PRIMARILY TO GIVE PATIENT IT IS BEST TREATMENT HE THINKS IS POSSIBLE. SO WE GOT THAT ONE. WHAT HE DID WAS A LITTLE IN BETWEEN. SO HE SAID OKAY, YOU WANT A RANDOMIZED TRIAL I WILL GIVE YOU A RANDOMIZED TRIAL. THIS WAS THE PAPER HE PUBLISHED. NEONATAL RESPIRATORY FAILURE A PROSPECTIVE RANDOMIZED STUDY. IT WASN'T LIKE THE TYPICAL RANDOMIZED TRIALS YOU ARE USED TO SEEING. HE USED A STRATEGY CALLED THE PLAY THE WINNER DESIGN. LET ME EXPLAIN HOW IT WORKS. I WILL DO IT TWICE. I WILL FIRST OF ALL EXPLAIN TO YOU IN WORDS THEN I WILL SHOW YOU HOW IT PLAYED OUT IN THIS TRIAL. IT'S A LITTLE BIT CONFUSING. HERE IS HOW IT GOES. WHEN YOU START THE TRIAL YOU START OUT WITH A BUCKET THAT HAS TWO MARBLES IN IT. LET'S SAY A BLACK AND YELLOW MARBLE. BLACK IS CONVENTIONAL THERAPY AND YELLOW IS FOR ECMO. CONVENTIONAL MEDICAL THERAPY INCLUDES EVERYTHING THAT WE WERE DOING IN NEONATOLOGY AT THE TIME. VENTILATORS, DRUGS, WHATEVER ELSE. ECMO WAS AD TO ALL THAT OTHER STUFF SO THE ONLY DIFFERENCE BETWEENS THE TWO GROUPS IS ONE WOULD GET ECMO AND ONE WOULDN'T. HERE IS HOW THE TRIAL WORKED. HERE WAS THE RULE. IF FOR THE FIRST BABY YOU REACH IN AND PULL OUR A MARBLE, THAT DETERMINE WHAT IS THE BABY GETS. IF THAT CHILD LIVES THEN THE NEXT DRAW ANOTHER MARBLE OF THE& SAME COLOR GOES IN THE BUCKET. IF THAT BABY DIES, THEN THE NEXT DRAW ANOTHER MARBLE OF THE OPPOSITE COLOR GOES IN THE BUCKET. YOU REPEAT THIS UNTIL THE TRIAL CONCLUDES. SO HERE IS HOW IT WENT. MENT WE STARTED OFF WITH THE TWO MARBLES, THE FIRST BABY THAT CAME DREW THE YELLOW MARBLE FOR ECMO AND SURVIVED. THEN THE RULE IS THAT FOR THE NEXT DRAW SINCE THAT BABY SURVIVED ANOTHER MARBLE OF SAME COLOR, YELLOW, GOES INTO THE BUCKET. SECOND BABY GOT THE BRAC MARBLE AND DIED SO THE RULE IS IF THAT PATIENT DIES ANOTHER MARBLE OF OPPOSITE COLOR WHICH WOULD BE YELLOW GOES INTO THE BUCKET. SO YOU CAN SEE WHY THIS IS CALLED PLAY THE WINNER, IS THAT THE RANDOMIZATION GRADUALLY BEGINS TO FAVOR TREATMENT THAT IS WINNING. THIS WENT ON AND THERE WERE AT THE END OF THE STUDY TEN PATIENTS WHO GOT ECMO ALL WHOM SURVIVE AND THE ONE PATIENT WITH CONVENTIONAL THERAPY THAT DIED. AT THIS POINT, YOU WILL HAVE TO TRUST ME ON THIS, I WILL SAY MORE ABOUT IT, AT THIS POINT THE P VALUE WAS LESS THAN .05 AN STUDY WAS DECLARED TO BE A CONCLUSIVE PROOF OF SUPERIORITY OF ECMO. SO I'LL COME BACK, WE WILL TALK MORE ABOUT THAT BUT I WANT TO MENTION A LITTLE BIT ABOUT THIS ONE WHO DIED. IT TUSHED OUT -- A FEW YEARS BACK I WAS ABLE TO HAVE DINNER WITH BOB BARTLETT AND I WAS TALKING WITH HIM ABOUT THE TRIAL AND I ASKED HIM ABOUT THIS PATIENT. THE ONLY PATIENT WHO DIED IN THIS TRIAL. AND TURNED OUT THIS WAS A PATIENT FROM KALAMAZOO,ISH MANY MESH, THE MOM IN HER 40s, SHE HAD DIFFICULTIES WITH FER TOLLTY, GONE THROUGH FER TOLLTY TREATMENTS, THIS IS THE FIRST TIME SHE WAS PREGNANT. AND THERE WERE COMPLICATIONS DURING THE PREGNANCY AND HAD TO HAVE A HYSTERECTOMY DURING DELIVERY SO IT WAS HER LAST OPPORTUNITY TO BE ABLE TO DELIVER A CHILD. THE NEONATAL ICU HAD NEVER REFERRED A PATIENT TO ANN ARBOR BUT THE DIRECTOR CALLED BOB AND SAID I HAVE HEARD YOU GOT ECMO YOU HAVE REALLY GOT TO TAKE THIS PATIENT AND TREAT WITH ECMO. THIS IS JUST A CASE WHERE JUST HAVE TO -- THIS PAY BY HAS TO SORROW BABY HAS TO SURVIVE. BARTLETT SAID WE'RE HAPPY TO TAKE THE PATIENT BUT GOT TO TELL YOU WE JUST STARTED THIS RANDOMIZE TRIAL AND WE HAVE TO RANDOMIZE THE BECAUSE BY. THE GUY IN KALAMAZOO SAYS YOU CAN'T DO THAT, YOU HAVE TO TAKE THE BABY OUT OF THE TRIAL, SO WE THOUGHT ABOUT IT AND DECIDED WE COULDN'T DO THAT. INITIALLY HE TOLD ME THE BABY STARTED TO GET BETTER AND PEOPLE WERE ABOUT TO BREATHE A SIGH OF RELIEF BUT THEN THINGS WENT SOUTH AND THE BABY ENDED UP DYING. HE RECALLED THIS ONE OF THE MOST EMOTIONALLY DIFFICULT TIMES OF HIS CAREER. THE IDEA BECAUSE YOU ARE DOING A TRIAL AND HERE IS A BABY THAT BABY DIED. HE TOLD ME LATER IN THE TRIAL HIS BROTHER THERE'S DAUGHTER HIS NIECE OLIVE IN INDIANAPOLIS ALSO WAS BORN OF ASPIRATION SYNDROME, HE NEVER GOT -- SHE NEVER GOT SICK ENOUGH TO NEED ECMO BUT IF SHE HAD COME UP WE WOULD HAVE ENROLLED HER AS WELL. SOME OF THE THINGS THAT GO ALONG WITH TRIALS OF THIS TYPE. SO HERE IS THE NEXT QUESTION FOR YOU. IMAGINE YOU WERE KNEE NAY TOLL GIST IN BOSTON. WHEN YOU READ THIS ARTICLE WOULD YOU HAVE TOLL YOUR HOSPITAL ADMINISTRATOR THAT YOU NEEDED TO START AN ECMO PROGRAM AND WHY OR WHY NOT? LET'S START WITH A VOTE. IMAGINE YOU ARE IN THIS ROLE, YOU HAVE BEEN WAITING FOR BOB BARTLETT TO DO RCT, HE'S DONE IT. DO YOU SAY OKAY, THAT WAS THE EVIDENCE WE NEEDED. OR NOT. AND SO HOW MANY OF YOU SAID THAT'S EVIDENCE THAT I NEEDED? HOW MANY WOULD SAY NOPE. I SAY IT'S 50/50. HOW ABOUT -- LET ME HEAR A COMMENT FROM SOMEBODY WHO SAID NO. HAND UP OVER HERE. CHRISTINE WILL GET HER EXERCISE IN. >> I'M NOT SUPER FAMILIAR WITH THIS PARTICULAR DESIGN PLAY THE WINNER BUT SEEMS LIKE IF I WASN'T CONVINCED BEFORE BY WHAT MAYBE I WOULD HAVE CALLED ANECDOTAL EVIDENCE THIS DOESN'T STRIKE ME AS SUPER CONVINCING BECAUSE EVEN IF P VALUE IS LESS THAN .05 SEEMS LIKE THAT ONE PATIENT COULD HAVE ANY NUMBER OF UNIQUE THINGS GOING ON. SO IT DOESN'T STRIKE ME AS SUPER CONVINCING DATA IF RCT IS WHAT I WAS LOOKING FOR IN THE FIRST PLACE. I THINK THIS WHOLE STUDY SEEMS TO TURN ON OUTCOME OF ONE PATIENT. THAT DOESN'T SEEM ALL THAT CONVINCING. HOW ABOUT FOR SOMEBODY WHO SAID YES. REALLY IS P LESS THAN .05. ANYBODY LIKE TO SHARE WHY THIS IS CONVINCE SOMETHING -- CONVINCING? NO TAKERS? >> I FEEL LIKE EVEN THOUGH YOU ONLY HAVE ONE OF THE CMT YOU HAVE TEN OF THE ECMO. SO IF YOU KIND OF LOOK AT IT FROM THE OTHER SIDE YOU BASICALLY HAVE NO EVIDENCE THAT SAYS ECMO IS BAD AND YOU HAVE LIKE ONE PATIENT THAT DIED SO YOU HAVE A LITTLE BIT OF DOUBT THAT CMT IS BETTER AND YOU HAVE NO DOUBT FROM ECMO BECAUSE NONE OF THE PATIENTS DIED. SO HEAR FROM THAT WAY YOU COULD ACCEPT IT. >> I LOVE THAT. IT'S SORT OF THE HALF GLASS EMPTY, HALF GLASS FULL KIND OF THING. THERE'S TEN PATIENTS, ALL LIVE WITH ECMO, THERE'S SOMETHING GOING FOR IT. THIS PAPER WAS PUBLISHED IN PEDIATRICS AND THERE WAS AN EDITORIAL A COMPANY DID FROM JIM WEHR DEAN OF HARVARD SCHOOL OF PUBLIC HEALTH AND MIKE EPSTEIN, CHIEF OF NEONATOLOGY.& THEY WERE SKEPTICAL. THEY SAID THE CLINICAL INDICATIONS FOR THIS NEW TREATMENT REMAIN UNDEFIND, RANDOMIZED CONTROL TRIALS WILL BE DIFFICULT BUT REMAIN NECESSARY. IN THE TRUE ENTREPRENEUR SPIRIT THEY WROTE THE EDITORIAL AND THEN THEY DID THEY THOUGHT THE TRIAL WAS NECESSARY. SO THAT IS THE TRIAL WE'LL TALK ABOUT IN MORE DETAIL HERE. SO MORE ABOUT LO CONTRIBUTION BECAUSE THEY MATTER I THINK FROM -- LO CONTRIBUTIONICS BECAUSE THEY MATTER FROM AN ETHICAL PERSPECTIVE. THE PLAN WAS TO DO THE TRIAL IN TWO LOCATIONS. CONVENTIONAL THERAPY IN NEONATAL ICU 7TH FLOOR, ECMO IN PEDIATRIC ICU ON THE FIFTH FLOOR. SO THERE WOULD BE FIRST A HEALTHY COMPETITION BETWEEN THE TWO CLINICAL TEAMS AND ALSO IT WOULD SEPARATE THE PARENTS OF CHILDREN DEPENDING WHAT THERAPY THEY WERE GETTING. SO YOU WOULDN'T HAVE THE PARENTS OF A BABY ON ECMO NEXT TO PARENTS OF BABY NOT ON ECMO. O THE NICU IS STAFFED BID NEONATAL GIST, PICU BY ANESTHESIOLOGISTS SURGEON, THAT'S WHERE I WAS WORKING AT THE TIME AS A FELLOW. NOW, ONE OF THE ADVANTAGES OF THE HARVARD TRIAL OVER THE BARTLETT PHASE IS WE HAD NEVER OFFERED ECMO FOR THIS DISEASE PPHN. SO WE DIDN'T FACE THE DILEMMA HE DID, WHICH IS YOU COULD GET ECMO IF NEEDED UNTIL THE TRIAL WAS STARTED THEN SUDDENLY IT WASN'T AVAILABLE. IN BOSTON IT HAD NEVER BEEN AVAILABLE. SO WE WEREN'T TAKING SOMETHING OFF THE TABLE IF YOU WERE THAT HAD PREVIOUSLY BEEN AVAILABLE. AND THE OTHER SORT OF UNIQUE ADVANTAGE WE HAD WAS THAT IN THE PEDIATRIC ICU WE HAD BEEN DOING ECMO BUT FOR A DIFFERENT DISEASE FOR C HOE CONGENITAL DIAFRAMATIC AND THE CONTENTS COME UP INTO THE CHEST. ECMO IS A HIGHLY TECHNICAL THERAPY WHERE THERE IS A STEEP LEARNING CURVE WHEN YOU ARE FIRST DOING IT THE FIRST BABIES DON'T DO HE WILL BUT EVENTUALLY YOU GET GOOD AD START TO SEE THE TRUE VALUE OF THE THERAPY. SO WE WERE ALREADY BEYOND THE STEEP PART OF THAT LEARNING CURVE WITH THIS OTHER DISEASE. SO IT'S GOING TO BE A FAIR COMPARISON OF ECMO VERSUS CONVENTIONAL THERAPY. THEN AGAIN, THERE WAS THIS HEALTHY COMPETITION THIS, NEONATOLOGIES, VERY SKEPTICAL ABOUT THE SURGICAL THERAPY, THE ANESTHESIOLOGISTS AND SURGEONS ON THE OTHER HAND MORE INCLINED TO BE PROSURGERY, CHANCE TO CUT IS A CHANCE TO HEAL MENTALITY. SO IT WAS A GOOD SET UP TO DO THE TRIAL. THEN HERE ARE SOME OF THE ENROLLMENT CRITERIA. ELIGIBLE NEWBORNS HAD THIS DISEASE PPHN AND PREDICTED MORTALITY OF 85% BASED ON RETROSPECTIVE DATA. LUCKY TO REMEMBER THAT NUMBER, 85%. THE TRIAL WAS DIVIDED IN TWO PHASES THOUGH THE ONLY PERSON WHO KNEW THAT WAS JIM WEHR, THE STATISTICIAN. THE WAY HE DESIGNED THE TRIAL, THERE WAS GOING TO BE PHASE 1 BABIES RANDOMIZED 50/50 AND THAT WOULD CONTINUE UNTIL THERE WERE FOUR DEATHS IN ONE ARM. AT THAT POINT THE STUDY WOULD ENTER PHASE 2 AND ALL PATIENTS WOULD BE ASSIGNED TO THE MORE SUCCESSFUL ARM UNTIL THERE WERE FOUR DEATHS IN THAT ARM OR UNTIL STATISTICAL SIGNIFICANCE WAS ACHIEVED. FINALLY, THE STUDY WAS DESIGNED TO SEEK CONSENT ONLY FROM THOSE RANDOMIZED TO EXPERIMENTAL THERAPY. I'LL COME BACK TO THAT LAST PART IN A MOMENT. RIGHT NOW I WANT TO CALL YOUR ATTENTION TO BREAKING POINT BETWEEN PHASE 1 AND 2 WHICH IS IT OCCURRED AT FOURTH DEATH. THIS WAS ALWAYS A MYSTERY TO ME, WHERE DID THAT NUMBER FOUR COME FROM? JIM WEHR UNFORTUNATELY DIED A COUPLE OF YEARS AGO BUT BEFORE THAT I HAD THE OPPORTUNITY TO TEACH THIS CASE WITH HIM AT THE SCHOOL OF PUBLIC HEALTH. IT WAS ONE OF THE FIRST QUESTIONS I ASKED JIM, WHERE DID THIS NUMBER FOUR COME FROM? HE SAID SIMPLE, TOOK OUT THE JOURNAL THAT HAD THE PAPER ABOUT IT AND HE GOES HERE IS THE ANSWER. AND I WAS LOOKING YOU GOT TO BE KIDDING. NO. HE SAID WELL I CAN SEE THERE'S A FOUR HERE AND SIMILARLY THERE'S A FOUR HERE. THAT WAS ABOUT THE MOST I WAS ABLE TO UNDERSTAND ABOUT THIS. AND SO AS WE TAUGHT IT I WOULD MAKE THIS JOKE, HE NEVER THOUGHT IT WAS FUNNY. IT WAS LIKE IT'S RIGHT THERE. BUT THE DEEPER POINT I WANT TO MAKE ABOUT THIS IS THAT THESE ADAPTIVE RANDOMIZATION SCHEMES ARE VERY COMPLEX. THEY ARE MATHEMATICALLY COMPLEX AND THEY AREN'T EXCUSETIVE. AS YOU SAW WITH THE BARTLETT TRIAL, LOOK AT THAT, WAIT, ONE PATIENT IN CONTROL GROUP IS NOT CONVINCING THOUGH MATHEMATICALLY IT'S SOUND. SO HOW DID IT TURN OUT? IN PHASE 1 NINE PATIENTS RANDOMIZE TO ECMO, ALL NINE SURVIVED. TEN PATIENTS WERE RANDOMIZED TO CONVENTIONAL THERAPY, SIX SURVIVED FOUR DIED SO REMEMBER THAT WHEN THERE'S A FOUR -- THE FOURTH DEATH IN ONE ARM THE STUDY ENTERS PHASE 2, ALL PATIENTS GET ASSIGNED TO THE MORE SUCCESSFUL THERAPY WHICH IN THIS CASE IS ECMO AND ADDITIONAL 20 PATIENTS WERE ENROLLED, 19 SURVIVED. ONE DIED. AND THE STUDY WAS DECLARED TO BE STATISTICALLY SIGNIFICANT AT THAT POINT. I WOULD SAY EVEN THE ONE THAT DIED WAS UNUSUAL, TURNED OUT DURING CANNULATION THE CANNELLA PERFORATED THE RIGHT VENTRICLE AND THE BABY DIED ALMOST IMMEDIATELY. SO A COMPLICATION OF ECMO TO BE SURE BUT NOT REALLY A FAILURE OF THE TECHNOLOGY ITSELF. JUST PARENTHETICALLY DO YOU REMEMBER WHAT THE ENROLLMENT CRITERIA WERE, IN OTHER WORDS WHAT WAS THE EXPECTED MORTALITY OF PATIENTS THAT WERE GOING TO BE ENROLLED IN THE STUDY? 85%. THAT WAS ON OUR OWN HOSPITAL IN OUR OWN NICU IMMEDIATELY PRIOR TO THE STUDY BEING PERFORMED. WHAT WAS THE MORTALITY SEEN ACTUALLY IN THE STUDY, IN THE CONVENTIONAL PATIENTS? 40%. SO YOU HAD TO HAVE PREDICTED MORTALITY 85% TO GET INTO THE STUDY BUT ONCE IN WE ONLY SAW 40% MORTALITY. ANY IDEA WHY THAT MIGHT BE? SPEND A LOT OF TIME ON THIS BUT YOU CAN CALL IT OUT. (OFF MIC) >> WELL, YEAH, BUT THE PATIENTS WERE AT LEAST IN PHASE 1 RANDOMIZED 50/50. SMALL NUMBERS. SO SMALL NUMBERS IS ONE POSSIBLE EXPLANATION HERE. IF WE DONE IT LONG ENOUGH WE WOULD HAVE SEEN 85%. ANOTHER POSSIBLE EXPLANATION? (OFF MIC) >> DILUTED. (OFF MIC) >> WELL THE OVERALL MORTALITY IN THE -- IT WENT -- SORRY. IN THE CONVENTIONAL ARM WAS ONLY 40% SO THESE PATIENTS BY ENROLLMENT CRITERIA SHOULD HAVE HAD 85% MORTALITY, THESE TEN BASED UPON OUR OWN DATA FROM RIGHT BEFORE THE STUDY WAS STARTED. THERE'S ALSO THE HAWTHORNE EFFECT. SO WHEN THE HAWTHORNE EFFECT IS WHEN YOU STUDY SOMETHING THE RESULTS CHANGE. I MENTIONED THAT WAS KIND OF A COMPETITIVE ATMOSPHERE HERE. WHETHER THE NEONATOLOGIES PERFORMED BETTER BECAUSE THEY KNEW THERE WAS ALSO -- THE RESULTS BEING STUDIED, I DON'T KNOW. PROBABLY THE MOST LIKELY THING. LET ME JUST ABOUT THE STUDY THE TECHNOLOGY, NOW WE ARE GOING TO TALK ABOUT THE EFFECTS. WE'RE GOING TO GET TO THAT IN A MINUTE. IF I DON'T COME BACK. SO IF THERE'S ONE THING I WANT YOU TO TAKE FROM THIS TALK, IT'S& WHAT I WOULD SAY IS THE FUNDAMENTAL CONFLICT HERE BETWEEN DOING RESEARCH AND DOING CLINICAL CARE IS THE DIFFERENT ROLES OF HEALER VERSUS INVESTIGATOR. THE BIOETHICIST JAY KATZ PUTS IT THIS WAY, A DILEMMA CONFRONTS PHYSICIAN INVESTIGATORS THEY ARE DEDICATED TO CARING FOR PATIENT BUS AS INVESTIGATORS THEY ARE DEDICATED TO CARING FOR THEIR RESEARCH AND THESE TWO COMMITMENTS CONFLICT WHENEVER AN INDIVIDUAL PHYSICIAN SLASH INVESTIGATOR COMES FACE TO FACE WITH AN INDIVIDUAL PATIENT SLASH SUBJECT. THE PUBLIC IS ON TO THIS, HERE IS A NEW YORKER CARTOON A NUMBER OF YEARS AGO. THE PUBLIC IS SUSPICIOUS ABOUT RESEARCH, YOU WILL BE PUT IN THAT PLACEBO GROUP AND THIS IS HOW YOU ARE GOING TO END UP. SO WHAT SHOULD WE DO? ABOUT THIS CONFLICT? GIVE YOU THREE POSSIBLE WAYS OF APPROACHING IT. THE FIRST IS TO SEPARATE ROLES OF CLINICIAN AND INVESTIGATOR. SO REBECCA DRESSER WROTE ABOUT THIS IN FAVOR OF IT AND SOMEWHAT TONGUE IN CHEEK PERHAPS SAID THE RESEARCHERS MUST GIVE PATIENTS STARK BOLD AND DRAMATIC SIGNS THAT RESEARCH IS DIFFERENT FROM CLINICAL CARE. INSTEAD OF THE WHITECOATS ASSOCIATED WITH MEDICAL CARE INVESTIGATORS COULD WEAR RED ONES. BE CLEAR TO PATIENT. WHEN SOMEBODY WALKS IN THE ROOM WITH WHITE COAT ON THEY ARE HERE TO HELP ME. IF THEY HAVE THE RED COAT ON HERE TO DO RESEARCH. IN REALITY WE ALL WEAR THE WHITE COAT, RIGHT? AND TO A CERTAIN EXTENT IT'S CONFLATTING THESE TWO ROLES. I SHOULD SAY LET ME SAY AGAIN THIS IS GOOD TO DO WHENEVER POSSIBLE. IN THE INTENSIVE CARE UNIT WHERE I WORK IF THERE IS A PATIENT ELIGIBLE FOR A STUDY I WOULD NEVER BE THE ONE ENROLLING A PATIENT IN THAT STUDY, YOU WOULD ALWAYS HAVE SOMEBODY FROM THE RESEARCH TEAM COME AND DO ENROLLING. IT'S NOT ALWAYS POSSIBLE. WHEN A PATIENT COMES TO THE CLINICAL CENTER HERE AND THEY HAVE GOT A RARE CANCER, MORE LIKELY THAN NOT THE PERSON WHO IS THE BEST DOCTOR FOR THAT PATIENT IS ALSO THE PERSON WHO IS DOING THE RESEARCH ON THAT DISEASE. NOT ALL POSSIBLY OR EVEN WISE, THEY DON'T WANT THAT SPRAYS, THEY WANT THAT KNOWLEDGEABLE PERSON TO BE THEIR DOCTOR AND THAT'S ALSO THE PERSON DOING RESEARCH ANOTHER POSSIBILITY IS WHAT'S CALLED PERSONAL EQUIPOISE WHICH WE CAN SAY REQUIRES THE INVESTIGATOR BE PERSONALLY UNBIASED BETWEEN THE TREATMENT ARMS PERFECTLY BALANCED ON THE EDGE OF A SWORD IF YOU WILL. I THINK FOR SOME OF YOU WHO THOUGHT IT WAS UNETHICAL FOR BOB BARTLETT TO BE ENROLLING PATIENTS IN THE TRIAL MAYBE WHAT WAS YOU HAD IN MIND, IF HE'S DOING THE RESEARCH HE HAS TO BE UNBIASED BETWEEN THE TWO ARMS AND OBVIOUSLY HE NEATS, HE THOUGHT ECMO OBVIOUSLY WAS THE SUPERIOR THERAPY. I THINK THERE'S A LOT OF PROBLEMS WITH THIS STANDARD OF PERSONAL EBB QUESTION POISE. FIRST RESEARCH O -- EQUIPOISE. RESEARCHERS BELIEVE IN THE STUDIES, BOB BARTLETT DID, IF THERE THERE'S PEOPLE HERE DOING CLINICAL RESEARCH YOU WOULDN'T HAVE PICKED THE TRIAL YOU HAVE IF YOU DIDN'T BELIEVE IT WAS HOPEFULLY GOING TO WORK. YOU WOULDN'T WASTE YEARS OF LIFE ON SOMETHING YOU WERE TRULY UNCERTAIN ABOUT, YOU WOULD HAVE A HUNCH THAT YEAH THIS WILL BE SUCCESSFUL. SO REQUIRING PERSONAL EQUIPOISE TENDS TO LEAVE INVESTIGATORS FEELING GUILTY OR CYNICAL. GUILTY IN THE SENSE THAT I'M NOT IN PERSONAL EQUIPOISE, I SHOULDN'T BE ENROLLING THESE PATIENTS OR CYNICAL AS IN I KNOW I'M NOT DOING SOMETHING WRONG. IF ETHICISTS ARE TELLING ME I'M DOING SOMETHING WRONG THERE HAS TO BE SOMETHING WRONG WITH OTHERS. WHERE DO WE GO FROM HERE? BENJAMIN FRIEDMAN BIOETHICIST FROM THE 1980s DIED YOUNG UNFORTUNATELY CAME UP WITH THIS THIRD SOLUTION, IDEA OF CLINICAL EQUIPOISE, NOT PERSONAL BUT CLINICAL EQUIPOISE NOT UNCERTAINTY WITHIN THE INDIVIDUAL BUT WITHIN THE MEDICAL COMMUNITY AS A WHOLE. THE IDEA IS AS FOLLOWS. SUPPOSE SOMEBODY COMES IN TO A CLINIC. SAY TO BE TREATED FOR HYPERTENSION. THE PHYSICIAN IS ALSO AN INVESTIGATOR SAYS YOU KNOW, I BELIEVE DRUG A WOULD BE BETTER FOR YOU. BUT IF YOUR APPOINTMENT HAPPENED TO HAVE BEEN WITH MY COLLEAGUE DOWN THE HALL I KNOW SHE WOULD HAVE RECOMMENDED DRUG B. WE JUST DISAGREE ABOUT THIS. SO WOULD YOU AGREE TO HAVE YOUR TREATMENT DETERMINED BY A COIN FLIP SO WE CAN LEARN FROM THE EXPERIENCE AND ACTUALLY COME TO AN UNDERSTANDING OF WHETHER A OR B IS THE BETTER DRUG. THIS IS THE IDEA BETWEEN CLINICAL EQUIPOISE, IT DOESN'T REQUIRE THE INVESTIGATOR TO BE EQUIPOISES, IT REQUIRES UNCERTAINTY WITHIN THE COMMUNITY AS A WHOLE. WE SAW IT PLAY OUT IN THE HARVARD ECMO TRIAL, LIKELY NO SINGLE INVESTIGATOR WAS IN PERSONAL EQUIPOISE WHEN THIS TRIAL STARTED. BUT THAT CLINICAL -- COLLECTIVELY IN THE HOSPITAL, THERE WAS CLINICAL EQUIPOISE IF YOU TOOK THE OPINIONS ON BOTH THE NICU AND PICU. SECOND THING I WANT TO DISCUSS IS ADAPTIVE RANDOMIZATION. WHICH IS BALANCING CONFLICTING OBLIGATION OBLIGATIONS. THE DEFINITION OF ADAPTIVE RANDOMIZATION IS DEVIATING FROM BALANCED OR 50/50 RANDOMIZATION WITH MORE PATIENT ACE SIGNED TO DURINGTHE TRIAL. THE PLAY THE WINNER STRATEGY THAT WE SAW IN BARTLETT'S TRIAL, BETTING ON THE HORSE OUT IN FRONT BEFORE WE KNOW HOW THE RACE IS GOING TO END. THIS IS ADAPTIVE RANDOMIZATION. WHY DO PEOPLE DO IT IT ATTEMPTS TO MINIMIZE THE LESS SUCCESSFUL THERAPY SO THE BARTLETT AND HARVARD TRIAL UTILIZED ADAPTIVE RANDOMIZATION IN THE BARTLETT TRIAL ONE PATIENT GOT CAN RANDOMIZED TO CONVENTIONAL THERAPY IN THE HARVARD TRIAL OUT OF 29 ENROLLED, ONLY TEN. GOT CONVENTIONAL THERAPY SO IT WAS EFFECTIVE IN THIS WAY, IT MITIGATES THE CONFLICT OF HEALER VERSUS INVESTIGATOR. IT ALLOWED BOB TO TO DO A TRIAL HE WAS ABLE TO CALL RANDOMIZE TOOL CONTROL TRIAL BUT STILL RESPECT HIS GREAT DISCOMFORT WITHHOLDING ECMO FROM THE BABIES. IT WAS FUNNY HOW THE HARVARD INVESTIGATORS JIM AND MIKE WERE CRITICAL OF THE BARTLETT TRIAL BECAUSE OF ADAPTIVE RANDOM IZATION BUT WHEN PUSH CAME TO SHOVE THEY CHOSE THE SAME STRATEGY. THE ONLY DIFFERENCE WAS IN THE BARTLETT TRIAL 50/50 RANDOMIZATION WAS GUARANTEED FOR THE FIRST PATIENT, IN THE HARVARD TRIAL IT WAS GUARANTEED UNTIL THERE WAS A FOURTH DEATH IN ONE ARM BUT FUNDAMENTALLY BOTH BECAUSE OF THE ETHICAL PRESSURES INVOLVED DECIDED TO ADOPT THIS STRATEGY. THE DISADVANTAGES OF ADAPTIVE RANDOMIZATION IS THERE'S ONE PRIMARY OUTCOME OF INTEREST BECAUSE YOU ARE USING IT TO ADJUST THE RANDOMIZATION AND MUST BE APPARENT THE OUTCOME MUST BE APPARENT WITHIN A SHORT PERIOD OF TIME SO YOU CAN FOLD BACK INTO THE RANDOMIZATION. THE ECMO CASE THIS WAS EASY, INTERESTED IN LIFE OR DEATH AND KNEW IN A SHORT PERIOD OF TIME DAYS TO WEEKS WHAT THAT OUTCOME WOULD BE. THIS DESIGN MAY SUFFER FROM ACCRUAL BIAS BECAUSE VOLUNTEERS MAY WANT TO BE RECRUITED INTO THE TRIAL LATER. THE LONGER YOU WAIT THE MORE LIKELY YOU ARE GOING TO GET THE BETTER THERAPY. NOT RELEVANT IN THE ECMO CASE SINCE THESE BABIES COULDN'T WAIT, THEY NEEDED ECMO IMMEDIATELY. THE HARVARD TRIAL WAS CRITICIZE FROM BOTH DIRECTIONS. WHEN THE TRIAL WAS PUBLISHED THERE WAS AN ENTIRE ISSUE IN JOURNAL STATISTICS MEDICINE DEVOTED TO THE TRIAL WITH BUNCH OF COMMENTARIES FROM LEADER IN STATISTICS. SO THESE ARE QUOTE FROM PEOPLE WHO WROTE ARTICLES IN THAT ISSUE. DON BERRY, THE CLEAR EXPECTATION WAS THAT MORE PATIENTS WOULD DIE ON CONVENTIONAL THERAPY. WAS HAVING AN EXCESS NUMBER OF DEATHS BALANCED BY THE WORTH OF THE INFORMATION GAINED? MY ANSWER IS A RESOUNDING NO. ON THE OTHER HAND THERE WERE THOSE WHO SAID THAT NOT ENOUGH PATIENTS WERE ASSIGNED CONVENTIONAL THERAPY. ONE SAID RESEARCHERS WERE SO PREOCCUPIED WITH ETHICAL PROBLEMS THEY STOPPED CONVENTIONAL THERAPY TOO SOON. ANOTHER SAID THERE IS A SLIGHTLY HYSTERICAL VIEW TO STOP A STUDY SOON AS WE HAVE AN IDEA WHICH TREATMENT WOULD BE BETTER. SO ON BALANCE, MAYBE THIS ENDED UP BEING A GOOD APPROACH, ANECDOTALLY I CAN THE HE WILL YOU IT WAS. THE ONLY ONES WHO KNEW ABOUT THIS PHASE 1 PHASE 2 WAS JIM WEHR THE STATISTICIAN. SO BABIES CAME IN RANDOM ILEUSESSED EQUALLY BETWEEN TWO UNITS BUT THE NURSES OFTEN CANARYIES IN THE COAL MINE WITH THIS THING. UP IN NEONATAL ICU THEIR BABIES WERE DYING AND BABIES GETTING ECMO WERE LIVING. BY THE TIME THERE WAS A FOURTH DEATH IN NICU THEY SAID ENOUGH IS ENOUGH. WE'RE NOT GOING TO DO THIS ANY MORE AND THEY CALLED AN ETHICS CONSULT AND THEY SAID THIS IS -- WE HAVE HAD ENOUGH. IN OUR MINDS ECMO WAS BETTER, NOT KEEPING BABIES ON THE TH FLOOR TO WATCH THEM DIE. THE ETHICS CONSULT WAS FOUR MEMBERS. THEY SPLIT TWO TO TWO. THEY DIDN'T KNOW WHAT TO DO. AND IT WAS AT THIS POINT THAT JIM WEHR THE STATISTICIAN CAME FORWARD AND SAID WE REACHED THE PHASE 2 OF THE STUDY, BABY GOING FORWARD GET ECMO. SO THAT'S HOW THE DILEMMA WAS RESOLVED. NOW WHEN I SAID THAT SOME OF THE ISSUES I'M TALKING ABOUT ARE MORE RELEVANT NOW THAN THEN THIS IS THE THING. ADAPTIVE TRIALS ARE BECOMING REALLY A GROWTH NDUSTRY. HERE IS A COUPLE OF ARTICLES FROM JAMA A WHILE BACK TALKING ABOUT THEIR POTENTIAL. PROBABLY THE POSTER CHILD FOR THIS IS THE I SPY TWO TRIALS FOR BREAST CANCER. THESE ARE LARGE MULTI-CENTER ADAPTIVE TRIALS, VERY COMPLEX. BUT WITH EVERY PATIENT THAT COMES INTO STUDY, THE RANDOMIZATION SCHEME IS ALTERED. SO PATIENTS ARE MORE LIKELY SHUNTEDDED IN TO AN ARM LOOKING TO BE MORE SUCCESSFUL THAN THE OTHERS. YOU SAW THE STATISTICS FOR THE ECMO STUFF THE STATISTICS ARE INFINITELY MORE COMPLICATED, REQUIRES COMPUTERS AND ALL SORTS OF THINGS, VERY UNINTUITIVE. AND FOR LARGE STUDIES LIKE THIS ADAPTIVE TRIALS ARE NOW BECOMING A VERY POPULAR CHOICE. THE LAST THING I WANT TO DISCUSS WITH YOU, MAYBE THE MOST CONTROVERSIAL PART OF THE HARVARD STUDY WAS THIS TECHNIQUE CALLED RANDOMIZED CONSENT. REMEMBER I TOLD YOU THE ONLY PARENTS THAT WERE APPROACHED FOR CONSENT WERE THOSE ALREADY RANDOMIZED TO ECMO. WHAT DO I MEAN BY THAT? LET'S LOOK AT SCHEMES FOR INFORMED CONSENT. MOST SIMPLE, PATIENT IS DETERMINED ELIGIBLE AND RANDOMIZED BETWEEN TREATMENTS A AND B. THIS IS THE PERFECT DESIGN. BUT YOU CAN ONLY DO IT WITH LABORATORY ANIMALS. WHAT IS MISSING OF COURSE IS INFORMED CONSENT WHICH IS REQUIRED IF YOU ARE GOING TO USE HUMANS. FOR A HUMAN STUDY NORMAL THING IS WE DETERMINE A PATIENT ELIGIBLE, SEEK INFORMED CONSENT, THEY SAY YES THEY'RE RANDOMIZED BETWEEN A AND B AND IF THEY SAY NO THEY ARE DROPPED FROM STUDY. THINGS ARE GETTING COMPLICATED BECAUSE WHEN YOU ANALYZE THE RESULTS, YOU HAVE TO BE ABLE TO SHOW THAT THOSE WHO ARE DROPPED FROM THE STUDY WERE NOT DIFFERENT IN ANY SYSTEMATIC WAY FROM THOSE WHO WERE ENROLLED. IN THE LATE 1970s MARVIN, A STAY SUBSTITUTION AT THIS AT HARVARD SCHOOL OF PUBLIC HEALTH CAME UP WITH THIS NEW DESIGN, RANDOMIZED CONSENT OR ZAILIN RANDOMIZATION. HERE IS HOW THAT WORKS. A PATIENT IS FOUND ELIGIBLE AND FIRST THING THAT HAPPENS IS THEY ARE RANDOMIZED. IF THEY RA RANDOMIZED TO THE TREATMENT, THEY ARE ASKED DO YOU ACCEPT THAT TREATMENT, YES, OTHERWISE THEY GET CONTROL TREATMENT. IF THEY ARE RANDOMIZED TO CONTROL TREATMENT THEY ARE NO TOLD ANYTHING THAT, HE'S WHAT THEY ARE GIVEN. SO HERE IS HOW THE RANDOMIZE SCHEME LOOKS IN THE HARVARD STUDY. SO CHILDREN'S DOES NOT HAVE BOSTON CHILDREN'S DOESN'T HAVE A DELIVERY SERVICE SO THE BABIES ARE BORN OUTSIDE THEY CAME INTO THE HOSPITAL, THEY WENT TO THE NICU ORIGINALLY BUT SOON AS THEY MET ECMO TRY TIERIA, USUALLY A MATTER OF MINUTES TO HOURS THEY WERE RANDOMIZED, IF THEY WERE RANDOMIZED TO ECMO THEY WERE TAKEN TO THE FIFTH FLOOR AND PARENTS WERE APPROACHED FOR CONSENT. IF RANDOMIZED TO CONVENTIONAL TREATMENT THEY STAYED IN THE NICU. HERE IS AN IMPORTANT POINT. THEY STAYED IN NI C,U AND GOT EXACTLY THE SAME TREATMENT, EXACTLY THE SAME TREATMENT, AS THEY WOULD HAVE GOTTEN IF NO STUDY HAS BEEN PERFORMED. SO HERE IS A QUESTION, WE'LL PAUSE HERE A COUPLE OF MINUTES. IMAGINE YOU WERE ON IRB OF BOSTON CHILDREN'S HOSPITAL WHEN STUDY WAS PROPOSED. WOULD HAVE YOU HAVE APPROVED THE ZAYLIN RANDOMIZATION SCHEME? SHOW OF HANDS FIRST. HOW MANY AGREE THIS WAS ETHICALLY ACCEPTABLE SCHEME? HOW MANY -- NO. YOU ARE A GOOD GROUP, WE ARE 50, 50, WE HAD MORE NOT VOTING ON THAT ONE. BUT STILL PRETTY 50. 50, HOW ABOUT SOMEBODY SAYS NO, THIS IS NOT ACCEPTABLE. CAN WE HEAR A REASON? GREAT. >> YOU SAY THEY IN CMT GROUP THEY WOULD HAVE SAME THERAPY THOUGH THE TRIAL WAS NOT HAPPENING BUT THE TRIAL WAS HAPPENING SO THEY KNEW THAT THERE MIGHT BE SUPERIOR THERAPY ECMO SO THIS IS A LITTLE BIT OF A HARD CHOICE TO MAKE. BECAUSE YOU KNOW SOMETHING MIGHT BE BETTER AND SAVE LIVES. FOR ME IT'S HARD ETHICAL DECISION. SO I WOULD NOT BE HAPPY IF -- >> YOU THINK IT'S UNETHICAL? >> YEAH IN A WAY. AT THIS TIME'S A HARD HARD TO SAY. >> WE HAVE COUPLE OF MINUTES HERE SO I WOULD LIKE TO HEAR FROM MORE OF YOU. DEFENDING IT OR CRITICIZING IT. >> THE HARD LINE HERE I THINK ANY TIME YOU TAKE, THEY HAVE A RIGHT TO KNOW WHAT IS GOING ON AND HOW THE MEDICAL IS BEING USED, HOW YOU TELL THEM CERTAIN THINGS ANOTHER ISSUE BUT I WORRY THAT THAT COMPARES IN A STUDY >> OKAY. SO THANK YOU. I THINK THAT'S VERY WELL PUT. HERE IS A RANDOMIZE TRIAL AND THEY ARE IN A STUDY AND WE ALL NOW THAT THE REGULATIONS REQUIRE THAT WE GET INFORMED CONSENT. BUT LET ME ASK YOU, IF ALL YOU'RE GOING TO DO IS A CHART REVIEW ON THESE PATIENTS. ALL YOUR CARE IS WHETHER THEY LIVED OR DIED, ALL YOU'RE GOING TO DO IS CHART REVIEW, WOULD AN IRB REQUIRE YOU GET INFORMED CONSENT FROM THESE PATIENTS? I THINK THE ANSWER -- YOU CAN DISAGREE WITH YOU WOULD LIKE BUT I THINK THE ANSWER IS NO. IF YOU ARE GOING TO MAINTAIN ANONYMITY YOU WON'T USE ANY INFORMATION OTHER INFORMATION THAT YOU COULD SIMPLY LOOK AT THEIR CHARTS AND SAY DID THEY LIVE OR DIE AND THAT AN IRB WOULD GIVE YOU PERMISSION TO DO THAT. THAT WAS ALL THE INVESTIGATORS WERE DOING HERE. LIVE ORGANIZE DYING. -- LIVING OR DYING. THEY WEREN'T CHANGING THE TREATMENT ANY ANYWAY, MERELY LOOKING AT THE OUTCOME. COME BACK TO THE NOTION THAT THE TREATMENT OF THE CHILD WAS NOT IN ANY WAY -- I'M TRYING TO BUILD THIS CASE A BIT BECAUSE SO MANY PEOPLE -- IMMEDIATELY SAY THIS IS UNETHICAL AND BELIEVE ME, I SEE WHY YOU SAY THAT. I'M NOT DISCOUNTING UNETHICAL EITHER BUT I'M TRYING TO BOLSTER THE POINT THE INVESTIGATORS HAD WHICH IS THEY WERE NOT ANY WAY AFFECTING THE CARE OF THOSE PATIENTS. PLEASE. >> SO ONE THING THAT I'M THINKING ABOUT IS THAT OFTEN WHEN WE SEEK PERMISSION TO DO WHAT I'LL CALL A RETROSPECTIVE REVIEW OF INFORMATION IN THE CHART, IT'S TECHNICALLY RETROSPECTIVE. BUT IN THIS CASE YOU KNOW PROSPECTIVELY YOU ARE GOING TO REVIEW THEIR CHART. AS KEVIN MENTIONED, YOU ARE USING SOME DATA AND MAYBE THAT MEANS THAT YOU NEED TO TELL THE PARENTS. >> YEAH. OKAY. I LIKE HOW YOU QUALIFIED IT WITH A MAYBE THERE. SO YOU ARE -- YOU LEFT A LITTLE WIGGLE ROOM. >> YES. >> OKAY. >> SO LET ME TELL YOU, I CAN RECK, I WAS A FELLOW DURING THIS TIME THE TRIAL WAS OVER. I CAN -- I HAVE THIS VISUAL MEMORY OF SITTING AT -- THE BREAKFAST TABLE WITH MY WIFE TESTIFY DAY AFTER THE PAPER WAS PUBLISHED. AND HERE IN THE BOSTON GLOBE IS THIS PAPER THIS ARTICLE DOWN IN THE LOWER RIGHT HAND CORNER OF THE PAGE HARVARD STUDY ON NEWBORNS DRAWS FIRE, DOCTORS FAULTED FOR LIMITING LIFE SAVING TREATMENT. YOU MIGHT RECOGNIZE THE JOURNALIST HERE, RICHARD KNOX REPORTER FOR THE GLOBE AT THE TIME, HE NOW REPORTS FOR NPR. INTERESTING AT THE TIME, WE DIDN'T HAVE WITH WEB AND FAST TRANSFER OF INFORMATION THAT WE DO NOW. SOMEBODY ACTUALLY CLIPPED THIS OUT OF THE NEWSPAPER AND SENT IT TO THE NIH. AND THEY LOOKED AT IT AND SORT OF SAID WHAT'S GOING ON HERE? SO THEY SENT A LETTER TO BOSTON CHILDREN'S HOSPITAL IRB AND SAY YOU HAVE TO EXPLAIN TO US WHY YOU THOUGHT IT WAS OKAY TO DO THIS WITHOUT CONSENT. HERE IS WHAT INVESTIGATORS WROTE BACK. THEY MADE THE POINT I HAVE BEEN TRYIG TO MAKE IN A HEAVY HANDED WADE TO YOU, THE CONTROL PATIENTS WITHER NOT REALLY RESEARCH SUBJECTS. NOTHING WAS BEING DONE TO THEM. THAT WOULDN'T HAVE HAPPENED IF THE TRIAL HAD NEVER EXISTED. THEY WERE GETTING EXACTLY THAT SAME CARE. THE OTHER POINT, THEY SAID FAMILIES OF CONTROL PATIENTS WERE NOT BEING OFFERED A CHOICE. I WOULD LIKE YOU TO IMAGINE WHAT THE CONVERSATION MIGHT HAVE LOOKED LIKE IF WE SAID THE CONTROL -- PARENTS OF CONTROL CHILDREN NEEDED TO KNOW. IT WOULD BE SOMETHING LIKE I NEED TO TELL YOU SOMETHING. WE ARE RESEARCHING THIS NEW THING CALLED ECMO, IT MIGHT BE LIFE SAVING. WE ARE DOING IT FOR BABIES THAT HAVE THE SAME PROBLEMS YOUR BABY HAS, BUT UNFORTUNATELY I NEED TO HE WILL YOU U YOU ARE NOT ELIGIBLE FOR IT. YOU WON'T GET IT. THAT -- GIVEN THE WAY THE RANDOMIZATION SCHEME WAS SET UP, THAT IS WHAT IT WOULD HAVE LOOKED LIKE. FROM THE MIKE EPSTEIN SAID THE DECISION TO DO THIS WAS CONTROVERSIAL, WE HAD SEVERAL WEEKS DISCUSSION OVER AUTONOMY VERSUS PATERNALISM. IN THE SAME INTERVIEW JIM WHEHR THE STATISTICIAN SAID I PREFER TO CALL IT OPENNESS VERSUS PASSION. I LIKED JIM'S EXPLANATION BETTER BECAUSE AUTONOMY IS RESPECTING THE PARENTS CHOICE. IN THIS CASE THERE WAS NO CHOICE TO BE MADE. WHETHER IT WAS AUTONOMY OR PATERNALISM WASN'T REALLY AT ISSUE. THE TREATMENT CHOICE WAS PRE-DETERMINED. I LIKE HOW JIM FRAMED IT, ALWAYS OPEN AND EXPLAIN TO FAMILIES WHAT IS GOING ON HERE OR ARE WE GOING TO CONCLUDE THAT HAVING THAT CONVERSATION WOULD BILL KIND OF CRUEL? THAT SAYING THERE'S A THING AVAILABLE BUT YOU CAN'T HAVE IT IS MAYBE MAKING US FEEL MORE COMFORTABLE BUT NOT DOING ANYTHING TO HELP THEM. SO HE WAS FRAMING IT BEING COMPASSIONATE. I DO KNOW THAT IN THE MONTHS AND YEARS FOLLOWING THAT, THERE WAS NEVER A FAMILY OF ONE O THOSE FOUR PATIENTS, ONE OF FOUR CHILDREN WHO DIED THAT CAME FORWARD. I'M SURPRISED WITH THAT'S SPECIALLY THE BOSTON GLOBE ARTICLE I IMAGINE SOMEBODY READING THE PAPER SAYING YEAH, OUR CHILD WAS AT BOSTON CHILDREN'S HOSPITAL WHEN THEY WERE DOING THAT STUDY AND HAD THIS DISEASE. I WONDER IF WE WERE ONE OF THOSE FAMILIES IN THE CONTROL GROUP AND OUR BABY WAS ONE OF THE FOUR THAT DIED. NOBODY CAME FORWARD WITH THAT. TO ME THAT'S PROBABLY THE ROOT OF THE ETHICAL PROBLEMS I HAVE WITH TE DESIGN. IS THAT I DON'T KNOW WHAT YOU WOULD HAVE SAID TO THOSE PARENTS. WHY -- WHY DIDN'T YOU TELL ME WHAT YOU WERE DOING? WHY DIDN'T YOU TELL ME THERE WAS A TRIAL GOING ON? YOU THOUGHT I WOULDN'T BE ABLE TO HANDLE IT OR SOMETHING. I THINK THAT LACK OF TRANSPARENCY MORE THAN ANYTHING ELSE IS WHAT MAKES THE RANDOMIZATION PROBLEMATIC IN THIS CASE. ANY LAST COMMENTS? I WILL MOVE ON AND WRAP UP SHORTLY. OKAY. SO THE RESPONSE TO THE ECMO TRIAL WAS THAT THE NIH REPRIMANDED THE HOSPITAL. FOR WHAT THEY DID. THE DIRECTOR OF OPRR AND OHRP NOW, CHARLES MCCARTHY SAID THE HOSPITAL IRB MADE DECISIONS THAT RIGHTLY BELONGED TO PARENTS, THEY BLEW IT AND GEORGE THE WELL KNOWN LAWYER ACROSS TOWN FROM US SAID THE DOCTORS WERE DOING EXACTLY WHAT PHYSICIANS DID BEEN DOCTOR INFORMED CONCEPT MAKING DECISIONS FOR PARENTS. THIS WAS THE TONE OF THE ETHICAL CRITICISM BROUGHT. I THINK IT'S ETHICALLY PROBLEMATIC BUT NOT FOR THESE REASONS. I DON'T THINK THAT A DECISION WAS BEING TAKEN AWAY FROM THE PARENTS. THE DECISION WAS ALREADY HAS BEEN MADE BY THE RANDOMIZATION. IT WAS A QUESTION HOW MUCH THE PARENTS KNEW ABOUT THAT. OKAY. IN WRAPPING UP HERE, I WANT TO BRING UP A DEEPER QUESTION THE TRIAL RAISES, ABOUT HOW WE GAIN KNOWLEDGE IN MEDICINE. WHAT COUNTS AS KNOWLEDGE? THE QUESTION OF WHETHER RCTs ARE THE ONLY WAY TO LEARN. WHEN YOU THINK ABOUT IT THERE ARE NO FACTS IN MEDICINE. EVERYTHING WE KNOW IN MEDICINE IS HELD CONTINGENTLY. BASED ON THE RESEARCH DONE. AND BASED ON DEGREE OF CONFIDENCE THAT WE HAVE IN THAT INFORMATION. SO AS YOU GO FROM THE BOTTOM OF THE LIST TO THE TOP, WHAT IS HAPPENING IS YOU ARE GETTING INCREASING DEGREES OF CONFIDENCE IN THE INFORMATION THAT IS BEING GLEANED. NOTICE RANDOMIZE CONTROL TRIALS ARE NOT THE TOP OF THE LIST, IT'S META ANALYSIS BUT NEVERTHELESS RANDOMIZE CONTROL TRIAL HAS COME TO THIS FOLDEN PRIVILEGED PLACE HOW WE THINK ABOUT INFORMATION IN MEDICINE. I WOULD LIKE TO CALL THAT INTO QUESTION A LITTLE BIT. IN SOME OF THE LITERATURE THAT'S BEEN DONE THAT SUBSTITUTION AT THISES MADE THESE COMMENTS. THE BRILLIANT SUCCESS OF THE RCT IS A FORM OF INTELLECTUAL TYRANNY AND WE SHOULDN'T PROCEED ON THE FALLACIOUS ASSUMPTION THAT WHERE THERE IS NO RANDOMIZATIONER THERE IS NO TRUTH. INDEED RESEARCH SUPPORTS THIS. HERE IS A STUDY 2000 FROM THE NEW ENGLAND JOURNAL. WE FOUND LITTLE EVIDENCE THAT ESTIMATES OF TREATMENT EFFECTS IN OBSERVATIONAL STUDIES, REPORTED AFTER 1984 ARE EITHER CONSISTENTLY LARGER THAN OR QUALITATIVELY DIFFERENT FROM THOSE OBTAINED IN RANDOMIZE CONTROL TRIALS. SO IN THE MODERN ERA, VERY WELL DONE OBSERVATIONAL STUDIES CAN IN AND OF THEMSELVES BE SUFFICIENT. HERE IS A PAPER FROM THE GURU IN MY FIELD CRITICAL CARE MEDICINE WHO SAID I WILL ARGUE IN MANY SITUATIONS IN THE ICU CONTEXT, THE RCT AS WE KNOW IT SHOULD BE ABANDONED. TEMPORARILY AND WELL DESIGNED OBSERVATIONAL STUDIES. WHAT WAS KNOWN FROM OBSERVATIONAL WERE AT THE TIME THE HARVARD TRIAL WAS BEING PLANNED. THERE WAS AN ECMO DATABASE KEPT LARGELY FROM PATIENTS FROM THE GROUP AT BOB BARTLETT'S GROUP IN ANN ARBOR. THERE WAS A DATABASE THAT HAD 715 NEWBORNS TREATED WITH ECMO. THE PROBLEM WITH THIS IS THERE WAS NO CONTROLS. IT WAS ALL PATIENTS WHO GOT ECMO AND THEY HAD AN 81% SURVIVAL. IF YOU DID THE MATH THEY FOUND ECMO WAS STATISTICALLY SUPERIOR TO ANY OTHER TREATMENT WITH SURVIVAL RATE LESS THAN 78%. PEOPLE HAVE ARGUED I THINK CONVINCINGLY THAT ANY EXPERIENCE CLINICIAN WOULD HAVE LOOKED AT THIS DATABASE AND SAID FOR PATIENTS THIS SICK THERE'S NO POSSIBLE WAY THEY WOULD HAVE HAD A 78% SURVIVAL RATE WITHOUT ECMO. WE SHOULD HAVE BEEN CONVINCED EVEN JUST BY LOOKING AT THESE DATA WITH NO CONTROLS. IT'S LIKE THE KIND OF THING WHERE DOES PUTTING YOUR FOOT ON THE BRAKE STOP THE CAR, DO PARACHUTES WORK? YOU DON'T NEED RANDOMIZED TRIALS TO GET THE ANSWERS TO THOSE THINGS. ONE OR TWO EXAMPLES CAN BE CONVINCING. ECMO IS NOT QUITE LIKE THAT BUT THIS IS THE ARGUMENT MADE. SO AT THIS POINT WE'LL DO A RAISING OF HANDS HERE. GIVEN ALL THAT YOU HAVE SEEN, ALL THAT I HAVE TOLD YOU, ARE YOU NOW CONVINCED THAT ECMO O IS SUPERIOR TO CONVENTIONAL THERAPY? BACK TO YOUR QUESTION, IS THIS WHAT WE DO, ANYBODY DOUBT ECMO IS AN EFFECTIVE THERAPY? ANYBODY DOUBT IT? I DON'T SEE ANY HANDS. WHAT'S SO INTERESTENING THAT REGARD IS A FEW YEARS LATER THE UNITED KINGDOM RAISED THE QUESTION WHETHER THEY SHOULD START TO DO ECMO. AND THEY DECIDED THEY NEEDED TO DO A REGULAR RANDOMIZE CONTROL TRIAL LIKE THE AMERICANS, THEY HAD THEIR CHANCE, BUT THEY JUST DIDN'T DO IT RIGHT. WE ARE GOING TO DO IT RIGHT. THE REASON THEY FELT IT NEEDED TO BE DONE IS EXISTING RCTs OF NEONATAL ECMO SUGGESTED REDUCTIONS IN MORTALITY BUT NOT CONCLUSIVE BECAUSE THEY USED ADAPTIVE DESIGN WHICH MAY HAVE INTRODUCED BIAS.& SO THEY DID IT IN THEIR VIEW THE RIGHT WAY 50/50 RANDOMIZATION. BETWEEN 1993 AND 1995, 185 NEONATES RANDOMIZED TO ECMO VERSUS CONVENTIONAL THERAPY. THE TRIAL WAS STOPPED EARLY BY DSMB WITH AS YOU CAN SEE A MUCH GREATER SURVIVAL IN THE ECMO GROUP EVERYBODY MORE IMPRESSIVE BECAUSE UNLIKE THE HARVARD TRIAL THESE WERE CENTERS THAT HAD NEVER DONE ECMO BEFORE SO THEY WERE GOING THROUGH THAT LEARNING CURVE. YET EVEN WITH THE LEARNING CURVE IT WAS COMING OUT TO BE VERY, VERY SUCCESSFUL. SO MY COLLEAGUE AND BIOETHICIST JONATHANTOS WROTE AN EDITORIAL IN THE LANSETT SAYING IT SHOULDN'T HAVE BEEN DONE, THIS WAS A DEMONSTRATION TRIAL PROVING SOMETHING THAT WAS ALREADY KNOWN OR SHOULD HAVE BEEN RECOGNIZED AS ALREADY KNOWN. AS A RESULT DO THE MATH, THERE WERE 22 BABIES THERE WHO WOULD HAVE SURVIVED HAD ALL THOSE PATIENTS GOTTEN ECMO. MY CONCLUSIONS. SOMETIMES I HEAR PEOPLE TALKING AFTER THEIR TALK THEY GO OH HE DOESN'T BELIEVE IN RCT, I DON'T WANT YOU COMING AWAY WITH THAT, THAT'S NOT TRUE. I THINK RCTs ARE USUALLY THE BEST APPROACH FOR EVALUATING NEW THERAPIES. BUT I BELIEVE THAT THIS CONFLICT BETWEEN CLINICIANS AN INVESTIGATORS IS PROFOUND. AND IT CAN NEVER BE ENTIRELY ELIMINATED. ADAPTIVE RANDOMIZATION IS A WAY TOLL BALANCE COMPETING OBLIGATIONS. AS WE ARE SEEING, IT IS INCREASINGLY USED. IT COMES WITH ITS OWN SET OF ETHICAL CONCERNS BUT IT'S A VERY PROMISING WAY WITH VERY LARGE STUDIES OF DESIGNING THEM. ZAYLIN RANDOMIZATION REDUCES PSYCHOLOGICAL BURDENS FOR INVESTIGATORS AND POSSIBLY THE PARENTS IN THE ECMO CASE BUT BASED ON THE NIH RESPONSE TO IT, IT WOULD BE A RESPONSE -- IRRESPONSIBLE TO RECOMMEND IT. I THINK YOU SHOULD REGARD IT AS UNACCEPTABLE AT THIS POINT. SO IN CONCLUSION LET ME FINISH WITH SOME WORDS FROM BENJAMIN FRIEDMAN, THE BIOETHICIST WHO GAVE US THE CONCEPTS OF CLINICAL EQUIPOISE. THE USE OF RESEARCH IN STATISTICS HAS BEEN COMPARED TO RELIGION, IT HAD HIGH PRIEST, SUPPLICANTS AND RESEARCHERS AND ORTHODOXIES THAT P LESS THAN .05 IS QUOTE UNQUOTE SIGNIFICANT. AND I THINK BENJAMIN FRIEDMAN IF HE WERE ALIVE HE WOULD BE FIRST TO TELL US TO RESIST THOSE WHO INSIST WE SHOULD NEVER EVER THINK OUTSIDE OF THE BOX. SO WITH THAT, I WILL CLOSE. I HAVE 50 SECONDS FOR QUESTIONS. BUT SO I WON'T KEEP PEOPLE -- I WON'T DELAY YOU BUT IF SOMEBODY WOULD LIKE TO COME DOWN AND RAISE A QUESTION, THAT WOULD BE FINE. THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] >> CAN WE HAVE THE LIGHTS UP MAYBE IF SOMEBODY IS STILL UP THERE? >> I HAVE A QUESTION WITH THE ZALIN RANDOMIZATION. ARE THEY ABLE TO USE THE DATA? I HAVE DONE PSYCHOLOGY RESEARCH IN COLLEGE AND WE COULD NOT USE THE DATA UNLESS CONSENTED THAT IT WAS OKAY. SO HOW DOES THAT WORK? >> THERE'S DEBATE ABOUT USING DATA THAT IS COLLECTED FROM UNETHICAL RESEARCH, THE NAZI EXPERIMENTS BEING MUCH TALKED ABOUT. THE QUESTION HERE IS WAS IT UNETHICAL. WHAT THE IRB FELT WITH INVESTIGATORS FELT IS IT WAS ETHICAL TO DO WHAT THEY DID. SPARE THE PARENTS, THE PSYCHOLOGICAL TRAUMA KNOWING THERE WAS PERHAPS A THERAPY THEIR CHILD MIGHT HAVE GOTTEN BUT THEY WEREN'T ELIGIBLE FOR IT. SO I THINK IF YOU CONCLUDE IT WAS UNETHICAL COULD WE USE THAT DATA, IT WAS EQUIVOCAL ENOUGH IN THIS CASE I NEVER HEARD ANYBODY SAY WHICH SHOULDN'T BE USING THIS DATA. >> ANYBODY ELSE? >> ONE MORE. >> THANKS. SOUNDS LIKE YOU ARE SUGGESTING MAYBE A CULTURAL SHIFT AROUND WAY WE VIEW STATISTICS IN MEDICINE. SO I'M WONDERING WHO IS RESPONSIBILITY IT IS TO SHIFT THAT CULTURE? AND HOW WE CAN WORK TOWARDS SHIFTING THAT? >> I HAVE ALLUDEDDED TO THE IDEA WE NEED TO MOVE FROM WORSHIP OF RANDOMIZED CLINICAL TRIAL IS THE ONLY WAY OF GATHERING DATA IN MEDICINE. SINCE THE STUDY HAPPENED WE HAVE IN FACT DONE THAT. TO A CERTAIN EXTENT, AND IN MEDICINE THERE IS -- IT'S NOT ENOUGH TO PROVE SOMETHING IS TRUE OR HAVE A LOT OF EVIDENCE SOMETHING IS TRUE. YOU ALSO HAVE COTO CONVINCE DOCTORS AND NURSES TO DO IT. SOMETIMES THAT RCT BECOMES MORE PSYCHOLOGICAL MOTIVATOR TO GET PEOPLE TO CHANGE THEIR PRACTICE THAN ANYTHING ELSE IF IT'S NOT RCT THEY GO YEAH NOT SURE IF IT'S TRUE OR NOT. I'M GOING TO KEEP DOING WHAT WE HAVE BEEN DOING. I THINK THAT WAS MAYBE SOME OF WHAT THE INVESTIGATORS WERE DOING IN THEIR TRIAL IN THE UK. BUT THAT I THINK IS WHERE YOU START TO RUN INTO PROBLEMS BECAUSE RCTs EXPOSE PEOPLE TO RISK. IF YOU DON'T NEED TO DO THAT IN ORDER TO BE CONFIDENT IN THE INFORMATION YOU ARE GETTING, I THINK WE SHOULD BE SATISFIED VERY OFTEN WITH WELL DONE STUDIES THAT HAVE A LOWER LEVEL OF CONFIDENCE SUCH AS WELL DONE OBSERVATIONAL STUDIES. OKAY. GREAT. >> THANK YOU, BOB. >> THANK YOU VERY MUCH. [APPLAUSE] >> FOR OUR THIRD SESSION THIS MORNING WE HAVE NEW TALK, ETHICS OF VACCINE RESEARCH. TO DO THAT WITH US IS HOLLY TAYLOR, A FACULTY MEMBER IN THE NIH CLINICAL CENTER DEPARTMENT OF BIOETHICS. YOU WILL HEAR FROM HOLLY INTERESTINGLY IN RESEARCH ETHICS WE PARADIGM WE THINK ABOUT IS TREATMENT RESEARCH. VACCINE RESEARCH HAS INTERESTING DIFFERENT KINDS OF CHALLENGES. THANK YOU, HOLLY. >> HI, EVERYONE. THIS IS MY FIRST LECTURE IN THIS COURSE, YOU WILL GET TO SEE ME AGAIN NEXT WEEK AND I'M VERY HAPPY TO BE HERE. SO I HAVE A PLAN IN MIND, I'M NOT SURE WE'RE GOING TO GET TO ALL THAT I PLAN TO GET TO. I AM HERE JUST AROUND THE CORNER SO THOSE WHO ARE HERE IN THE AUDITORIUM WE CAN CERTAINLY CHAT ABOUT THINGS, I'M NOT ABLE TO COVER AND FELLOWS ET CETERA, NOWHERE I AM. SO MY PLAN IS TO TALK VERY BRIEFLY ABOUT VACCINATION. I COME HERE TO THE NIH WITH BACKGROUND IN PUBLIC HEALTH SO VACCINES TO ME ARE -- WE ALWAYS THINK OF FROM THE PUBLIC HEALTH PERSPECTIVE VACCINES ARE THE SUCCESS STORY FROM THE PUBLIC HEALTH PERSPECTIVE. THEN I WANT TO TALK ABOUT VACCINE TRIALS AS CHRISTINE MENTIONED, I THINK THEY ARE SOME UNIQUE ASPECTS THAT I'D LOVE TO SHARE WITH YOU. I THEN WANT TO FOCUS USING A LITTLE BIT OF THE FRAMEWORK THAT YOU WERE INTRODUCED TO EARLY IN THE COURSE AND TALK THROUGH THOSE ISSUES. THEN I WILL TALK A LITTLE BIT ABOUT DOING VACCINE RESEARCH IN LOW AND MIDDLE INCOME COUNTRIES. I WILL FOCUS THE BEGINNING HERE IN THE UNITED STATES YOU ARE ALSO GOING TO HAVE AN OPPORTUNITY TO TALK ABOUT SOME THOSE ISSUES IN A COUPLE OF WEEKS. IF I HAVE TIME, I ALSO WANT TO TALK ABOUT CONTROLLED HUMAN INFECTION TRIALS. I HAVE A LOT ON MY LIST, NOT SURE HOW FAR I'LL GET BUT WE SHOULD GET STARTED. HERE IS MY DISCLAIMER. THOSE OF YOU WHO DON'T KNOW, VACCINES ARE REALLY GREAT. THEY ARE THE MOST IMMEDIATE AND DEFINITIVE PREVENTIVE SOLUTION FORS ALL SORTS OF INFECTIOUS DISEASES. WE HAVE -- I, NOT I, WE HAVE ERADICATED SMALLPOX, WE ARE DOING A LOT TO ERADICATE POLIO. AND IN THE NEWS RECENTLY I'M SURE MANY OF YOU NOTICED HERE IN THE UNITED STATES WE HAVE HAD 300 PERCENT INCREASE IN GLOBAL CASES IN TERMS OF CASES OF MEASLES MUMPS AND RUB WILL. OUR ERADICATION STATUS HERE IN THE UNITED STATES IS ACTUALLY AT RISK. WE HAVE TOO MANY CASES TO CONTINUE TO QUALIFY SO THERE'S ALSO A LOT OF DEBATES ABOUT VACCINATION. JUST TO MAKE SURE WE ARE ON THE SAME PAGE, VACCINATION IS MEANT TO ACHIEVE AND MAINTAIN SOMETHING WE CALL POPULATION IMMUNITY OR HEARD IMMUNITY. THE IDEA IS IF THE MAJORITY OF US ARE VACCINATED, WE PROTECT OURSELVES AND THOSE AROUND US WHO CAN'T BE VACCINATED FOR SOME REASON. THEY ARE IMMUNOCOMPROMISED OR PREGNANT OR OLDER OR I WERE FANTASTIC UNDER ONE, ET CETERA. BENEFITS PROTECT INDIVIDUAL FROM INFECTION AND REDUCE TRANSMISSION. IF THERE'S A CHAIN OF INFECTION WHEN THE VIRUS HITS SOMEONE VACCINATED THAT CHAIN CAN BE BROKEN. AND IMPORTANTLY, THERE IS NO VACCINE WITHOUT RISK EVEN THE VACCINES THAT WE USE ON A DAILY BASIS ARE NOT COMPLETELY WITHOUT RISK. SO THAT'S SOMETHING ALWAYS TO KEEP IN MIND. WHEN WE THINK ABOUT VACCINE TRIALS THE WORDS WE USE ARE VERY SIMILAR TO THE ONES WE USE WHEN TALKING RANDOMIZE CONTROL TRIALS OF INTERVENTIONS OR TRIALS OF INTERVENTIONS, PHASE 1 IS WHEN WE JUST HAVE A FEW PEOPLE IN THE TRIAL. WE ARE ASKING THE QUESTION, IS THE VACCINE SAFE? NEXT WE DO A PHASE 2 TRIAL WHERE WE HAVE MANY MORE PEOPLE USUALLY AND WE ARE GOING TO START LOOKING AT COMMON SHORT TERM SIDE EFFECTS. AND WE ARE ALSO GOING TO DO ADDITIONAL BLOOD WORK TO SEE HOW THE BODY IMMUNE SYSTEM IS RESPONDING. IT'S ONLY AFTER PHASE 2 THAT WE THEN GET INTO THE PHASE 3 TRIAL OF HUNDREDS OR IN FACT THOUSANDS OF VOLUNTEERS WHO ARE RECRUITING RANDOMIZED TO GET THE VACCINE OR NOT AND BE FOLLOWED OVER TIME TO FIND OUT WHETHER OR NOT THE RENNE IS DOING WHAT WE WOULD LIKE IT TO. WE ALSO WANT TO KNOW THAT THE VACCINE IS SAFE, EFFECTIVE AND KEEP TRACK OF SOME OF THOSE COMMON SIDES EFFECTS. SO I WANT TO TALK THROUGH A LITTLE BIT ABOUT VACCINATION WITH THE EXAMPLE OF HIV. THIS IS MY SECOND STINT AT NIH, I WAS FIRST HERE BACK IN THE LATE 1980s, EARLY 1990s WHEN A LOT WAS GOING ON WITH HIV. I ACTUALLY DIDN'T REALLY UNDERSTAND OR KNOW MUCH ABOUT HIV UNTIL MY FIRST YEAR OUT COLLEGE, THINGS WERE HAPPENING BUT IT WASN'T ON MY RADAR SCREEN UNTIL 1987. TO REMIND YOU, BACK IN 1981 WAS THE FIRST CASE OF NOVEL DISEASE REPORTED. THE FIRST PATIENT IN 1981 WAS ADMITTED HERE TO THE NIH CLINICAL CENTER. IT WASN'T UNTIL 1982 WE ADOPTED THIS TERM ACQUIRED IMMUNE DEFICIENCY TO CATEGORIZE THOSE WHO HAVE THIS INFECTION. IT WASN'T FOR TWO YEARS LATER WE IDENTIFIED THIS HTLD 3 VIRUS THAT WAS THEN LATER PHRASED HIV AS IDENTIFIED AS THE CAUSE. AND THIS IS SOMETHING THAT I ACTUALLY DO REMEMBER IN THE BACK OF MY MIND BEFORE I LEARNED MORE ABOUT HIV AND WHEN I THOUGHT ABOUT THE VACCINE LECTURE TODAY THIS IS THE FIRST THAT CAME TO MIND. THIS IS MARGARET HECKLER, SECRETARY OF DEPARTMENT OF HEALTH AND HUMAN SERVICES BACK IN 1984. IN THAT YEAR WE FIGURED OUT A TEST WAS DEVELOPED DIAGNOSTIC BLOOD TEST FOR HIV. AND SHE SAID AT A NEWS COVERAGE WITH ROBERT GAL LOW, WE ALSO BELIEVE THE NEW DIAGNOSTIC BLOOD TEST WILL ENABLE US TO DEVELOP A VACCINE TO PREVENT AIDS IN THE FUTURE. WE HOPE TO HAVE SUCH A VACCINE READY FOR TESTING IN APPROXIMATELY TWO YEARS. œDO WE HAVE AN HIV VACCINE? NO. DO WITH NEED AN HIV VACCINE? RAISE YOUR HANDS, YES. YOU THINK THAT'S A GOOD IDEA? GREAT. WE WILL ROLL FORWARD AND SEE HOW, I AGREE, I THINK IT'S REALLY IMPORTANT BUT CONDUCTING VACCINE TRIALS BECOMES MORE COMPLICATED AS WE MOVE AWAY FROM 1986 WHEN DR. HECKLER THOUGHT WE MIGHT HAVE A VACCINE. SO I WILL ROLL FORWARD A BIT IN THE TIME LINE. 1985, 10,000 CASES OF AIDS REPORTED. 1987 FIRST PHASE 1 CLINICAL TRIAL IN HIV VACCINE WAS START HERE. SO THREE YEARS LATER BUT THE FIRST PHASE 1. THAT SAME YEAR THE NATIONAL INSTITUTE OF ALLERGY INFECTIOUS DISEASE ESTABLISHED AN AIDS VACCINE EVALUATION GROUP AND THEN ALMOST FIVE YEARS LATER WE GOT TO A PHASE 2 CLINICAL TRIAL SO THINGS ARE MOVING FORWARD WHICH IS A GROUP THING. SO I WANT TO STOP THE TIME LINE A BIT IN 1998. THIS WAS THE -- AT THE TIME WHERE WE WERE CONTEMPLATING NIAID AND OTHERS WERE CONTEMPLATING THE FIRST PHASE 3 RANDOMIZED PLACEBO CONTROL TRIAL OF HIV VACCINE HERE IN THE UNITED STATES. SO LET'S THINK ABOUT WHAT IT WAS LIKE IN 1998. WE HAD ACROSS THE GLOBE 30 MILLION PEOPLE INFECTED WITH HIV AND ABOUT 11 MILLION DEATHS FROM AIDS. IT WAS ALSO THE CASE IN 1988 WE HAD ONE REALLY LOVELY SUCCESS THAT IN 1994 THE ACTG 076, THAT WAS THE NAME OF THE TRIAL, FOUND EZT DURING PREGNANCY MEANT THAT THE MATERNAL INFANT TRANSMISSION COULD BE INTERRUPTED. WE ALSO HAD THE CASE IN 1998, 94% OF PEOPLE WITH HIV WERE ON COMBINATION THERAPY. THIS IS A GRAPH FROM THAT TIME, YOU CAN SEE THE STARK CHANGE THAT ONCE PROTEASE INHIBITORS BECAME AVAILABLE AND PART OF COMBINATION THERAPY, THE DEATH RATE PLUM METED. THIS IS -- AT THE BEGINNING WHEN FOLKS ARE STARTING TO SAY THINGS LIKE MAYBE HIV IS A CHRONIC DISEASE, NOT A FATAL DISEASE. SO THERE WERE ALSO A COUPLE OF OTHER THINGS TRUE. ONE STILL TRUE, ONE LESS SO. THAT IN THE UNITED STATES WE HAD LACK OF UNIVERSAL HEALTHCARE, IT WAS TRUE THAT THOSE WITH PRIVATE INSURANCE WERE MORE LIKELY TO BE ON THE PROTEASE INHIBITOR AND LESS LIKELY TO GET SICK AND DIE SO DISPARITIES STILL. HOSTILITY AND DISCRIMINATION TOWARDS THOSE PERCEIVED TO THE HIV INFECTED WERE AT RISK. I WOULD LOVE TO SAY THIS IS NO LONGER TRUE BUT I THINK THERE IS SOME HOSTILITY AND DISCRIMINATION, MAYBE NOT HOSTILITY, CERTAINLY SOME DISCRIMINATION. SO WHAT I WANT TO DO NOW IS REPRODUCE THE -- INTRODUCE THE ETHICAL PRINCIPLES THAT WE HAVE BEEN TALKING ABOUT AND FOCUS ON FOUR OF THEM BECAUSE I THINK THEY ARE VERY RELEVANT TO VACCINE RESEARCH. I'M GOING TO DO THEM SLIGHTLY DIFFERENT ORDER. I WILL TALK FIRST ABOUT SCIENTIFIC VALIDITY AND THEN A BIT ABOUT INFORMED CONSENT, RESPECT FOR PARTICIPANTS AND SORT OF CONCLUDE THIS PART OF THE LECTURE ON COLLABORATIVE PARTNERSHIPS. SO LET'S TALK PANT SCIENTIFIC VALIDITY. WHEN WE TALK SAMPLE SIZE IN THE CONTEXT OF HIV OR IN VACCINES GENERALLY, AND IN HIV IN PARTICULAR, THE HIGHER THE INCIDENCE OF THE DISEASE THE SMALLER SAMPLE YOU NEED TO DETERMINE WHETHER THE VACCINE IS EFFECTIVE. THE LOWER THE INCIDENCE THE LARGER THE SAMPLE SIZE YOU NEED TO DETERMINE WHETHER IT'S EFFECTIVE. WHEN THINKING SAMPLE SIZE, THERE'S A COUPLE OF KEY THINGS TO KEEP IN MIND ONE THE ANNUAL INCIDENCE RATE, THE TOP COLUMN, TOP ROW. TOP ROW. AND THEN ON MY LEFT YOUR LEFT, THE LENGTH OF THE TRIAL SO YOU HAVE TO THINK ABOUT THE INCIDENCE RATE AND THEN BASICALLY HOW LONG IS IT GOING TO TAKE TO ENROLL THE NUMBER OF PEOPLE YOU NEED AND PERHAPS HOW MUCH MONEY TO COMPLETE THE TRIAL. ET CETERA. SO LET'S FOCUS IN ON THIS I JUST ARBITRARILY DECIDED TO LOOK AT THIS HYPOTHETICAL TRIAL OF TWO YEARS WITH INCIDENCE RATE OF 4% IN THE BACKGROUND. IF YOU DID RANDOMIZE PLACEBO CONTROL TRIAL, IF YOU HAVE THAT SAMPLE OF 4,000 PEOPLE AND RANDOMIZED THEM TO VACCINE OR PLACEBO, ACCORDING TO WHAT OUR ESTIMATES ARE OF THE BACKGROUND AND INCIDENCE RATE YOU END UP WITH 43 PEOPLE HIV INFECTED AND 86 INFECTED OR ANOTHER WAY TO SAY THAT RIGHT IS 43 FEWER HIV INFECTIONS. SO WHEN YOU THINK ABOUT THIS, IT'S HARD TO TRANSPORT YOURS BACK TO 1998 FOR SOME OF YOU, I'M GUESSING THERE ISN'T ANYBODY WHO WASN'T ALIVE BUT CERTAINLY VERY YOUNG. WHAT DO WE HAVE TO THINK ABOUT FOR THOSE WHO ARE IN THE PLACEBO ARM? WHAT SHOULD OUR STANDARD OF PREVENTION BE? IN THE GRAND SCHEME OF THINGS THE BEST WAY TO GET THE ANSWER AS QUICK AS YOU CAN, HAVE HALF THE PEOPLE GET VACCINE AND HALF PEOPLE GET PLACEBO. BUT WHAT MIGHT SOME OF THOSE PEOPLE GETTING THE PLACEBO BE DOING? THEY ARE ENGAGING IN SEXUAL ACTIVITY, THEY ARE SHARING NEEDSLESS WITH THEIR FRIENDS. WHAT MIGHT THEY BE DOING IN ADDITION? ANYTHING TO PROTECT THEMSELVES? SORRY WHAT? NO GUESSES? I'LL SPOIL IT. SO WHEN WE ARE TALKING ABOUT STANDARDS OF PREVENTION, THIS BECOMES A REALLY IMPORTANT QUESTION. SO HIV VACCINE -- I BORROWED A BUNCH OF THIS THESE NOTES IN MY LECTURE FROM A PRODUCT OF A DELIBERATION BACK IN 1994. AND I THINK IN MY RECOLLECTION IT WAS THE FIRST TIME I MET CHRISTINE. SHE WAS THERE, I WAS THERE AS MORE OF A FLY ON THE WALL BUT IT WAS A REALLY GREAT CONVERSATION, REALLY WEIGHTY FROM MY PERSPECTIVE ETHICAL ISSUES BEING DEBATED. ONE OF THE STANDARDS IS HIV VACCINE TRIALS MUST INCORM RATE THE BEST BEHAVIORAL RISK REDUCTION INTERVENTIONS TO ENCOURAGE PARTICIPANTS TO AVOID BEHAVIORS THAT PLACE THEM AT RISK FOR INFECTION SO IN THAT TRIAL IN 1998, THE SUGGESTION WAS THOSE ENROLLED IN THE TRIAL BE RANDOMIZED TO GET VACCINE OR PLACEBO RIGHT, YOU GET -- EVERYONE GETS A SHOT, SOME GET VACCINE SOME DON'T. BUT THERE WAS EXPECTATION THAT THEY WOULD BE TOLD, EVERYBODY WOULD BE TOLL THAT NOT HAVING SEX WOULD LIKELY REDUCE YOUR RISK OF HIV, CONDOM USE, USE OF STERILE NEEDLESS. SO THERE IS ETHICAL OBLIGATION IF NOT EXPECTATION TO SHARE PREVENTION MESSAGES EVEN IN A TRIAL WHEN YOU ARE TESTING OUT WHAT YOU THINK TO BE REALLY IMPORTANT PREVENTION METHOD. THERE ARE SOME STANDARDS OR SOME SUGGESTED STANDARDS ABOUT WHAT THIS PREVENTION IN THAT PLACEBO ARM BUT WE ARE TALKING BOTH THOSE IN VACCINE AND PLACEBO ARM. WE ARE NOT MERELY SAYING OKAY, YOU GOT THE VACCINE YOU DON'T HAVE TO BE ENGAGING IN OTHER BEHAVIORAL WAYS TO REDUCE INFECTION. WE ARE TELLING EVERYBODY THAT THERE ARE KNOWN EFFECTIVE PREVENTIVE METHODS. THAT IT'S ACHIEVABLE AS A STANDARD IN THE LOCAL SETTING. WE WILL TALK MORE ABOUT THIS AND REASONABLY ACCESSIBLE BY THOSE ENROLLED IN HIV PREVENTION. ONE OF THE BOTTOM LINES OF THIS IS THAT AS SCIENCE ADVANCES, AS WE DEVELOP MORE AND MORE PREVENTION METHODS, THE ETHICS OF THE TRIAL ASSESSMENT IS GOING TO CHANGE. THE ETHICS HAVE TO KEEP TRACK WITH THAT SCIENCE AND WITH THE TIME LINE. SO I'M GOING TO SKIP OVER THESE TWO IDEAS. AND ASK YOU GUYS, SO FOR BACK IN THAT TRIAL WHERE EVERYBODY IS GOING TO BE RANDOMIZED TO A PLACEBO OR A VACCINE BUT EVERYBODY GETS PREVENTION MESSAGE, IS THERE A REASON TO MAKE SURE THAT RISK REDUCTION MESSAGE IS GIVEN BY SOMEONE OTHER THAN THE INVESTIGATOR. THIS IS A VARIATION ON BOB'S THEME. CHRISTINE, DO YOU HAVE THE MIC TO KEVIN, ABOUT THIS WEARING TWO HATS. THE INVESTIGATOR AND THE PROVIDER. BUT IN THIS CASE REMEMBER, THIS INDIVIDUAL WHO IS THE INVESTIGATOR AND PERHAPS PHYSICIAN, IT COULD BE A Ph.D. TRAINED MEDICAL MICROBIOLOGIST PERHAPS. THESE AREN'T PATIENTS PER SE. THESE ARE PEOPLE AT RISK. OF AN INFECTION. KEVIN. >> SPEAKER5: AS WEIRD AS THIS WILL MIGHT BE TO SAY, >> AS WEIRD AS THIS MIGHT BE TO SAY, WITH HIV, I WOULD WANT EITHER OR ASSUME ONE WITH COMMUNITY KNOWLEDGE OR -- TO PEOPLE WE GUESS THAT THERE'S SOMETHING HAVE BEST OF INTENTIONS BUT BECAUSE SEX AND OTHER TABOO BEHAVIORS ARE INVOLVED -- >> GREAT. THANK YOU. SO THAT'S AT LEAST ONE REASON, RIGHT, WHY WE MIGHT WANT SOMEONE OTHER THAN THE INVESTIGATOR TO PROVIDE THAT RISK REDUCTION MESSAGE. RIGHT? THE IDEA HERE IS THAT ALL SORTS OF PEOPLE FOR WHOM THEY ARE TRAINED TO ACTUALLY GIVE THIS HIV RELATED COUNSELING. AND THAT WOULD BE AN IMPORTANT PERSON TO INCLUDE ON YOUR STUDY TEAM. WHAT I WAS THINKING OF, IS THAT THE INVESTIGATOR MIGHT HAVE A CONFLICT OF INTEREST. IF I'M THE INVESTIGATOR AND I REALLY, REALLY, REALLY WANT TO IDENTIFY THAT VACCINE FOR HIV BECAUSE I APPRECIATE IT'S IMPORTANT TO THE COMPLIMENT OF PREVENTIVE METHODS THAT WE HAVE, I REALLY, REALLY, REALLY WANT TO HAVE SOME OF THE PEOPLE IN THE ARM THAT DON'T GET THE VACCINE TO GET HIV. RIGHT? BECAUSE THE ONLY WAY I KNOW WHETHER OR NOT MY VACCINE WORKS IS THAT IT PREVENTS HIV INFECTION. SO AS -- IT'S ANOTHER WAY OF THINKING ABOUT THIS CONFLICT, IT'S A CONFLICT IN A WAY WHERE THE IDEA IS THAT I MIGHT HAVE A CONFLICT AND EVEN IF I'M NOT AWARE OF IT, I MAY NOT AS STUDIOUSLY JUDICIOUSLY REMIND PEOPLE ABILITY PREVENTING HIV. I MIGHT IN THE BACK OF MY MIND WANT FOLKS WHO I HAVE ENROLLED TO -- I HAVE ENROLL BECAUSE THEY ENGAGE IN HIGH RISK ACTIVITIES TO CONTINUE IN THOSE ACTIVITIES. TO GET MY TRIAL DONE. SO I WANT TO NOW TALK A LITTLE ABOUT A TRIAL THAT JUST STARTED IN 2016. SKIPPING AHEAD NOW. AND WE ARE SORT OF SKIPPING AHEAD TO THE PRESENT BECAUSE THIS IS AN ONGOING TRIAL. IT TURNS OUT IN THE 2009 THERE WAS A TRIAL OF A PRODUCT THAT WAS CONDUCTED IN THAILAND WHERE WE HAD FIRST EVIDENCE, 2009, SO MARGARET HECKLER THOUGHT WE MIGHT HAVE A VACCINE IN 1986, WE ARE A LITTLE WAYS AWAY FROM THAT. AND THERE WAS SOME CONTROVERSY ABOUT THE TRIAL. THE RESULTS SHOWED THAT THOSE WHO RECEIVEDDED THE VACCINE HAD A 31% REDUCTION IN RISK OF GETTING HIV COMPARED TO THOSE WHO GOT THE PLACEBO. SEVEN YEARS LATER IT WAS DECIDED THAT MAYBE WE SHOULD MOVE FORWARD WITH ANOTHER TRIAL IN ANOTHER POPULATION. SO QUITE A BREAK BETWEEN TRIALS. SO THERE IS NOW A TRIAL UNDERWAY IN SOUTH AFRICA USING A NEW VERSION OF THE SAME VACCINE, WITH INTENT OF TRYING TO FIND OUT WHETHER OR NOT THEY HAVE ACTUALLY REFORMULATED IT SLIGHTLY WITH THE HOPES THAT IT WILL BE BETTER THAN THE TRIAL THAT WILL HAVE A BETTER EFFECT MORE EFFECT. WHAT'S SOMEONE -- MILLION VACCINES ARE 100% EFFECTIVE. RIGHT? WE ARE NOW LOOKING AT A VACCINE PRODUCT THAT MIGHT REDUCE THE LIKELIHOOD OF INNEXT 30%. IS THAT ENOUGH? IS THAT ENOUGH TO PURSUE? DID YOU WANT TO ANSWER? NO? SO THERE WAS CONTROVERSY WHETHER OR NOT, IS THIS AMOUNT OF REDUCTION IN INFECTION ENOUGH? PERHAPSES SPECIALLY BECAUSE ALL THE OTHER WAYS WE HAVE TO PREVENT HIV IN THE MIX. SO IN THIS PARTICULAR TRIAL, SO BACK IN 1998 THERE WAS EXPECTATION OF THOSE THREE THINGS, CONDOMS COUNSELING AND STD DIAGNOSIS AND MANAGEMENT. NOW IN 2016 THE TRIAL IS EXPECTED TO MAKE REFERRALS FOR MALE CIRCUMCISION, POST EXPOSURE PROF LACKSIS, MIGHT BEER MEANING -- PROF LACKSIS, ONE I HAD I GO TO THE DOCTOR AND START A COCKTAIL, ANTI-RETROVIRAL COCKTAIL AND PREEXPOSURE PROF LACKSIS, WHERE I TAKE ANTI- RETROVIRAL TODAY SO THIS IS A DIFFERENT LANDSCAPE AND I MOVED IT TO 2019. THE OTHER THING HAPPENING IN TERMS OF EPIDEMIOLOGY OF HIV IS THAT BECAUSE WE HAVE TREATMENT AS PREVENTION, THERE'S ALSO BEEN& A REDUCTION OF VIRAL LOAD IN THE COMMUNITY. SO I GUESS TO SAY IT'S REALLY CHALLENGING TO DO A VACCINE TRIAL ESPECIALLY IN THE CONTEXT OF HIV WHERE YOU HAVE SPENT A LOT OF TIME AND ENERGY IN DEVELOPING AND FINDING WAYS TO REDUCE LIKELIHOOD OF INFECTION. SO I DON'T THINK WE ARE AT THE POINT WHERE WE HAVE TO SAY MAYBE WE JUST HAVE TO FIGURE OUT A DIFFERENT THING, MAYBE WE HAVE ENOUGH IN THE CHEST. SO WHAT IS THE ONE THING, IF YOU LOOK AT THIS LONG LIST, WHAT IS SOMETHING THAT THE VACCINE THAT IS TRUE ABOUT THE VACCINE THAT ISN'T TRUE ABOUT ANY OF THESE OTHER INTERVENTIONS? KEVIN HAS AN ANSWER. IT'S SOMETHING I LEARNED IN -- WHEN I WAS IN GRADUATE SCHOOL MANY YEARS AGO I HAD TO TAKE A COURSE IN INJURY PRESECTION. >> I MIGHT BE WRONG BUT INTUITIVELY WHAT I KNOW ABOUT WHAT'S ON THIS A VACCINE WOULD BE EITHER ONCE NUMBER LIFE WHERE IT JUST HASN'T -- AS AN EXAMPLE TO THE EXTENT THAT THEY DO PREVENTION LIKE BIRTH CONTROL HAVE OR WHETHER THEY JUST INGEST IT EVERY DAY. >> EXACTLY. RIGHT? SO THE CLOSEST TO A VACCINE MEANING THAT YOU GET ONE SHOT OR MAYBE THREE SHOTS, OF THE VACCINE, THE CLOSEST MIGHT BE MALE CIRCUMCISION, BUT CLEARLY MALES CIRCUMCISION IS DIFFERENT CALL -- QUALITATIVELY THAN GETTING A SHOT. SO THE LAST EFFORT ON THE BEHALF OF THE PERSON, THE BETTER PREVENTION MODE. SO I LEARNED THIS IN INJURY PREVENTION, THERE'S THIS THING CALLED THE HAYDEN MATRIX. YOU ALWAYS WANT TO PUSH TOWARDS THING WHERE THE PERSON DOESN'T HAVE TO DO ANYTHING. SO AIR BAGS. RIGHT? YOU THE DRIVER DON'T HAVE TO DO ANYTHING BUT WHEN YOU NEED IT THAT AIR BAG HOPEFULLY WILL POP OUT OF YOUR STEERING WHEEL. IN THIS CASE THE BEST INTERVENTION OR BEST WAY TO PREVENT DISEASE IS FOR THERE TO BE JUST ONE SHOT, TWO SHOTS THEN YOU ARE PROTECTED. AND THIS BRINGS UP THE QUESTION, IS IT OKAY TO HAVE A VACCINE THAT IS NOT 100% EFFECTIVE? MAYBE IT WILL BE THE CASE WITH HIV THAT EVERYONE WILL HAVE A VACCINE BUT EVERYONE WILL ALSO NEED TO CONTINUE TO USE CONDOMS FOR EXAMPLE. OR STERILE NEEDLESS, ET CETERA. -- NEEDLES, ET CETERA. SO I WANT TO SPEND A COUPLE OF MOMENTS ON A COUPLE OF ADDITIONAL PRINCIPLES. IN THINKING ABOUT INFORMED CONSENT YOU WILL HAVE A WHOLE LECTURE ABOUT INFORMED CONSENT BUT I WANT TO HIGHLIGHT A COUPLE OF THINGS UNIQUE WHEN TALKING ABOUT VACCINE TRIAL. SO THE FIRST THING ABOUT A VACCINE TRIAL IS THERE'S GOING TO BE A SCREENING. IF YOU ALREADY HAVE THE DISEASE YOU ARE GOING TO BE SCREENED OUT. I'M NOT GOING TO GIVE YOU A VACCINE IF YOU ALREADY HAVE HIV. SO I THE PI IN THIS HYPOTHETICAL CASE NEED TO BE READY TO REFER TO CARE. THIS TOO IS A COMPLICATED THING. IF YOU ARE TALKING ABOUT HERE IN THE UNITED STATES EVEN, REFERRAL TO CARE MAY NOT BE REFERRAL TO HIGH QUALITY AND EXPENSIVE CARE. YOU MAY NOT HAVE INSURANCE, YOU MAY NOT HAVE A JOB THAT PROVIDES YOU WITH INSURANCE. SO WHAT IS THAT OBLIGATION IN TERMS OF REFERRAL TO CARE? DO I JUST SAY WELL, THERE'S AN HIV CLINIC OVER THERE OR HERE IS A BUS FARE TO GET TO THAT HIV CLINIC. LET ME PICK UP THE PHONE AND MAKE AN APPOINTMENT FOR YOU. WHAT IS REFERRAL MEAN IN THIS CONTEXT IN SO THEN THINKING ABOUT INFORMED CONSENT IN PARTICULAR, FOR THOSE WHO ARE ELIGIBLE, IT'S IMPORTANT TO THINK ABOUT THE FACT THAT THERE ARE THESE POTENTIAL BIOLOGICAL AND SOCIAL RISKS INHERENT IN HIV VACCINE RESEARCH, SOME OF WHICH ARE COMPLICATED BUT SOLVABLE. SO FIRST DEPENDING ON THE COMPOUND BEING USED, OR THE VACCINE ITSELF THE TRIAL SUBJECTS MAYBE RENDERED HIV POSITIVE ON A CONVENTIONAL TEST. IF WE TESTED THEM NOT WITH JUST IN AN ELISA TO SEE IF THEY DEVELOPED ANTIBODIES TO HIV BUT WE USE A DNA TEST FOR EXAMPLE, WE WILL BE ABLE TO TELL BUT NOT IN ALL CASES AND SOMETIMES PEOPLE ARE TESTED FOR HIV AT THE HOSPITAL WHEN THEY ARRIVE FOR POTENTIAL FRACTURED LEG. HOW WILL I HELP SUBJECTS EXPLAIN THAT TO OTHER HEALTHCARE PROVIDERS? THERE'S THIS REMOTE RISK THE VACCINATION COULD INCREASE SUSCEPTIBILITY, I THINK WE HAVE SOME EVIDENCE THAT THIS IS NOT GOING TO BE THE CASE. THEN PARTICIPATION MAY MAKE THEM INELIGIBLE FOR FUTURE TRIALS OR UNRESPONSIVE TO FUTURE VACCINE PRODUCTS. POTENTIALLY MORE EFFECTIVE CONVENIENCE. IT IS ALSO ESSENTIAL TO NOT GUARANTEE A PROTECTION AGAINST HIV. SO THIS PHENOMENON IS CALLED BEHAVIORAL DISINHIBITION. I ALLUDED TO IT EARLIER. IF I ENROLL IN HIV VACCINE TRIAL AND I COME TO BELIEVE THAT I HAVE RECEIVED THE ACTIVE VACCINE I MAY SAY YOU KNOW WHAT, I HAVE GOT THAT VACCINE, I DON'T NEED TO USE CONDOMS ANY MORE. I DON'T NEED TO USE STERILE NEEDLES. SORTS OF INCIDENTALLY, -- COINCIDENCELY, THIS MAYBE WHAT YOU NEED TO GET THE TRIAL DONE AS QUICKLY AS POSSIBLE. BUT AT THE SAME TIME, YOU DON'T WANT TO GUARANTEE PEOPLE OR YOU DON'T WANT PEOPLE TO GIVE -- YOU DON'T WANT TO GIVE THEM THE ILLUSION OR PERCEPTION THAT THEY ARE PROTECTED JUST BY PARTICIPATING IN YOUR VACCINE TRIAL. AND A TOPIC WE STARTED WITH, IT'S IMPORTANT FOR THEM TO KNOW THAT THERE IS A POSSIBILITY THEY MAY SUFFER DISCRIMINATION AS THOUGH THEY WERE INFECTED WITH HIV. SO IMAGINE THERE'S A TRIAL OPENING UP AND THE PRIMARY ELIGIBILITY CRITERIA IS THAT YOU ARE AT HIGH RISK OF HIV INFECTION. IT WOULD NOT BE A GOOD IDEA TO DO AN HIV VACCINE TRIAL AMONG A GROUP OF PEOPLE WHO ARE ABSTINENT. BECAUSE YOU NEED THAT EXPOSURE. MAYBE ABSTINENT DRUG USERS WOULD BE OKAY. SO THE IDEA HERE IS THAT THOSE WHO ARE IN YOUR TRIAL, IF SOMEONE KNOWS EVEN THAT YOU ARE IN THE TRIAL, THEY MAY SAY OH, YOU ARE AT RISK OF HIV OR YOU MUST HAVE HIV. SO IT'S NOT DISCRIMINATION ABOUT THE HIV STATUS PER SE, BUT IT'S ABOUT THE FACT THAT YOU MIGHT BE AT RISK FOR HIV. THAT MEANS IN TERMS OF HOW YOU ARE DOING THE STUDY. I GIVE A TALK AN PRIVACY AND CONFIDENTIALITY AND HAVE AS A AN EXAMPLE, A BIG SIGN ON FRONT DOOR OF CLINIC SAYING HIV VACCINE STUDY HERE. PROBABLY SOMETHING YOU DON'T WANT TO DO. BUT MAYBE NOT SOMETHING YOU WOULD ALWAYS THINK ABOUT. OR RETURN ENVELOPE OF THE LETTER YOU WANT TO SEND TO REMIND SOMEBODY ABOUT FOLLOW-UP APPOINTMENT. YOU DON'T WANT TO PUT HIV VACCINE STUDY AS YOUR RETURN ADDRESS. SO I'LL SPEND A COUPLE OF MINUTES ON RESPECT FOR PARTICIPANTS AND FOR COLLABORATIVE PARTNERSHIPS AND THOSE OF YOU WHO ARE INTERESTED IN CHALLENGE STUDIES CAN COME CHAT WITH ME IN MY OFFICE. SO WHAT IS RESPECT FOR PARTICIPANTS MEAN? AMONG THE PRINCIPLES THAT ARE IN THE FRAMEWORK THAT WAS INTRODUCED EARLIER IN THE COURSE, I WOULD SAY THIS IS THE MOST TO ME ANYWAY, THE MOST NOVEL IN THE SENSE IT IS SOMETHING THAT I THINK INVESTIGATORS, WELL THEY MIGHT THINK ABOUT IT, MAYBE DON'T PUT AS MUCH THOUGHT INTO THIS AS THEY DO INTO THE STUDY DESIGN OR INFORMED CONSENT PROCESS. THIS IS ABOUT WHAT DO WE OWE PARTICIPANTS ONCE THEY ARE IN OUR STATUS? THEY HAVE GIVEN INFORMED CONSENT AND NOW WE HAVE SOME RESPONSIBILITY FOR THEM. IN TERMS OF RESPECT FOR PARTICIPANTS IN THE CONTEXT OF VACCINE TRIAL, WE MIGHT WANT TO MAKE SURE THAT THEY HAVE COMPREHENSIVE PSYCHOSOCIAL COUNSELING AND WE SHOULD BE ABLE TO HAVE THEM BRING IN PARTNERS OR PROVIDERS FOR PARTNERS OR INTIMATE ASSOCIATES IF THEY WANT. I HAVE BEEN TRYING TO EXPLAIN TO MY BOYFRIEND I'M IN THIS HIV VACCINE STUDY, THAT DOESN'T MEAN I HAVE HIV. CAN I BRING HIM IN AND COULD WE HAVE A CONVERSATION ABOUT IT, FOR EXAMPLE. AND A REALLY IMPORTANT QUESTION THAT I THINK THERE'S STILL SOME DISAGREEMENT ABOUT IS, WHAT DO WE OWE THE PERSON WHO ENROLLS IN OUR HIV VACCINE TRIAL AND GETS HIV? HIV IS TODAY A CHRONIC DISEASE, I READ RECENTLY IF YOU LOOK AT THE AVERAGE LIFE SPAN OF SOMEONE WHO JUST RECENTLY BEEN INFECTED WITH HIV, AND STARTED ANTI-RETROVIRAL THERAPY, THEIR LIFE SPAN IS NO DIFFERENT THAN THE PERSON NEXT TO THEM WHO DOESN'T HAVE HIV. SO WE HAVE MADE VERY IMPORTANT ADVANCES BUT THAT'S A LIFETIME, MANY YEARS OF TREATMENT. IN THE CONTEXT OF UNIVERSAL HEALTHCARE COVERAGE THAT MIGHT BE A EASY STRAIGHT FORWARD THING TO DO. YOU SAY LOOK, IF YOU BECOME HIV INFECTED IN MY STUDY, I HAVE A REFERRAL SYSTEM IN PLACE. IF YOU SEROCONVERT YOU WILL GO TO THIS CLINIC AND THEY WILL TAKE CARE OF YOU FOR THE REST OF YOUR LIFE. WE DON'T REALLY HAVE THAT SORT OF SYSTEM HERE IN THE UNITED STATES, IT'S CERTAINLY TRUE IN OTHER LOW AND MIDDLE INCOME COUNTRIES THAT AS MUCH AS THEY WOULD LIKE TO BE ABLE TO DO THAT BECAUSE THEY HAVE A UNIVERSAL HEALTHCARE SYSTEM THE LEVEL OF CARE THEY ARE UNIVERSAL SYSTEM PROVIDES ISN'T QUITE AT THE SAME LEVEL AS OURS. AND THAT IT'S REALLY IMPORTANT TO CONDUCT LONG TERM FOLLOW-UP, TO MAINTAIN THAT RELATIONSHIP OVER TIME ONCE YOU ENROLLED SOMEONE IN YOUR TRIAL. FOR THOSE IN PARTICULAR WHO HAVE BECOME HIV INFECTED ON THE VACCINE ARM, WE ARE GOING TO WANT TO FOLLOW THEM EXTENSIVELY BECAUSE THEY ARE PERHAPS IN SOME WAY DIFFERENT BIOLOGICALLY OR IN TERMS OF EXPOSURE THAT MAKES THEM DIFFERENT. SO LAST THING I'LL MENTION TODAY IN THE LAST COUPLE OF SECONDS IS IMPORTANCE OF INVOLVING COMMUNITY IN A MEANINGFUL WAY AND KEVIN ALLUDED TO THIS IN A SLIGHTLY DIFFERENT WAY EARLIER ON. WHEN YOU ARE DOING RESEARCH IN A COMMUNITY OF PEOPLE WHO MAY FEEL DISENFRANCHISED OR DISADVANTAGED DIFFERENT THEIR SOCIAL STATUS, IT IS IMPORTANT TO INVOLVE THEM IN DEVELOPMENT OF THE TRIAL, IN THE CONSENT PROCESS PERHAPS. BUT IT'S ALSO AN IMPORTANT QUESTION TO WHO REPRESENT IT IS COMMUNITY. WHO DO I APPROACH? WHO -- IF I'M THE PRINCIPLE INVESTIGATOR WHO IS IT THAT I OUGHT TO BE REACHING OUT TO TO GET THAT ENGAGEMENT EARLY ON. AND THROUGHOUT THE TRIAL. ANOTHER REALLY TOUGH QUESTION THAT WILL ALSO TALK ABOUT LATER IN THE TERM LATER IN OUR CLASS IS HOW WILL THEIR BENEFITS FOR THE COMMUNITY BE ASSUREDD? IMAGINE THIS COMMUNITY OF PEOPLE WHO ARE OTHERWISE DISADVANTAGED PERHAPS THINKING ABOUT THE UNITED STATES, WHAT SORT OF BENEFITS IFNY OUGHT TO GO TO COMMUNITY FROM WHICH YOU IDENTIFIED AND ENROLLED YOUR SUBJECTS. DO WE OWE THEM FIRST DOCUMENT IN LINE FOR THE VACCINE WE DEVELOP OR ARE THEY JUST IN LINE WITH EVERYBODY ELSE? WHAT ABOUT THE LARGER NEIGHBORHOODS OR STATE OR REGION? DO WE OWE ANYTHING IN PARTICULAR TO THOSE CLOSEST TO WHERE THE TRIAL HAPPENS FOR EXAMPLE. SO I WAS GOING TO FINISH WITH COLLABORATIVE VIEWS OF THE FOLKS INVOLVED IN A SOUTH AFRICAN STUDY,. THESE TERMS OF THEIR PARTICULAR INTERESTS, THEY WERE ASKED TO COMPARE A COUPLE OF DIFFERENT ETHICAL GUIDELINES. FROM THEIR PERSPECTIVE THESE STAKEHOLDERS WERE PROVIDERS, INVESTIGATORS, MEMBERS OF THE COMMUNITY, AGAIN. DEFINED IN THE STUDY. THINGS THEY THOUGHT MOST IMPORTANT OR RANKED ACCOUNTANTLY WERE CARE RELATED MEANING WHAT'S GOING TO HAPPEN IF I'M SCREENED OUT OF YOUR STUDY OR I GET HIV ON YOUR STUDY. THOSE ETHICAL CONCERNS ARE MOST IMPORTANT TO US AS STAKEHOLDERS AND INTERESTINGLY THE BOTTOM RANGE WERE THESE PREVENTION REMITTED QUESTIONS THAT WE WERE TALKING ABOUT EARLIER. I WILL END HERE IN TERMS OF THINKING ABOUT HOW WE OUGHT TO CONVEY THE TRIALS TO THE POTENTIAL SUBJECTS. THESE ARE TOP TWO THINGS THEY THOUGHT MOST IMPORTANT FOR POTENTIAL SUBJECTS TO HEAR, THAT THEY SHOULD BE TOLD WHAT PREVENTION SERVICES THEY WILL RECEIVE AND WHAT AND SHOULD BE TOLD WHAT CARE AND TREATMENT SERVICES THEY WILL RECEIVE. SO APART FROM ALL OTHER THINGS THAT MIGHT BE GOING ON IN HIV VACCINE THESE WERE THINGS THEY THOUGHT MOST IMPORTANT. THAT MAY DIFFER FROM DIFFERENT POPULATIONS. SO I GUESS TO SAY, IT'S A PITCH FOR THINKING CAREFULLY ABOUT THE POPULATION YOU ARE GOING TO AND WHETHER OR NOT THERE'S ROOM FOR A LEVEL OF COMMUNITY PARTNERSHIP COLLABORATIVE PARTNERSHIP THAT ALLOWS YOU TO TAILOR THE WAY IN WHICH YOUR PROVIDING INFORMED CONSENT TO HIT THE THINGS MOST IMPORTANT TO THAT GROUP. I WILL STOP THERE AND LOVE TO TAKE ANY QUESTIONS ABOUT ANYTHING I HAVE COVERED TODAY. [APPLAUSE] >> I'LL MENTION TOO ON THE CHALLENGE STUDIES, MY COLLEAGUE WAS VERY HELPFUL IN HELPING ME PREPARE FOR THAT BUT WE ALSO HAVE A READING FOR TODAY ON THAT TOPIC THAT DOES A LOVELY JOB OF COVERING THAT ISSUE. SO I ENCOURAGE ANYONE WHO IS INTERESTED IN THAT TO TAKE A LOOK AT THAT. NO QUESTIONS? >> ANY QUESTIONS? IF NOBODY HAS A QUESTION MAYBE YOU COULD SAY IN A SENTENCE OR TWO WHAT A CHALLENGE STUDY IS. >> SURE. >> PEOPLE DON'T KNOW. >> ABSOLUTELY. WE WILL SKIP TO THAT QUICKLY. GIVE YOU A LITTLE TASTE FOR THINKING ABOUT WHAT YOU ARE GOING TO DO IN YOUR SARE TIME MAYBE READING THIS ARTICLE. SO A CHALLENGE STUDY INVOLVES EXPOSING PARTICIPANTS TO INFECTIOUS AGENTS IN ORDER TO TEST A VACCINE OR TREATMENT CANDIDATE AND/OR STUDY HOST OR PATHOGEN BIOLOGY IN A CONTROLLED MANNER. YOU MAY HAVE SEEN THIS IN THE NEWS, THEY ARE TESTING A NEW MALARIA VACCINE AND YOU SEE SOMEONE ROLE UP THEIR SLEEVE AND STICK THEIR ARM TO WHAT LOOKS LIKE INCUBATOR FROM A NICU FULL OF MOSQUITOES. THE IDEA HERE IS THAT YOU ARE TESTING WHETHER OR NOT THAT MALARIA VACCINE HAS IS ACTUALLY EFFECTIVE. IS A DIRECT CHALLENGE. SOMETHING WE DON'T DO IN THE HIV SETTING. SO THE IDEA IS THAT THERE ARE SOME CIRCUMSTANCES UNDER WHICH DOING A CHALLENGE STUDY IS GOING TO BE VERY EFFICIENT. YOU ARE GOING TO KNOW RIGHT AWAY WHETHER OR NOT THE VACCINE YOU HAVE DEVELOPED ACTUALLY REDUCES LIKELIHOOD OF TRANSMISSION BY EXPOSING THE PERSON YOU VACCINATED TO IN THIS CASE MOSQUITO WHO WILL GIVE YOU THE MALARIA. SOME OF THE WORRIES ABOUT THIS ARE JUST ABOUT THE IDEA. THE PUBLIC SKI MOUSENESS ABOUT YOU'RE GOING TO DO WHAT TO WHO? ASK SOMEONE TO PURPOSEFULLY BE EXPOSED TO A VACCINE THAT YOU KNOW NOTHING ABOUT AND BE EXPOSED TO POTENTIAL ILLNESSNESS AND WATCH THEM? YES THAT IS WHAT THEY DO. PART OF THE ETHICAL ANALYSIS WHAT AMOUNT OF SOCIAL VALUE IS NEEDED TO BALANCE THE BURDEN, AT LEAST BURDEN, IN THE CONTEXT OF THOSE CHALLENGE STUDIES. >> QUESTIONS ABOUT THAT OR ANYTHING? >> I THINK IT'S AN INTERESTING IN LIGHT OF THE DISCUSSION EARLIER, THAT BOB GAVE ABOUT ADAPTIVE RANDOMIZE TRIALS, HOLLY'S SLIDE ON EFFICACY TRIAL WITH 4% INCIDENCE OF HIV YOU NEED 4,000 WHATEVER THE NUMBER WAS PEOPLE. 4,000 SOME OF WHOM GET BASICALLY NO BENEFIT BUT ALL RISK. AND 43 GET BENEFIT. IF YOU DO A CHALLENGE STUDY YOU HAVE A VERY SMALL NUMBER OF PEOPLE. THEY GET ALL THE RISK TOO. BUT YOU GET AN ANSWER MORE QUICKLY AND YOU GET INFORMATION OUT OF A SMALL NUMBER OF PEOPLE YOU CAN ONLY GET OUT OF HUGE NUMBERS OF PEOPLE IN THE NATURAL ENVIRONMENT WHICH IS SOME OF THE ARGUMENT FOR DOING THEM. BUT IT'S CONTROVERSIAL FOR THE REASONS YOU CAN PROBABLY IMAGINE. >> HI. GREAT LECTURE, JUST WANTED TO SAY THANK YOU. ALSO I WAS WONDERING THROUGHOUT YOUR LECTURE, HOW THE CHALLENGES WITH DESIGNING THE HIV VACCINE WHEN TALKING ABOUT PEOPLE'S BEHAVIOR AND PREVENTION, HOW WOULD THAT RELATE TO THE DESIGN OF THE STUDY FOR THE HPV VACCINE GIVEN THE FACT THAT THE POPULATION IS IN THE SAME -- AT THE SAME RISK. SO HOW WAS THAT DONE AND HOW WOULD THAT APPLY TO THE HIV VACCINE STUDY? >> I'M NOT EXACTLY SURE WHAT I -- WHAT YOU ARE ASKING BUT HERE IS WHAT I THINK YOU ARE ASKING. SO WE ARE TALKING ABOUT HIV. HOW DID THIS WORK IN HPV AND FOR THOSE WHO DON'T KNOW, HPV IS A VIRUS THAT WE NOW HAVE A VACCINE AVAILABLE FOR, THE THING YOU ARE PREVENTING IS THE TRANSMISSION OF THAT VIRUS BUT YOU ARE ALSO PREVENTING HOPEFULLY DEVELOPMENT OF CANCER MANY, MANY, MANY YEARS LATER. SO ONE OF THE CHALLENGES IN DOING THE HIV -- HPV VACCINE TRIALS NO PUN INTENDED, IS THAT THE THINGS YOU ARE PREVENTING IS MANY, MANY YEARS OFF IN TERMS OF HOW YOUR RECRUITING INDIVIDUALS AND IN FACT RECRUITING THEIR PARENTS, INTO TRIALS BECAUSE YOU WANT KIDS IN YOUR TRIALS WHO HAVE NOT YET BEEN EXPOSED TO HPV WITH THE EXPECTATION THAT ALL OF THEM WILL SOON BE EXPOSED TO HPV. THANKS. >> OTHER QUESTIONS? >> ONE ADDITIONAL THING I WILL SAY, I WILL ASK TALIA TO POST, THERE WAS A RECENT ARTICLE ABOUT ADAPTABLE TRIAL DESIGNS FOR HIV VACCINES. WHICH IS A VERY INTERESTING READ. FOR EXAMPLE, ONE OF THE POSSIBLE WAYS TO DO IT WOULD BE SOMETHING LIKE THE FOLLOWING. LET'S IDENTIFY A WHOLE BUNCH OF PEOPLE AT RISK OF HIV, LET'S ASK THEM TO USE PREP FOR THREE MONTHS AND SEE HOW IT GOES. IF AT THE END OF THAT THREE MONTHS THERE ARE X NUMBER OF PEOPLE FOR WHOM IT JUST DID NOT WORK, THEY RESPONDED POORLY TO MEDICATIONS, THEY WEREN'T VERY ADHERENT, MAYBE THAT'S THE TYPE OF PERSON WE WANT IN OUR TRIAL. IN THAT CASE YOU WOULDN'T NEED TO GUARANTEE THEM PREP DURING THE TRIAL. BECAUSE YOU ALREADY FOUND OUT THAT IT DIDN'T WORK OUT FOR THEM. SO IT'S JUST -- I THINK BECAUSE THE WAYS IN WHICH WE CAN PREVENT HIV ARE MOUNTING UP THERE WILL NEED TO BE CREATIVITY ABOUT HOW WE ACTUALLY TEST THESE THINGS GIVEN THAT ALL THOSE PREVENTIVE METHODS ARE GOING TO REDUCE INCIDENCE FURTHER WHICH MEANS YOU HAVE TO HAVE LARGER TRIALS TO ACTUALLY GET AN EFFECT. THANKS. >> OKAY. [APPLAUSE]