I'M GOING TO GO AHEAD AND GET STARTED. YOUR FIRST SPEAKER OF THE DAY HAPPENS TO BE YOURS TRULY. I'M GOING TO TALK ABOUT INFORMED CONSENT, AND I KNOW THERE ARE PEOPLE STRAGGLING IN, BUT I THINK ARGUABLY THIS IS A TOPIC THAT A LOT OF PEOPLE FIGURED WOULD BE ON THE AGENDA FOR THIS COURSE, AND HOPEFULLY IN ONE HOUR, WE CAN COVER SOME OF THE MOST IMPORTANT POINTS ABOUT INFORMED CONSENT. OF COURSE MY DISCLAIMER, BOTH OF MY VIEWS AND CONFLICTS. SO I WANT TO START BY RECOGNIZING THAT INFORMED CONSENT IS SOMETHING THAT'S WELL ENTRENCHED IN AMERICAN VALUES. THAT'S NOT TO SAY IT'S NOT WELL ENTRENCHED IN OTHER SOCIETY'S VALUES, BUT IN THE UNITED STATES IT'S SOMETHING THAT PEOPLE -- IN MEDICAL PRACTICE AND IN CLINICAL RESEARCH. JERRY MANIKOT, CURRENTLY THE HEAD OF OFFICE OF RESEARCH PROTECTIONS WROTE THIS ALMOST 10 YEARS AGO NOW, INFORMED CONSENT IS THE BEDROCK PRINCIPLE ON WHICH MOST MODERN RESEARCH ETHICS RESTS. THIS IS AT THE HEART OF THE CRUCIAL ETHICAL PROVISION STATED IN THE FIRST WORDS OF THE NUREMBERG CODE AND IT REMAINS EQUALLY COMPELLING A HALF A CENTURY LATER. SO WHAT IS INFORMED CONSENT? THE LITERATURE SAYS INFORMED CONSENT IS AUTHORIZATION OF AN ACTIVITY BASED ON UNDERSTANDING WHAT THE ACTIVITY IS. IN OTHER WORDS, YOU UNDERSTAND WHAT SOMEBODY IS ASKING YOU TO DO AND BASED ON THAT UNDERSTANDING, YOU EITHER AUTHORIZE OR REFUSE TO AUTHORIZE AUTHORIZE. IT'S ALSO A LEGAL, REGULATORY AND ETHICAL REQUIREMENT IN BOTH HEALTHCARE AND IN MOST RESEARCH WITH HUMAN SUBJECTS. IT'S A PROCESS, IMPORTANTLY A PROCESS, AND I'M SURE EVERYONE IN THIS ROOM HAS HEARD THIS, IT'S NOT JUST A FORM, IT'S A PROCESS, IT'S NOT JUST AN EPISODE, IT'S NOT JUST A ONE-TIME DEAL, IT'S A PROCESS THAT'S ONGOING. AND THE LAST BULLET ON THIS SLIDE IS CONSISTENT WITH THINGS WE'VE SAID IN THIS COURSE TO DATE, IT'S ONLY ONE ASPECT OF CONDUCTING ETHICAL CLINICAL RESEARCH. IT MAY BE AN IMPORTANT ONE, BUT IT'S NOT THE ONLY ONE, AND IT MAY NOT EVEN BE THE FIRST ONE, IF YOU FOLLOW OUR PARADIGM. SO LET'S GO VERY BRIEFLY, IESM GOINI'MGOING TO SAY SOMETHING ABOUT LEGAL REQUIREMENT. ACTUALLY THERE'S A HUGE HISTORY HERE AND A LOT OF VERY INTERESTING LITERATURE SO IT IF YOU'RE INTERESTED IN THIS, YOU SHOULD LOOK IT UP, BUT BRIEFLY, FOR A LONG TIME, THE LEGAL LANDSCAPE WAS, YOU COULDN'T DO SOMETHING WITHOUT SOMEBODY'S CONSENT BECAUSE IT WAS ASSAULT AND BATTERY. AND THEN 40 YEARS AGO, A CASE CHANGED THAT, SO THAT NOW INFORMED CONSENT -- LACK OF INFORMED CONSENT IS SEEN AS NEGLIGENCE. YOU FAIL TO GIVE PEOPLE INFORMATION THAT WOULD BE MATERIAL TO THE DECISION THAT THEY WOULD MAKE. SO THAT'S REALLY THE LEGAL LANDSCAPE IN ONE SENTENCE. THE MOST FAMOUS QUOTE OF HOW INFORMED CONSENT IN THE LEGAL LITERATURE IS FROM JUSTICE CARDOZO IN 1914, IT HAD TO DO WITH A SURGICAL CASE AND HE WAS A SUPREME COURT JUSTICE, JUST CARDOZO WHO SAID EVERY HUMAN BEING OF ADULT YEARS AND SOUND MIND HAS A RIGHT TO DETERMINE WHAT WILL BE DONE WITH HIS BODY. THIS IS A WAY OF SAYING BASED ON LEGAL PERSPECTIVE, PEOPLE HAVE A RIGHT TO HAVE THE INFORMATION THAT THEY NEED TO MAKE A DECISION, AND THEN TO MAKE A DECISION ABOUT THINGS THAT ARE GOING TO HAPPEN WITH THEIR OWN BODY. FROM AN ETHICAL PERSPECTIVE, WE THINK OF INFORMED CONSENT AS BASED ON A PRINCIPLE OF RESPECT FOR AUTONOMY, THAT WE RESPECT PEOPLE'S CAPACITY FOR AND RIGHT TO DEFINE THEIR OWN LIFE GOALS AND THEN MAKE CHOICES CONSISTENT WITH THOSE GOALS. SO THAT SEEMS PRETTY NON-CONTROVERSIAL. IT'S PACKED, YOU HAVE TO REALLY UNPACK IT TO UNDERSTAND IT, BUT IT'S A REALLY STRONG PRINCIPLE IN ETHICAL LITERATURE AND ETHICAL DIALOGUE. THE PRESIDENT'S COMMISSION IN THE 1980s TALKED ABOUT THIS, TALKED ABOUT INFORMED CONSENT AND ITS BASIS IN AUTONOMY. INFORMED CONSENT IS ROOTED IN THE FUNDAMENTAL RECOGNITION THAT ADULTS ARE ENTITLED TO ACCEPT OR REJECT HEALTHCARE INTERVENTIONS ON THE BASIS OF THEIR OWN PERSONAL VALUES AND IN FURTHERANCE OF THEIR OWN PERSONAL GOALS. SO THIS IS JUST A STATEMENT OF, WE DO IT OUT OF RESPECT FOR PEOPLE'S AUTONOMY. NOW, HOW MANY OF YOU HAVE EVER GIVEN INFORMED CONSENT IN CLINICAL PRACTICE? I SEE A FEW HANDS. I THINK THERE'S AN INTERESTING -- SOMETHING WE'RE NOT GOING TO TALK ABOUT TODAY ACTUALLY, INFORMED CONSENT IN CLINICAL PRACTICE, BUT I THINK SOME OF YOU KNOW HOUSE, THE FAMOUS HOUSE FROM TELEVISION WHO IS A -- ARGUABLY NOT THE BEST EXAMPLE OF HOW TO GET INFORMED CONSENT FROM PATIENTS. BUT CERTAINLY I THINK MANY OF YOU, AND I CERTAINLY HAVE MY OWN STORIES, CAN PROBABLY TELL A STORY OR TWO ABOUT HOW YOU WERE ASKED OR TOLD TO DO SOMETHING IN THE CLINICAL SETTING WITHOUT GIVEN MUCH INFORMATION OR MUCH TIME TO MAKE A DECISION. SO INFORMED CONSENT IS CERTAINLY NOT PERFECT IN MEDICAL PRACTICE, AND THERE'S BEEN A NUMBER OF STUDIES THAT HAVE TRIED TO LOOK AT THAT, AND EXPLAIN IT AND EVEN SOME STUDIES TO TRY TO LOOK AT WAYS TO IMPROVE IT. BASICALLY THE STUDIES THAT ARE OUT THERE CONCLUDE MORE OR LESS ALONG THESE LINES. IT'S FREQUENTLY INADEQUATE IN CLINICAL PRACTICE. PHYSICIANS ACTUALLY RECEIVE VERY LITTLE TRAINING ABOUT HOW TO OBTAIN INFORMED CONSENT. THEY ALSO SOMETIMES MISUNDERSTAND THE REQUIREMENTS AND THE LEGAL STANDARDS AROUND INFORMED CONSENT. THEY ALSO ARE OPERATING UNDER TIME PRESSURES AND MANY COMPETING DEMANDS. PATIENT COMPREHENSION IS OFTEN VERY POOR ABOUT WHAT IS BEING OFFERED TO THEM. HOWEVER, RECENT STUDIES HAVE DEMONSTRATED THAT THIS CAN BE IMPROVED THROUGH TEACHING PHYSICIANS GOOD COMMUNICATION SKILLS, SO THIS IS SOMETHING THAT'S HAPPENING IN A LOT OF MEDICAL TRAINING, AND THE STUDIES THAT HAVE BEEN DONE THUS FAR THAT HAVE LOOKED HOW IT HAS AN IMPACT ON INFORMED CONSENT HAVE SHOWN IN CLINICAL PRACTICE THAT IT ACTUALLY MAKES A DIFFERENCE. IT IMPROVES THE PATIENT'S UNDERSTANDING OF WHAT'S BEING OFFERED. IN RESEARCH, INFORMED CONSENT IS ALSO REQUIRED BY OUR FEDERAL REGULATIONS. SO THE FIRST BULLET IS A REFERENCE TO BOTH THE COMMON RULE, 45 CFR 46, AND THE FDA RULES -- REGULATIONS, EXCUSE ME, AND IT BASICALLY SAYS THE SAME THING IN BOTH SET OF REGULATIONS THAT NO INVESTIGATOR MAY INVOLVE A HUMAN BEING AS A SUBJECT IN RESEARCH UNLESS THE INVESTIGATOR HAS OBTAINED THE LEGALLY EFFECTIVE INFORMED CONSENT OF THE SUBJECT OR THE SUBJECT'S LEGALLY AUTHORIZED REPRESENTATIVE. NOW THERE ARE IN THE REGULATIONS SOME LIMITED EXCEPTIONS. THE EXCEPTIONS DIFFER BETWEEN THE COMMON RULE AND THE FDA REGS REGS. BUT BOTH SETS OF REGULATIONS ALSO SAY THAT INFORMED CONSENT MUST BE SOUGHT PROSPECTIVELY, BEFORE YOU START THE RESEARCH, AND DOCUMENTED. AGAIN, THERE ARE SOME EXCEPTIONS IN THE REGS ABOUT DOCUMENTATION. I THINK LAST WEEK, SOME OF THOSE WERE REFERRED TO. SO LET'S DIG A LITTLE DEEPER. SO RUTH THADEN AND TOM BEECHAM, LONG-STANDING SCHOLARS, WROTE A BOOK MORE THAN 10 YEARS AGO NOW, "HISTORY AND THEORY OF INFORMED CONSENT." GREAT BOOK. AND THEY DESCRIBE IN THE BOOK THAT THERE REALLY ARE TWO SENSES OF INFORMED CONSENT. THERE'S THIS ONE THAT I'VE ALREADY DESCRIBED, THIS AUTONOMOUS AUTHORIZATION, WHERE PEOPLE INTENTIONALLY SAY YES OR NO, I'M GOING DO SOMETHING, BECAUSE I UNDERSTAND WHAT IT IS, NOBODY'S FORCING ME TO DO IT AND IT'S CONSISTENT WITH WHAT I WANT. THAT'S AUTONOMOUS AUTHORIZATION. THEY ALSO POINT OUT THAT THERE IS IT THIS SORT OF OTHER SENSE OF INFORMED CONSENT THAT OFTEN ACTUALLY DOMINATES, AND THAT'S THE SORT OF OF SOCIAL RULES OF CONSENT. THIS IS SOMETHING THAT MIGHT BE INSTITUTIONALLY OR LEGALLY EFFECTIVE, BUT IS NOT REALLY AUTONOMOUS AUTHORIZATION. SO I USED TO TELL TWO STORIES, I'LL TELL THEM VERY BRIEFLY. ONE IS A WOMAN WHO WAS ASKED TO UNDERGO A CERTAIN SURGERY FOR A CANCER THAT SHE HAD, AND SHE SAT WITH THE INVESTIGATOR, WHO EXPLAINED WHAT THE SURGERY WAS ABOUT, WHAT THE POSSIBLE BENEFITS WERE TO HER, WHAT THE RISKS OF THE SURGERY WERE, WHAT THE ALTERNATIVES WERE. SHE WENT BACK AND SPOKE TO HER FAMILY, HER PRIMARY DOCTOR, AND SAID SOMETHING LIKE, IT WAS A VERY DIFFICULT DECISION, I'M NOT SO REALLY SURE THAT IT'S THE RIGHT THING FOR ME TO DO, BUT I WANT TO DO IT, AND THEN SHE GAVE HER WRITTEN INFORMED CONSENT AND WENT TO SURGERY. CONTRAST THAT WITH A WOMAN WHO HAS A CANCER OF A SIMILAR NATURE, OFFERED TO UNDERGO A SIMILAR PROCEDURE, HAD NO OPPORTUNITY TO SPEND TIME TALKING ABOUT IT WITH THE CAREGIVERS, IS IN THE O.R., PRE-O.R. SUITE AND SOMEBODY COMES BY AND SAYS, HERE'S THE CONSENT FORM FOR THE SURGERY, WILL YOU SIGN IT? SHE HADN'T BEEN MEDICATED OR ANYTHING, SHE WAS STILL COMPETENT, BUT SHE HAD NO OPPORTUNITY TO DISCUSS ANYTHING AND SHE WAS ALREADY ON THE STRETCHER IN THE PRE-O.R. AREA. SHE MAY VERY WELL SIGN THE CONSENT FORM AND SAY YES, I'LL HAVE THE SURGERY. BUT YOU CAN SEE THE DIFFERENCE BETWEEN THE TWO SENSES OF INFORMED CONSENT. MOST PEOPLE AGREE INFORMED CONSENT INVOLVES AT LEAST THESE FOUR ELEMENTS. DISCLOSURE OF INFORMATION, UNDERSTANDING OF THAT INFORMATION, VOLUNTARINESS, WHETHER IT'S SOMETHING THE PERSON WANTS TO DO, AND THEN SOME KIND OF CONSENT AUTHORIZATION. I'M GOING TO TALK ABOUT EACH OF THESE AREAS IN THE FOLLOWING SENSE: I'M GOING TO TALK ABOUT HOW CHALLENGING THEY SOMETIMES CAN BE, AND I'M ALSO GOING TO LOOK AT SOME OF THE DATA THAT'S OUT THERE ON HOW WELL WE'RE DOING ON THESE FOUR ELEMENTS IN THE CONTEXT OF CLINICAL RESEARCH RESEARCH. DISCLOSURE OF INFORMATION. THERE ARE LOTS OF INTERESTING CHALLENGES HERE. IF WE SAY TO OURSELVES THAT THE IDEA IS TO GIVE SOMEBODY THE INFORMATION THEY NEED TO UNDERSTAND WHAT THE ACTIVITY ENTAILS AND A THEN MAKE A DECISION ABOUT WHETHER OR NOT IT'S CONSIST IT TENT WITH THEIR INTERESTS -- CONSISTENT WITH THEIR INTERESTS AND THEIR VALUES, WHAT INFORMATION DOES THAT INCLUDE? NOW IF YOU THINK ABOUT THE KINDS OF EXPERIMENTS, CLINICAL EXPERIMENTS THAT WE DO HERE, THERE'S A RANGE OF INFORMATION FROM THE SORT OF PROCEDURES THAT ARE GOING TO BE INVOLVED TO THE MECHANISMS OF THE DRUGS THAT ARE GOING TO BE INVOLVED TO THE BACKGROUND SCIENCE THAT LED UP TO IT. AND CLEARLY, THERE'S SOME INFORMATION THAT'S MORE RELEVANT TO A PERSON'S DECISION THAN OTHER KINDS OF INFORMATION. THERE'S REALLY AN INTERESTING TENSION BETWEEN REGARDING THE HOW MUCH OF INFORMATION. YOU CERTAINLY WANT TO GIVE SOMEBODY ENOUGH INFORMATION TO MAKE AN INFORMED DECISION BUT IF YOU GIVE THEM TOO MUCH INFORMATION, IT IT OVERLOADS THEM AND THEY DON'T UNDERSTAND ANYTHING. SO THERE'S A BALANCE AND CONSTANT TENSION. THERE ARE INTERESTING CHALLENGES WITH HOW SHOULD THE INFORMATION BE PRESENTED. THIS IS BOTH IN TERMS OF THE WRITTEN INFORMATION AND WHAT WE SAY TO PEOPLE. SO WITH RESPECT TO WRITTEN INFORMATION, YOU MIGHT ASK QUESTIONS ABOUT, WELL, YOU KNOW, OUR CONSENT FORMS IN THE FORMAT THAT WE USUALLY SEE THEM, STA THE BEST WAY TO PRESENT INFORMATION? SHOULD WE BE USING VIDEO PRESENTATIONS, SHOULD WE BE USING PATIENT EDUCATION PAMPHLETS, INTERACTIVE COMPUTERS? SOME PEOPLE ARE USING ALL OF THOSE FORMS OF INFORMATION. THERE'S ALSO QUESTIONS ABOUT THE FORMAT, IF YOU'RE JUST WRITING INFORMATION, HOW DO YOU FORMAT IT? WHAT LEVEL OF READABILITY DO YOU CHOOSE? THERE'S A MILLION QUESTIONS TO -- NOT MILLION -- THERE ARE MANY QUESTIONS TO BE THOUGHT THROUGH BEFORE YOU DECIDE. IN TERMS OF PRESENTING INFORMATION IN A CONVERSATION OR IN A DISCUSSION, IS IT BETTER DONE ONE ON ONE, IS IT BETTER DONE WITH A GROUP FIRST AND THEN ONE ON ONE, IS IT BETTER DONE WITH THE PRINCIPAL INVESTIGATOR AND PROSPECTIVE PARTICIPANT, OR IS IT BET INVENTORY HAVE A RECRUITER OR STUDY COORDINATOR OR SOMEBODY ELSE FIRST OR SECOND OR IN THE MIX? THERE'S ALL OF THOSE DECISIONS. SOME OF THEM, THERE'S EVIDENCE TO SUPPORT, BUT VERY LITTLE EVIDENCE IN GENERAL ABOUT THAT. THERE'S ALSO SOME INTERESTING CHALLENGES, OF COURSE, ABOUT CIRCUMSTANCES AND SETTING. SO THE STORY I TOLD YOU ABOUT THE WOMAN ON THE STRETCHER IN THE PRE-OP AREA, THAT'S NOT -- SITTING IN THE CLINIC WAITING ROOM WITH PEOPLE ALL AROUND YOU IS NOT SO GREAT EITHER. A PRIVATE ROOM IS BETTER, BUT THERE ARE LOTS OF CIRCUMSTANCES THAT ARE OUT OF OUR CONTROL. EMERGENCY ROOMS, DELIVERY ROOMS, COMMUNITY SETTINGS, SO THINGS THAT WE HAVE TO STILL THINK ABOUT WHAT'S THE BEST SETTING AND CIRCUMSTANCES GIVEN WHERE WE ARE, WHAT WE HAVE TO DO IN THIS PARTICULAR CASE. IT'S AN EXAMPLE OF HOW EVEN THE BEST INTENTIONED, IT'S SO CONVOLUTED, YOU CAN'T MAKE HEADS OR TAILS OF IT. HE HAS FOUR OPTIONS ON THE LEFT, A, B, C, D, THEY GO OVARIES BEINGS, BENEFITS, LINES ALL OVER THE PLACE, AND THE PERSON IS SCRATCHING THEIR HEAD SAYING, WHAT? SO WHAT ABOUT WRITTEN CONSENT FORMS? REGULATIONS REQUIRE WRITTEN CONSENT FORMS IN MOST CASES. SO THERE'S AN INTERESTING CHALLENGE TO WRITE THEM. HOW MANY OF YOU HAVE WRITTEN A CONSENT FORM? YOU'LL RELATE THOUGH. I THINK THE CHALLENGE IS, THIS IS SUPPOSED TO BE A SUMMARY OF THE STUDY INFORMATION THAT EXPLAINS THE IMPORTANT THINGS THAT A PERSON NEEDS TO DO IN ORDER TO MAKE A DECISION. SO THE PROCEDURES, THE RELATED RISKS AND BENEFITS, ALTERNATIVES, RIGHTS, PURPOSES, ET CETERA, WITH THE GOAL OF INFORMED DECISION-MAKING. OF COURSE THESE FORMS ARE APPROVED AND REVIEWED BY IRB BEFORE THEY'RE USED. ADVERTISEMENTS, FLYERS, BROCHURES, ALL THE KINDS OF THINGS, THE WRITTEN INFORMATION PEOPLE SEE BEFORE THEY MAKE A DECISION TO ENROLL IN A RESEARCH STUDY ARE CONSIDERED PART OF THIS PROCESS AND ALSO REQUIRE IRB REVIEW. SO THE CHALLENGE IS WHAT INFORMATION TO INCLUDE, HOW TO MAKE IT READABLE AND UNDERSTANDABLE, WHAT THE FORMAT SHOULD BE LIKE AND HOW LONG AND COMPLEX YOU DON'T WANT IT TO BE. THE REGULATIONS GIVE US SOME GUIDANCE. THE REGULATIONS TELL US WHAT ARE THE ELEMENTS THAT HAVE TO BE INCLUDED IN THE WRITTEN CONSENT FORM. THESE INCLUDE OBVIOUS THINGS, STATEMENT THAT THIS IS RESEARCH, WHAT THE PURPOSE IS, WHAT THE PROCEDURES ARE, THE FORESEEABLE RISKS AND DISCOMFORTS, ANY BENEFITS TO SUBJECTS OR TO OTHERS, APPROPRIATE ALTERNATIVES, EXTENT TO WHICH CONFIDENTIALITY WILL BE PROTECTED, TREATMENT OR COMPENSATION FOR INJURY, IF ANY, WHO TO CONTACT FOR ANSWERS TO QUESTIONS, AND THAT PARTICIPATION IS VOLUNTARY. THIS IS PROBABLY A FAMILIAR LIST TO A LOT OF YOU. SO I'M GOING TO GIVE YOU TWO PARAGRAPHS THAT WERE PULLED OUT OF CONSENT FORMS AND JUST GIVE YOU -- JUST TO GIVE YOU A FLAVOR OF HOW THIS CAN BE DONE IN DIFFERENT WAYS. THIS CAME OUT OF A CONSENT FORM, AN NIH CONSENT FORM, AND I'M GOING TO GIVE YOU A MINUTE TO READ IT. READ IT CAREFULLY. SEE WHAT YOU LEARN FROM IT. LET ME SEE WHAT YOU THINK. DO YOU THINK IT'S PRETTY GOOD? SHOW OF HANDS. DO YOU THINK IT'S PRETTY GOOD? DO YOU UNDERSTAND WHAT THEY'RE SAYING? NOT A PROBLEM. NOT BAD. OKAY. I'M GOING TO GIVE YOU ANOTHER SLIDE WHICH IS THE SAME INFORMATION, I BELIEVE, IN A DIFFERENT FORMAT. NOW I THINK ARGUABLY THESE TWO PARAGRAPHS SAY THE SAME THING. ONE OF THEM IS ABOUT TWICE AS LONG IN TERMS OF THE NUMBER OF WORDS. IT'S ALSO 11TH GRADE READING LEVEL AND THIS ONE IS A SIXTH GRADE READING LEVEL, SO IT'S JUST AN ILLUSTRATION OF THERE ARE DIFFERENT WAYS TO SAY THE SAME THING, AND WE SHOULD TRY OUR BEST TO WRITE THINGS DOWN ON CONSENT FORMS IN A WAY THAT THE PEOPLE THAT WE'RE TRYING TO REACH HAVE THE BEST CHANCE OF UNDERSTANDING THEM. WELL, FIRST OF ALL READING THEM, AND SECOND OF ALL UNDERSTANDING THEM. THERE ARE SOME SOURCES OF GUIDANCE OUT THERE ABOUT HOW TO DO THIS. THIS IS AN NCI PROCESS THAT'S GONE ON FOR MANY YEARS AND HAS RECENTLY BEEN REPEATED TO HELP PEOPLE SIMPLIFY THEIR CONSENT FORMS, AND HERE'S SOME OF THE THINGS THAT THEY SUCCESS IN THE REFERENCES AT THE BOTTOM. USE FAMILIAR WORDS. USE WORDS THAT PEOPLE UNDERSTAND, NOT SCIENTIFIC WORDS. AND THEN BE CONSISTENT WITH THE WORDS THAT YOU CHOOSE. DON'T KEEP CHANGING THEM FROM ONE SENTENCE TO ANOTHER. SHORT, SIMPLE AND DIRECT SENTENCES, LIMITED LENGTHS OF THE LINE, EACH LINE, SHORT FAIR PARAGRAPHS, ONE IDEA PER PARAGRAPH. THIS SOUNDS LIKE EIGHTH GRADE ENGLISH, RIGHT? VERBS IN ACTIVE VOICE, PERSONAL PRONOUNCE, CLEAR AND LONLICALLY SEQUENCED IDEAS, HIGHLIGHT IMPORTANT POINTS, PRESENT THE STUDY PURPOSE EARLY IN THE TEXT. NONE OF THESE ARE SURPRISING, EVERYBODY'S PROBABLY SAYING I'VE HEARD THIS A MILLION TIMES BEFORE. BUT NEXT TIME YOU TRY TO WRITE A CONSENT FORM, TRY TO DO THIS AND SEE IF YOU CAN REALLY GET IT DONE, OR READ THE CONSENT FORMS YOU USE AND SEE HOW OFTEN THEY ADHERE TO THESE KINDS OF GUIDANCES. THERE'S ALSO ON THE SAME WEBSITE AND THE SAME PROCESS A BUNCH OF THINGS THAT THEY SUGGEST WITH RESPECT TO FORMAT. I'M NOT GOING TO READ THE LIST BUT I JUST WANT TO EMPHASIZE THAT FORMAT MATTERS, SO IF YOU HAVE A PAGE OF TEXT, YOU KNOW, THAT'S 10-POINT FONT, IT'S A LOT DIFFERENT TO READ THAT THAN IF IT'S A 13-POINT FONT. HEADINGS REALLY HELP. WHITE SPACE REALLY HELPS. DIAGRAMS AND CHARTS AND GRAPHICS REALLY HELP. SO THINGS THAT YOU CAN DO TO MAKE THE FORMAT MORE READER FRIENDLY ARE VERY IMPORTANT FOR A CONSENT FORM. I ALREADY TALKED ABOUT THIS A LITTLE BIT, HOW SHOULD IT BE PRESENTED, SHOULD IT BE PERSON TO PERSON, SHOULD IT BE FORMAL. I HAVE A STORY THAT SOME OF YOU HAVE PROBABLY HEARD ME TELL, YEARS AGO, I WAS -- IT WAS A CONSULT ACTUALLY, A YOUNG MAN, A VERY SCARED YOUNG MAN WITH LITTLE EDUCATION AND RELATIVELY NON-VERBAL KIND OF GUY HERE FOR A VERY INTENSE, SCARY PROTOCOL, HAD ADVANCED CANCER, AND HE -- AND I SAT WITH HIM THROUGH THE CONSENT PROCESS. AND THERE WAS THREE SURGEONS WHO STOOD WHILE HE SAT. THEY ALL HAD WHITE COATS ON AND IN THOSE DAYS PAGERS THAT WENT ON AND OFF 10 TIMES DURING THE CONVERSATION, AND THEY WERE EXQUISITELY COMPREHENSIVE. THEY TOLD HIM EVERYTHING. BUT THEY DID IT IN RAPID FIRE, YOU KNOW, HE WAS SITTING IN THE CHAIR, THEY WERE STANDING HERE WITH THEIR WHITE COATS, DUMPING INFORMATION ON HIM IN A WAY THAT WAS -- I MEAN, THE VISUAL, I CAN'T PORTRAY WELL ENOUGH. IT'S JUST -- IT JUST WASN'T THE WAY YOU WANT THAT KIND OF A CONVERSATION TO GO. THAT'S ALL I CAN SAY. I'VE ALREADY TALKED ABOUT SETTINGS. IT DOESN'T REALLY NECESSARILY MEAN YOU HAVE TO HAVE A PRIVATE ROOM IN THE CLINIC WITH THE DOOR CLOSED. I MEAN, THIS GROUP DOWN HERE, THIS IS A GROUP THAT WE'VE DONE SOME WORK WITH IN UGANDA AND THEY HAVE A REALLY SOPHISTICATED PROCESS OF INFORMED CONSENT. THEY DO IT OUTSIDE, THEY TAKE A BENCH UNDER A TREE AND GO IN ANOTHER PART OF THE CAMPUS THAT THEY HAVE, THEY ALSO DO SOME GROUP WORK, THEY DO SOME THEATER TO PORTRAY THE MESSAGE ABOUT WHAT THE STUDY IS ABOUT. THEY GIVE PROSPECTIVE PARTICIPANTS A TOUR OF THE LABORATORY SO THEY CAN SEE WHAT HAPPENS TO THEIR BLOOD AFTER IT'S DRAWN, SO LOTS OF CREATIVITY IN TERMS OF HOW THEY PRESENT INFORMATION. SO WHAT DO WE KNOW ABOUT INFORMED CONSENT DOCUMENTS BASED ON STUDIES THAT HAVE BEEN DONE? YOU MIGHT THINK THERE ARE TWO CATEGORIES OF STUDY, ONE LOOKING AT THE DOCUMENTS, ONE LOOKING AT THE DISCUSSION. I HAVE TO UNFORTUNATELY SAY THE AMOUNT OF RESEARCH THAT'S BEEN DONE TO EVALUATE THE DISCUSSION THAT HAPPENS BETWEEN RESEARCHERS AND PROSPECTIVE PARTICIPANTS IS ALMOST ZERO. THEY USED TO INCLUDE A STUDY IN THIS PRESENTATION, AND I ACTUALLY TOOK IT OUT BECAUSE IT'S SO OLD AND IT JUST SEEMED TOO SMALL, TOO OLD, AND I JUST DON'T THINK IT'S WORTH IT, BUT WE NEED STUDIES OF THE DISCUSSION BECAUSE YOU CAN MANL, SOME PEOPLE ARE LEARNERS BY LISTENING TO WHO THEY TRUST. THEY DON'T EVEN BOTHER WITH THE CONSENT, THE WRITTEN CONSENT FORM OR THEY DON'T GET MUCH IN ADDITION. SO THE REAL INFLUENCE MIGHT BE, IN MANY CASES, THE DISCUSSION BETWEEN THE INVESTIGATOR AND THE PARTICIPANT. BUT LET'S LOOK AT THE CONSENT FORMS. SO THERE HAVE BEEN A NUMBER OF STUDIES THAT BASICALLY HAVE SHOWN THE CONSENT FORMS AND TEMPLATES ARE ALMOST ALWAYS WRITTEN AT A GRADE LEVEL THAT'S HIGHER THAN THE AVERAGE READING LEVEL IN THE UNITED STATES. SO THEY'RE WRITING AT GRADE LEVEL 11 AND 12 WHEREAS THE AVERAGE READING LEVEL IN THE UNITED STATES IS SOMEWHERE AROUND SIXTH TO EIGHTH GRADE. A LOT OF INSTITUTIONS HAVE GUIDELINES THAT SAY CONSENT FORMS SHOULD BE WRITTEN AT THE EIGHTH GRADE LEVEL, SOME OF OUR IRBs PROBABLY HAVE THAT, BUT I'M NOT SURE IT'S ALWAYS ENFORCED. BECAUSE CONSENT FORMS ARE COMPLICATED WHEN YOU READ THEM. I'M SURE YOU'VE ALL SEEN SOME. THEY'RE ALSO LONG, AND DOCUMENTS HAVE BEEN GETTING INCREASINGLY LONG OVER TIME, AND THERE HAVE BEEN STUDIES THAT HAVE LOOKED AT THAT. IF YOU LOOK AT CONSENT FORMS USED IN THE 70s, FOR EXAMPLE, THEY'RE LIKE THREE PAGES LONG. NOW WE HAVE -- THE AVERAGE IS PROBABLY MORE LIKE 10 OR 15. THEY'RE LONG. THIS IS AGAIN A SLIDE THAT'S MAYBE A LITTLE HARD TO READ, BUT I THINK THIS GUY HAS DONE SOME REALLY INTERESTING WORK. HIS NAME IS MARK HACKHAUSER, HE'S DONE A LOT OF WORK ON READABILITY. WHAT I PARTICULARLY LIKE ABOUT THIS PAPER THAT HE DID WAS HE TALKED ABOUT WHAT'S THE AVERAGE READING SPEED FOR -- WORDS PER MINUTE, FOR PEOPLE -- I'M SORRY, AVERAGE READING SPEED FOR SLOW READERS, AVERAGE READERS AND FAST READERS, THEN HE LOOKED AT CONSENT FORMS OF VARIOUS LENGTHS AND SORT OF ESTIMATED HOW LONG IT WOULD TAKE FOR SOMEBODY TO READ THE CONSENT FORM ONCE. I LOOKED RANDOMLY SELECTED AT INTRAMURAL NIH CONSENT FORMS, AND IT WAS LONGER THAN 12,000 WORDS, IT WAS 14,000 WORDS, AND SO YOU CAN SEE DEPENDING ON THE READING LEVEL OF THE PARTICIPANT, IT WOULD TAKE ANYWHERE FROM ON HOUR, LET'S BE GENEROUS AND SAY 45 MINUTES TO TWO-PLUS HOURS TO READ THE CONSENT FORM. AND I JUST BET YOU THAT THERE ARE A LOT OF PEOPLE WHO WOULD NOT SIT DOWN AND SPEND THAT AMOUNT OF TIME READING A CONSENT FORM. SO WHAT ABOUT THE CONTENT IT? THEY'RE TOO LONG AND THEY'RE HARD TO READ. THERE HAVE BEEN A FEW STUDIES THAT HAVE LOOKED AT CONTENT, ONE STUDY DONE BY HENRY SILVERMAN AND COLLEAGUES, BASICALLY LOOKED AT CONSENT FORMS AND COMPARED THEM TO THE REQUIRED ELEMENTS FROM THE FEDERAL REGS AND FOUND THAT ONLY THREE OUT OF 16 OF THE CONSENT FORMS HAD EVERYTHING THAT THEY WERE SUPPOSED TO HAVE IN THEM. WE DID A STUDY ABOUT 10 YEARS AGO WHERE WE LOOKED AND PHASE ONE ONCOLOGY CONSENT FORMS FROM ALL OVER THE COUNTRY, AND WE TRIED TO LOOK AT HOW THEY DESCRIBED RISK AND BENEFITS IN PARTICULAR, BUT ALSO LOTS OF THE OTHER THINGS THAT CONSENT FORMS ARE SUPPOSED TO INCLUDE, AND THEY LOOKED PRETTY GOOD. 99% OF THEM DESCRIBED THAT IT WAS RESEARCH, OVER 90% -- ABOUT TWO THIRDS THE RISK OF DEATH, 80% UNKNOWN RISKS, AND ONLY A VERY SMALL PERCENT MENTIONED BENEFIT IN A VERY POSITIVE WAY, WHICH IS PROBABLY NOT ACCURATE FOR A PHASE ONE. ANOTHER STUDY WAS DONE LOOKING AT 27 TRIALS IN FOUR DIFFERENT HOSPITALS, AND BASICALLY FOUND LOTS OF MISSING INFORMATION. THEY WERE NOT LOOKING AT THE REG LA TORELY REQUIRED INFORMATION BUT MORE MAKING JUDGMENTS ABOUT WHAT PEOPLE MIGHT REALLY WANT TO KNOW ABOUT THE STUDY, LIKE HOW MUCH IT WOULD COST THEM AND THINGS LIKE THAT, AND SHOWED THAT MOST OF THAT WAS MISSING FROM CONSENT FORMS. THIS WAS A STUDY THAT LOOKED AT INVESTIGATORS IN A SURVEY, SURVEYED INVESTIGATORS, AND ASKED THEM ABOUT THEIR PRACTICES, THEIR CONSENT PRACTICES, SO IT'S NOT REALLY LOOKING AT WHAT THEY ACTUALLY SAY TO PEOPLE, BUT ASKING THEM ABOUT THEIR PRACTICES. MOST OF THEM GIVE THEIR PARTICIPANTS OR THEIR PROSPECTIVE PARTICIPANTS A COPY OF THE CONSENT FORM, TIME TO READ IT, AND A LOT OF INFORMATION ABOUT THE RISKS AND THE PURPOSE. FEWER EMPHASIZE THINGS LIKE RANDOMIZATION AND A VERY SMALL PERCENT HAVE ANY FORMAL ASSESSMENT OF HOW WELL THEIR PARTICIPANTS UNDERSTAND THE INFORMATION THEY'RE GIVEN. BOTH OF THESE, WE'LL COME BACK TO LATER. SO THE SUMMARY OF DATA ON DISCLOSURE IN THE PROCESS OF INFORMED CONSENT, THERE ARE LIMITED DATA. WE NEED MORE. BUT GENERALLY WHAT THE DATA SHOW US IS THAT CONSENT DOCUMENTS USUALLY INCLUDE RELEVANT INFORMATION BUT ARE NOT ALWAYS COMPLIANT WITH THE REGULATIONS, AND ARE INCREASINGLY LONG AND COMPLEX AND WRITING AT A HIGH READING LEVEL. THEY'RE THERE ARE VERY FEW STUDIES THAT LOOK AT DISCLOSURE BY INVESTIGATORS AND THERE'S LIMITED TRAINING FOR INVESTIGATORS ON INFORMED CONSENT, ALTHOUGH WE DO HAVE A COURSE HERE THAT THE HSPU OFFERS, SO IF YOU'RE INTERESTED IN THAT, I CAN GIVE YOU MORE. SO LET'S TALK ABOUT UNDERSTANDING THEN. SO IF YOU GIVE PEOPLE INFORMATION AND THEN YOU HOPE THAT THEY UNDERSTAND IT IN ORDER TO MAKE A CHOICE, RIGHT? SO THERE ARE LOTS OF FACTORS THAT MIGHT AFFECT UNDERSTANDING. I'M GOING TO TALK ABOUT SOME OF THOSE IN A MINUTE. I THINK THERE'S AN INTERESTING QUESTION AND ONE THAT BOTH ME AND SOME OF MY COLLEAGUES IN OUR DEPARTMENT HAVE BEEN SORT OF TALKING ABOUT FOR YEARS, AND THAT IS HOW SHOULD UNDERSTANDING BE ASSESSED IN THE CONTEXT OF RESEARCH AND HOW MUCH UNDERSTANDING IS REQUIRED, WHAT SHOULD PEOPLE REALLY BE ABLE TO UNDERSTAND? SO I'M GOING TO GO BACK TO THAT YOUNG MAN I WAS TELLING YOU ABOUT A FEW MINUTES AGO. IN THE END, HE UNDERSTAND -- THE PROCESS WAS FLAWED, BUT IN THE END, HE UNDERSTOOD HE HAD A VERY SERIOUS CANCER. HE HAD THE OPTION OF AN EXPERIMENTAL TREATMENT HERE THAT MIGHT SPARE HIS ARM, OTHERWISE IT WOULD HAVE TO BE AMPUTATED. HE WAS A PAINTER, HE DIDN'T WANT TO LOSE HIS ARM. HE KNEW HE WOULD HAVE TO BE IN THE HOSPITAL AND THAT IT MIGHT BE VERY RISKY, AND THAT IF IT DIDN'T WORK, HE WOULD EITHER DIE OR HAVE TO GET AN AMPUTATION SOMEWHERE ELSE. HE KNEW THAT MUCH. HE DIDN'T KNOW THE NAMES OF THE DRUGS, HE DIDN'T KNOW -- COULDN'T LIST ALL OF THE SEVERE RISKS. BASICALLY THE QUESTION REALLY WAS, DOES HE KNOW ENOUGH TO BE ABLE TO GIVE INFORMED CONSENT FOR THIS STUDY. HOW MANY OF YOU THINK HE DOES, BASED ON WHAT I'VE SAID? COUPLE PEOPLE. HOW MANY THINK HE DOESN'T? OKAY. MOST OF YOU AREN'T VOTING. I THINK IT'S A VERY IMPORTANT QUESTION TO ASK IN EVERY CASE. THEN OF COURSE THERE'S THE QUESTION, WHAT HAPPENS OR WHAT SHOULD HAPPEN IF SOMEBODY DOESN'T UNDERSTAND U.S SUFFICIENTLY, DO YOU TELL THEM THEY CAN'T PARTICIPATE, DO YOU GO OVER IT AGAIN, GIVE THEM ANOTHER TEST? I'M GOING TO LEAVE THAT AS AN OPEN QUESTION. SO WHAT ARE SOME OF THE THINGS THAT MIGHT AFFECT UNDERSTANDING? WELL, CERTAINLY AGE. THE ONES THAT I'VE PUT AN ASTERISK NEXT TO ON THIS SLIDE ARE ONES FOR WHICH THERE ARE DATA TO SUPPORT THAT THESE THINGS DO MAKE A DIFFERENCE. VERY YOUNG PEOPLE, VERY OLD PEOPLE HAVE MORE DIFFICULTY UNDERSTANDING THAN PEOPLE IN THE MIDDLE. SEVERITY OF ILLNESS MIGHT AFFECT HOW MUCH YOU'RE UNDERSTANDING AND HOW DESPERATE YOU ARE FOR THE INTERVENTION THAT'S BEING OFFERED. EDUCATIONAL LEVEL SEEMS TO MATTER, COGNITIVE CAPACITY, MAYBE THE NOT SURPRISINGLY MATTERS. I THINK THERE ARE LOTS OF INTERESTING SUPPOSITIONS ABOUT WHETHER FAMILIARITY WITH RESEARCH MATTERS, LANGUAGE AND CUSTOMS AND LITERACY. THESE ARE THINGS THAT PEOPLE WORRY ABOUT. SOME PEOPLE SAY HOW CAN WE GIVE INFORMED CONSENT, THIS PERSON DOESN'T SPEAK ENGLISH. WE'VE ALL COME PAST THAT PROBLEM. I THINK WE CAN GIVE CONSENT TO PEOPLE -- HAVE A PROCESS OF CONSENT IN A DIFFERENT LANGUAGE AND THAT'S FINE. EVEN LITERACY IS NOT AN INSURMOUNTABLE PROBLEM. THERE ARE OTHER WAYS TO PRESENT INFORMATION BESIDES WRITTEN INFORMATION, SO WE NEED TO BE CREATIVE IN SOME OF THESE, BUT THESE ARE SOME OF THE KINDS OF FACTORS THAT PEOPLE WORRY ABOUT DO AFFECT OR CAN AFFECT WHAT PEOPLE UNDERSTAND. SO WHAT DO THE STUDIES SHOW? THERE HAVE BEEN A LOT OF STUDIES THAT LOOKED AT HOW WELL PEOPLE UNDERSTAND INFORMATION ABOUT RESEARCH STUDIES THAT THEY ARE IN. AND I'VE DIVIDED IT BY SORT OF TOPICS, SO THIS IS UNDERSTANDING OF THE RESEARCH PURPOSE OR THE FACT OF RESEARCH, THE FACT IT'S EXPERIMENTAL. I WANT TO YOU LOOK AT TWO THINGS. ONE IS THE RANGE. SO FROM 27% IN ONE STUDY WHO UNDERSTOOD THAT THE STUDY INVOLVED AN UNPROVEN VACCINE TO 100% IN ANOTHER STUDY, WHERE PEOPLE SAID THEY UNDERSTOOD THAT THEY WERE IN A MEDICAL EXPERIMENT. THE GOAL HERE OF THE SLIDE IS REALLY TO SHOW YOU THAT THERE IS A WIDE RANGE, THERE'S LOTS OF VARIABILITY. THE QUESTION IS, WHAT ACCOUNTS FOR THAT VARIABILITY? WE DID A STUDY A COUPLE OF YEARS AGO THAT TRIED TO LOOK AT WHETHER OR NOT THERE WAS A CATEGORICAL DIFFERENCE BETWEEN PEOPLE IN THE DEVELOPING WORLD AND PEOPLE IN THE DEVELOPED WORLD IN TERMS OF THEIR ABILITY TO UNDERSTAND STUDY INFORMATION, AND THE ANSWER FROM THE REVIEW STUDY THAT WE DID WAS, NO, THIS KIND OF VARIABILITY SEEMS TO OCCUR REGARDLESS OF WHERE YOU ARE IN THE WORLD. THERE AREN'T ENOUGH STUDIES TO BE ABLE TO SAY WHETHER THE VARIABILITY IS TRUE FOR ALL CERTAIN KINDS OF STUDIES, BUT THAT'S SOMETHING THAT WE COULD LOOK AT IN THE FUTURE. BUT A LOT OF VARIABILITY ON UNDERSTANDING OF THE RESEARCH PURPOSE OR NATURE, AND YET IN SOME STUDIES, PRETTY GOOD. UP TO 100%. WHAT ABOUT RISKS AND SIDE EFFECTS, SOMETHING THAT WE THINK IS VERY IMPORTANT FOR PEOPLE TO UNDERSTAND BEFORE THEY DECIDE IT TO PARTICIPATE IN RESEARCH? AGAIN, THE RANGE IS HUGE, 28% IN A STUDY IN THE UNITED STATES, HYPERTENSION STUDY, TO 100% AGAIN IN THE UNITED STATES OF CANCER PATIENTS. I JUST SELECTED A FEW STUDIES. THERE ARE MANY MORE THAT YOU COULD LOOK AT THAT HAVE THIS KIND OF DATA ON IT. COUPLE OF REALLY INTERESTING THINGS ABOUT THIS SET OF DATA. THERE ARE LOTS OF WAYS TO ASK PEOPLE ABOUT SIDE EFFECTS. NONE OF THE OF STUDIES USE THE SAME METHOD. SO YOU CAN IMAGINE, SOMEBODY YOU'RE WORKING WITH, THAT THEY LIST THE SIDE EFFECTS FOR ME, THAT WOULD BE HARDER THAN IF YOU GAVE SOMEBODY A LIST AND SAID WHICH ONES ON THIS LIST ARE RELEVANT TO THIS STUDY? PEOPLE DO BETTER ON THAT KIND OF THING. IN SOME STUDIES, THEY JUST ASKED, ARE THERE SIDE EFFECTS? AND THE QUESTION YES OR NO. AND SO THERE'S A VARIATION IN TERMS OF HOW THOSE STUDIES HAVE BEEN DONE, BUT THE BOTTOM LINE IS, LOTS OF -- A WIDE RANGE, EXCUSE ME, IN TERMS OF UNDERSTANDING RISKS AND SIDE EFFECTS. WHERE PEOPLE SEEM TO DO THE WORST IS ON THINGS LIKE -- THINGS RELATED TO STUDY METHODS, LIKE RANDOMIZATION. AND EVERY STUDY THAT I HAVE BEEN ABLE TO FIND THAT MEASURED PEOPLE'S UNDERSTANDING OF RANDOMIZATION. IT'S NO MORE THAN 50%. PEOPLE IN THE STUDY THAT CAN ACTUALLY ANSWER A QUESTION CORRECTLY ABOUT RANDOMIZATION. SO THIS IS AN INTERESTING FINDING. I SHOWED YOU THAT DATA A FEW MINUTES AGO WHERE THE INVESTIGATORS DON'T EMPHASIZE THAT AS MUCH AS THEY EMPHASIZE SOME OTHER THINGS, SO WHAT'S GOING ON HERE WITH RANDOMIZATION RANDOMIZATION? VERY INTERESTING PROBLEM AND ONE THAT SOME PEOPLE ARE WORRIED ABOUT AND OTHER PEOPLE SAY DOESN'T REALLY MATTER. I THINK RANDOMIZATION IS AN EXAMPLE OF SOMETHING THAT PEOPLE HAVE TALKED ABOUT IN TERMS OF UNDERSTANDING THAT'S VERY SALIENT, AND THAT IS THAT THERE'S A DIFFERENCE BETWEEN UNDERSTANDING OR BEING ABLE TO RECITE BACK THE RELEVANT INFORMATION THAT YOU WERE GIVEN AND HOW YOU APPRECIATE IT APPLIES TO YOU. SO WHAT PEOPLE HAVE TALKED ABOUT THIS DIVIDE IS THE DIFFERENCE BETWEEN WHAT YOU HEAR AND REMEMBER AND WHAT YOU THINK APPLIES TO YOU. RANDOMIZATION MIGHT BE CAUGHT UP IN THIS PROBLEM. HOW MANY OF YOU HAVE HEARD ABOUT THE THERAPEUTIC MISCONCEPTION? SO IT'S A PHENOMENON THAT PEOPLE TALK ABOUT A LOT, THERE'S DISAGREEMENT ABOUT EXACTLY WHAT IT MEANS, BUT BASICALLY MOST PEOPLE THINK THAT IT MEANS THAT THERE'S A CONFUSION OR CON CONFLATION BETWEEN WHAT THE PERSON UNDERSTANDS IS HAPPENING TO THEM IN A RESEARCH STUDY AND THEY THINK IT'S MORE LIKE INDIVIDUALIZED CARE THAT'S BENEFITING THEM. AND IT REALLY COMES, I THINK, FROM THIS -- THIS IDEA THAT THERE'S A DIFFERENCE BETWEEN HOW YOU UNDERSTAND INFORMATION AND HOW YOU APPRECIATE THAT IT APPLIES TO YOU. SO THE FIRST STUDY WHERE PAUL APPELBAUM WHO COINED THE TERM WAS INTERVIEWING PATIENTS WITH SCHIZOPHRENIA WHO HAD JUST ENROLLED IN RANDOMIZED CONTROL TRIAL, AND HE ASKED ONE OF THEM, TELL ME WHO'S GOING TO GET THE DRUG AND WHO'S NOT GOING TO GET THE DRUG, AND THE PERSON WAS ABLE TO FAIRLY ACCURATELY SAY, WELL, HALF THE PEOPLE WILL GET THE DRUG AND HALF THE PEOPLE ARE GOING TO GET PLACEBO AND THEY'RE GOING TO SEE HOW IT WORKS. THEN HE ASKED THE PATIENT OR THE PARTICIPANT, HOW ABOUT YOU? THE RESPONSE WAS MY DOCTOR IS GOING TO GET ME THE ONE THAT'S GOING TO HELP ME THE MOST. SO THERE WAS A DISCOULD NEBT BETWEEN WHAT THEY UNDERSTOOD ABOUT THE STUDY INFORMATION AND WHAT THEY THOUGHT APPLIED TO THEM. SO PEOPLE WORRY ABOUT THIS THERAPEUTIC MISCONCEPTION WHEN A PARTICIPANT FAILS TO RECOGNIZE THIS DISTINCTION, APPELBAUM AND COLLEAGUES ARGUE THAT IT JEOPARDIZES THEIR ABILITY TO PROVIDE MEANINGFUL OR EVEN VALID INFORMED CONSENT. SO WHAT DO WE KNOW ABOUT UNDERSTANDING? AGAIN, THE DATA ARE LIMITED, UNDERSTANDING IS VARIABLE ACROSS LOTS OF CONTEXTS. MOST SUBJECTS SEEM TO KNOW THAT THEY ARE IN RESEARCH, BUT THINGS LIKE RANDOMIZATION AND OTHER RESEARCH METHODOLOGIES ARE RELATIVELY POORLY UNDERSTOOD AND UNDERSTANDING AND KNOWLEDGE -- SORRY -- KNOWLEDGE AND APPRECIATION ARE DIFFERENT. WHAT ABOUT VOLUNTARINESS? SO WHAT DOES VOLUNTARINESS MEAN? ACCORDING TO THE REGULATIONS, IT MEANS ABSENCE OF COERCION AND UNDUE INFLUENCE. WE THINK OF IT AS A PERSON IS ABLE TO MAKE A CHOICE, MAKE A FREE CHOICE OR A RELATIVELY FREE CHOICE. I THINK -- I ALWAYS LOVE THIS CARTOON BECAUSE I THINK THIS IS NOT WHAT WE WANT INFORMED CONSENT TO LOOK LIKE. NOW THIS YEAR, YOU MISSED THE, I THINK, GREAT LECTURE THAT ALAN GIVES ON COERCION AND UNDUE INDUCEMENT. IF YOU HAVE A CHANCE TO LOOK AT THE VIDEO, I WOULD, BECAUSE HE REALLY DESCRIBES, YOU KNOW, FIRST HOW THEY'RE DIFFERENT, THE TWO CONCEPTS ARE VERY DIFFERENT, BUT IMPORTANTLY, TO UNDERSTAND WHAT THEY ARE AND HOW THEY MIGHT INFLUENCE THE PROCESS OF INFORMED CONSENT IS A COMPLICATED ENDEAVOR. BASICALLY, THOUGH, WHAT I WANT TO SAY TODAY IS THAT NO CHOICE IS COMPLETELY FREE OF INFLUENCE, RIGHT? EVERYTHING WE DECIDE IS BASED ON WHAT WE KNOW, BUT ALSO WHAT OUR PREVIOUS EXPERIENCES HAVE BEEN, WHAT WE THINK, YOU KNOW, OUR FAMILIES WANT, WHAT WE THINK THE DOCTOR WANTS. THERE'S A LOT OF INFLUENCE, WHAT WE THINK OUR CHOICES ARE. THERE'S A LOT OF INFLUENCES ON HOW WE MAKE OUR CHOICES AND WHAT INFLUENCES THE CHOICES WE MAKE. OUR TASK IN TERMS OF THINKING ABOUT INFORMED CONSENT IS TO SORT OF BE CONFIDENT THAT THE PERSON IS MAKING A RELATIVELY VOLUNTARY CHOICE, BUT NO ONE IS FORCING THEM TO DO THIS, BUT NO ONE IS TYING THEIR HAND THAT THEY BASICALLY UNDERSTAND SUFFICIENTLY WELL WHAT THEY'RE BEING ASKED TO DO IN MAKING THAT DECISION WITHOUT SOMEBODY HOLDING A CLUB OVER THEIR HEAD. SO WHAT ARE THE POSSIBLE INFLUENCES ON VOLUNTARINESS? OF COURSE THERE'S MANY. YOU KNOW, THE SORT OF TRADITIONAL ONES ARE DEPENDENT POSITION. THE PARENT INFLUENCES THE CHILD, THE BOSS INFLUENCES THE EMPLOYEE, THE MILITARY COMMANDER INFLUENCES THE PEOPLE IN THE PLATOON. THE PROFESSOR INFLUENCES THE STUDENTS. I MEAN, THAT'S THE KIND OF DEPENDENT RELATIONSHIP AND THOSE ARE POWER RELATIONSHIPS AS WELL THAT DO MAKE IT DIFFICULT FOR PEOPLE TO MAKE VOLUNTARY CHOICES. ONE OF THE CATEGORY OF VULNERABLE POPULATIONS IN THE REGULATIONS ARE PRISONERS, AND PRISONERS SORT OF FIT INTO THIS CATEGORY VERY EVIDENTLY, RIGHT? THEY CAN'T MAKE -- SO IT GOES, THEY CAN'T MAKE VOLUNTARY CHOICES IN THE CONTEXT OF THE PRISON, ESPECIALLY IF A PRISON PERSON IS ASKING THEM ABOUT PARTICIPATION IN RESEARCH. BUT THERE ARE OTHER AREAS OF INFLUENCE THAT WE SORT OF KNOW ABOUT BUT ARE HARDER TO MEASURE AND HARDER TO UNDERSTAND. PRESSURE FROM OTHERS, FROM FAMILY, FROM FRIENDS. I'M SURE YOU'VE HAD ENCOUNTERS WITH PEOPLE WHO HAVE SAID, I DON'T REALLY WANT TO DO THIS BUT MY HUSBAND WANTS ME TO, OR MY DAUGHTER WANTS ME TO OR SOMETHING LIKE THAT. HOW MUCH IS THAT A PRESSURE VERSUS A LOVING FAMILY MEMBER THINKING THEY'RE PUSHING SOMEBODY TO DO THE RIGHT THING? TRUST IN HEALTHCARE PROVIDERS IS AN INTERESTING ISSUE. THERE'S BEEN SOME DATA TO SHOW THAT SOME PEOPLE DON'T EVEN PAY ATTENTION TO THE RISKS AND BENEFITS OF A STUDY BECAUSE MY DOCTOR TOLD ME TO DO IT AND I TRUST MY DOCTOR. RESTRICTED CHOICES IS A QUESTION, IF PEOPLE HAVE VERY LIMITED CHOICES, DOES THAT MAKE THEIR CHOICES NOT VOLUNTARY? I THINK THE ANSWER IS PROBABLY NO, BUT PEOPLE WORRY ABOUT THIS CATEGORY. AND CERTAINLY THERE'S A LOT OF ATTENTION ON ILLNESS AND INCENTIVES. IF YOU PAY SOMEBODY, DO YOU TAKE AWAY THEIR ABILITY TO MAKE A VOLUNTARY CHOICE, FOR EXAMPLE? INTERESTINGLY ALSO, DATA ON VOLUNTARINESS IS HARD TO GET. SO HOW DO YOU MEASURE IT? HOW DO YOU THINK ABOUT VOLUNTARINESS IN A STUDY? THERE ARE A COUPLE OF WAYS PEOPLE HAVE DONE IT. SEVERAL STUDIES HAVE ASKED PEOPLE, DO YOU FEEL PRESSURE TO JOIN? AND YOU CAN SEE THAT IN A -- A COUPLE THINGS ABOUT THIS SLIDE. FIRST OF ALL, A VERY SMALL NUMBER OF PEOPLE IN THE STU IT DIS THAIN THE STUDIESTHAT HAVE ASKED THIS QUESTION REPORT THEY FEEL PRESSURE FROM OTHER PEOPLE. SO THE SORT OF WORRY FROM COERCION FROM SOMEBODY ELSE DOESN'T SHOW UP. BUT IF YOU ASK PEOPLE A MORE NUANCED QUESTION, DO YOU FEEL PRESSURE TO JOIN, WHERE DOES IT COME FROM, YOU GET A DIFFERENT STORY. YOU GET NOT TOO MUCH PRESSURE FROM OTHER PEOPLE BUT PRESSURE FROM THEIR CIRCUMSTANCES. THEY HAVE A BAD ILLNESS, THEY DON'T HAVE ANY INSURANCE, THEY HAVE WHATEVER. AND THAT IS PRESSURE. BUT THERE ARE SOME STUDIES, THE LAST ONE ON THE SLIDE, 25% OF THE PARTICIPANTS, PARENTS IN THIS CASE, FELT OBLIGED. THAT WOULD BE SOMETHING I'D LIKE TO FOLLOW UP AND THEN FIND OUT WHY. ANOTHER WAY THAT PEOPLE HAVE LOOKED AT THIS ISSUE OF VOLUNTARINESS IS ASKING PEOPLE, DO YOU KNOW THAT YOU COULD SAY NO OR THAT YOU COULD QUIT? SO THIS IS SORT OF A KNOWLEDGE QUESTION BUT IT'S MORE THAN A KNOWLEDGE QUESTION. IT'S A KNOWLEDGE QUESTION THAT TAKES INTO ACCOUNT THE CIRCUMSTANCES ON HOW IT APPLIES TO ME. AND I THINK THE -- AGAIN, THERE'S A RANGE. SOME STUDIES HAVE SHOWN ONLY A SMALL NUMBER, 44%. SOME STUDIES UP TO 90 IT%. I THINK THIS IS AN INTERESTING SET OF DATA. IF WE BELIEVE PEOPLE SHOULD KNOW IT'S VOLUNTARY, THEY DON'T HAVE TO JOIN, THEY DON'T HAVE TO STAY, THEY AT LEAST SHOULD KNOW THAT, BUT THEY DON'T SEEM TO KNOW THAT IN HIGH NUMBERS. AGAIN, SOMETHING WE SHOULD LOOK INTO. NOW WHEN YOU ASK FURTHER, PEOPLE SAY, WELL, I DON'T REALLY HAVE ANOTHER OPTION FOR GETTING TREATMENT. THAT'S DIFFERENT THAN SAYING THEY TOLD ME I CAN'T QUIT OR I CAN'T QUIT UNTIL THE DOCTOR TELLS ME I CAN, WHICH SOME RESPONSES ARE. ANOTHER WAY WE CAN THINK ABOUT REFUSAL IS LOOK AT A BUNCH OF STUDIES AND SAY DO PEOPLE ACTUALLY REFUSE, DO THEY MAKE A VOLUNTARY CHOICE NOT TO PARTICIPATE, AND THERE HAVE BEEN A NUMBER OF STUDIES THAT HAVE BEEN ABLE TO SHOW THAT, IN FACT, AT VARIABLE RATES, PEOPLE DO SAY NO, I DON'T WANT TO PARTICIPATE. PEOPLE WHO ARE INVITED TO PARTICIPATE SAY I DON'T WANT TO PARTICIPATE IN THAT STUDY. SOMETIMES AS HIGH AS ALMOST 60% IN THIS STUDY THAT WAS DONE IN PARAGUAY. SO THERE ARE DATA TO SUPPORT THE FACT THAT PEOPLE ACTUALLY ARE MAKING CHOICES. AGAIN, THE DATA ARE LIMITED, THE WAY TO MEASURE VOLUNTARINESS IS LIMITED -- IS DIFFICULT, EXCUSE ME. SMALL NUMBERS FEEL PRESSURE FROM OTHERS, BUT MANY SAY THAT THEY CAN'T QUIT OR COULD NOT SAY NO, AND PEOPLE DO REFUSE. SO WHAT I'VE SHOWN YOU BASICALLY ARE STUDIES OF THE QUALITY OF INFORMED CONSENT. I WANT TO SPEND JUST A FEW MINUTES AT THE END ON STUDIES THAT HAVE BEEN DONE OF INTERVENTIONS TO IMPROVE CONSENT. MOSTLY IMPROVING UNDERSTANDING IS WHAT THEY'RE LOOKING AT. THERE WAS A CYST AT THE MA IT TICSYSTEMATIC REVIEWDONE ALMOST 10 YEARS A GO THAT LOOKED AT STUDIES UP UNTIL THAT POINT AND CATEGORIZED THEM INTO FOUR GROUPS. MULTIMEDIA, ENHANCED CONSENT FORLS, MEANING MODIFIED STYLE IN TERMS OF FORM OR LENGTH OR READABILITY, EXTENDED DISCUSSION, MORE TIME WITH THE TEAM MEMBERS OR A NEUTRAL EDUCATOR, AND TEST FEEDBACK. YOU GET A MEASURE OF UNDERSTANDING, YOU DON'T DO WELL, WE GIVE YOU MORE INFORMATION, WE TEST AGAIN. AND THE BOTTOM LINE IS NONE OF OF THESE ARE A SLAM DUNK. LET ME SAY THAT. BUT LET ME GO THROUGH THEM A LITTLE BIT ONE BY ONE. SO THE MULTIMEDIA STRATEGIES OF 12 THAT WERE LOOKED AT IN THIS REVIEW, ONLY ONE SHOWED A SIGNIFICANT IMPROVEMENT IN UNDERSTANDING, AND THAT WAS A COMPUTER -- IP INTERACTIVE COMPUTER STUDY. THE OTHERS WERE NOT ABLE TO SHOW A SIGNIFICANT DIFFERENCE. SO THE CONCLUSION THERE IS THEY MAY BE AS GOOD AS THE USUAL PROCESS BUT MAYBE NOT BETTER, AND IN CERTAIN CIRCUMSTANCES, THEY ACTUALLY MAY BE MORE APPROPRIATE FOR THE PARTICULAR PARTICIPANT GROUP THAT YOU'RE TRYING TO GIVE INFORMATION TO. THEY'RE ALSO VERY USEFUL IN STANDARDIZING THE DISCLOSURE. SO IF WE'RE WORRIED ABOUT HOW DIFFERENT PEOPLE TALK TO PARTICIPANTS, OR EVEN IF WE'RE NOT WORRIED ABOUT IT, WE JUST WANT TO STANDARDIZE IT, MAKING A VIDEOTAPE OR AN AUDIOTAPE MIGHT BE A WAY TO DO THAT. THERE WAS ANOTHER COCHRAN REVIEW DONE A COUPLE YEARS LATER, 2006, I THINK? 2008. WHICH BASICALLY HAD FEWER STUDIES THAT IT REVIEWED BUT BASICALLY CAME TO THE SAME CONCLUSION THAT THERE WAS NO CONSISTENT INCREASE IN UNDERSTANDING BY USING THESE METHODOLOGIES. WITH RESPECT TO ENHANCED CONSENT FORMS, A LITTLE BIT BETTER BUT STILL NOT GREAT. SIX OUT OF 15 SHOWED SOME IMPROVEMENT IN UNDERSTANDING. UNFORTUNATELY, IT THIS GROUP OF 15 STUDIES IS VERY VARIABLE IN TERMS OF WHAT THEY ACTUALLY DID, HOW THEY MEASURED THE CHANGE AND THE POPULATION STUDY. I'VE DONE SOME OF THIS KIND OF EMPIRICAL WORK MYSELF WITH RANDOMIZING PEOPLE TO A STANDARD CONSENT FORM AND A CONCISE CONSENT FORM, THEN MEASURING UNDERSTANDING AFTERWARDS. SO FAR IN TWO GROUPS OF HEALTHY POPULATIONS, WE HAVE SEEN NO DIFFERENCE IN UNDERSTANDING. WE'RE ABOUT TO BEGIN ANALYZING A COHORT OF 4,000 PATIENT SUBJECTS AND WE'LL SEE -- HOPEFULLY THAT WILL BE A CONCLUSION TO THIS STORY. IN THIS SAME SYSTEMATIC REVIEW, THERE WERE LIMITED DATA -- LIMITED DATA SUGGEST THAT MORE PERSON TO PERSON CONTACT, THE NUMBERS ARE VERY SMALL, YOU SEE THREE OUT OF FIVE AND FIVE OUT OF FIVE, SO THAT'S ONE THING TO BE AT LEAST CAUTIOUS ABOUT MAKING TOO STRONG OF A CONCLUSION. SECOND THING I THINK IS MORE PERSON TO PERSON CONTACT SEEMS LIKE A GREAT IDEA. I CAN'T IMAGINE A REASON TO ARGUE AGAINST THAT EXCEPT FOR MAYBE RESOURCE CONSTRAINTS, BUT CERTAINLY PEOPLE RESPOND TO OTHERS AND LEARN BY DISCUSSING THINGS WITH OTHERS, SO THAT'S A GREAT IDEA IF THE RESOURCES ALLOW IT. THE TEST/FEEDBACK STRATEGIES MAY BE USEFUL IN SOME CIRCUMSTANCES BUT THEY'RE ALSO POSSIBLY A LITTLE DECEPTIVE. SO IF I GIVE YOU A TEST TODAY AND I DON'T USUALLY CALL IT A TEST, BUT P IT I GIVE YOU A TEST TODAY AND ASK YOU ABOUT WHAT ARE THE RISKS IN THIS STUDY AND YOU DON'T DO WELL ON THAT TEST, THEN I SIT DOWN WITH YOU FOR ANOTHER 20 MINUTES AND GO OVER THE RISKS AGAIN, THEN I GIVE YOU THE TEST AGAIN AND YOU DO BETTER, HAVE YOU REALLY UNDERSTOOD IT BETTER OR HAVE YOU SORT OF MEMORIZED FOR THE TEST KIND OF? THAT'S, I THINK, ANISH OO AN ISSUE WITH WE HAVE TO THINK ABOUT IN TERMS OF THIS METHOD. HERE'S BE AN EXAMPLE OF THIS STUDY THAT WAS INCLUDED IN THE REVIEW THAT BASICALLY USED THIS TEST-RE-TEST. YOU CAN SEE 20% PASSED WHEN ATTENDED A SINGLE CONSENT MEETING, BUT THEN WHEN THEY WENT TO SEVERAL INFORMATION SESSIONS AND A CONSENT MEETING, THEN 80% OF THEM WERE ABLE TO PASS A TRUE-FALSE TEST. SO MY CONCLUSIONS, BASICALLY INFORMED CONSENT IN RESEARCH IS ETHICALLY IMPORTANT, BUT IMPERFECTLY REALIZED. THE DATA THAT WE HAVE SUGGESTS CONSENT FORMS ARE LONG AND COMPLEX. WE CAN DO BETTER THERE. UNDERSTANDING IS VARIABLE AND CERTAINLY MORE DIFFICULT IN CERTAIN AREAS LIKE RANDOMIZATION, WE CAN DO BETTER THERE. MANY PARTICIPANTS EITHER DON'T KNOW OR DON'T BELIEVE THAT THEY CAN QUIT OR SAY NO. AND SPENDING MORE TIME WITH PEOPLE IN THE PROCESS OF GIVING THEM INFORMATION ABOUT A STUDY MIGHT ENHANCE THEIR UNDERSTANDING OF THE STUDY. BUT IMPORTANTLY, WE NEED MORE DATA, AND MORE RIGOROUS DATA, TO IMPROVE OUR UNDERSTANDING OF WHAT INFORMED CONSENT IS, TO IMPROVE THE PROCESS IN A VARIETY OF DIFFERENT SETTINGS AND TO ENHANCE PARTICIPANTS' EXPERIENCE AND UNDERSTANDING AND DECISION-MAKING. SO ANY OF YOU WHO ARE INTERESTED IN THAT KIND OF WORK, GO FOR IT. I ALSO THINK IT HELPS US ALL TO BE CLEAR ABOUT THE PURPOSE OF INFORMED CONSENT IN RESEARCH. SO REMEMBER THE GOAL IS TO GIVE PEOPLE INFORMATION THAT THEY CAN USE TO MAKE A DECISION AND WE'VE GOTTEN AWAY FROM THAT GOAL A LITTLE BIT, I THINK OUR LENGTHENINGED CONSENT FORMS INDICATE WE'RE WORRIED ABOUT INSTITUTIONAL LIABILITY AND THINGS LIKE THAT, THAT THINGS AREN'T ALWAYS CONDUCIVE OR ARE RARELY CONDUCIVE TO IMPROVED UNDERSTANDING. WE ALSO KNOW THERE NEEDS TO BE MORE ATTENTION TO HOW WE TRAIN OUR RESEARCH TEAMS AND OUR IRBs ABOUT INFORMED CONSENT, AND WE NEED SOME CREATIVITY, WE NEED NEW WAYS TO PRESENT INFORMATION AND HELP PEOPLE UNDERSTAND WHAT STUDIES ARE ABOUT BEFORE THEY ENROLL. THAT'S IT. QUESTIONS, COMMENTS? DISAGREEMENTS? PLEASE. USE THE MICS. >> HI, MY NAME IS LILIANA. I HAVE NO QUESTIONS BUT I NEED TO KNOW YOUR OPINION ABOUT INFORMED CONSENT IN CLINICAL RESEARCH DONE IN THE CONTEXT OF PATIENT CARE. I HAVE WITNESSED SOME OF THESE PROBLEMS THAT THE PATIENT IS GOING ACTUALLY TO BE SEEN BY A REGULAR DOCTOR BUT THEY FOUND THOUGH THERE WAS AN OFFER TO PARTICIPATE AT THE SAME TIME, THEIR FIRST VISIT, AND THE STUDY HAS THAT INFORMED CONSENT. HOW MUCH INFERENCE IS THE FACT THAT A PATIENT IS TAKING CARE AND THEN UNDERSTANDS UNDER THOSE CIRCUMSTANCES INFORMED CONSENT. >> THAT IS A GREAT QUESTION, AND I AM ACTUALLY GOING TO DEFER TO OUR NEXT SPEAKER WHO ACTUALLY GIVES AN EXAMPLE OF THAT. I THINK THERE ARE SOME PROFESSIONAL ORGANIZATIONS THAT RECOMMENDATION THAT THE TREATING PHYSICIAN NOT BE THE PERSON TO ENROLL HIS OR HER PATIENT IN A CLINICAL STUDY. BUT I THINK THAT THERE ARE CIRCUMSTANCES WHERE THAT'S ACTUALLY NOT -- CERTAINLY THAT THERE ARE CIRCUMSTANCES WHERE THAT'S NOT DONE, THERE ARE SOME CIRCUMSTANCES WHERE I THINK THAT'S ACTUALLY NOT REALISTIC. BUT IT IS PROBLEMATIC, BECAUSE -- FOR THE REASONS THAT YOU'RE SUGGESTING, YOU KNOW, A PERSON GOES TO A PHYSICIAN FOR A CERTAIN REASON, AND THEY MAY FEEL LIKE THEY DON'T WANT TO DISAPPOINT THAT PERSON, THEY DON'T WANT TO JEOPARDIZE THAT PERSON'S WILLINGNESS TO TAKE CARE OF THEM AND, THEREFORE, THEY MIGHT BE MORE WILLING TO PARTICIPATE IN A STUDY IF THAT PERSON ASKS THEM. SO FOR THAT REASON, IT'S IMPORTANT TO THE EXTENT POSSIBLE TO SEPARATE THOSE ACTIVITIES. BUT I THINK BOB IS GOING TO GIVE AN EXAMPLE OF SOMETHING THAT WILL ALSO SPEAK TO THAT ISSUE. >> THANK YOU. >> I JUST WANT TO MAKE A COMMENT ABOUT TAKING ACCOUNT ALSO THE CULTURAL BACKGROUND BECAUSE I HAVE A VERY SIMPLE EXAMPLE OF THAT. I WAS PART OF A VERY SIMPLE -- IT WAS A REGISTRY FOR A MULTI-ETHNICITY CLINIC, DIDN'T HAVE ANY PROBLEM BEING PART OF THE REGISTRY, BUT THEY START LOOKING THAT MANY TIMES IN MANY OF THE SPANISH SPEAKING PATIENTS, THEY REFUSE TO BE PART OF THE REGISTRY, I DECIDE TO BE PART OF THAT WHEN THEY WERE DOING, AND I TALK WITH THEM AND BASICALLY THE LEVEL OF LANGUAGE, THE AMOUNT OF LEGAL DOCUMENTATION THAT IT WAS PLACED TO PROTECT THEM WAS STILL -- SITUATION, WHEN SOMEBODY TELLS ME 10 TIMES, DON'T WORRY, EVERYTHING IS SAFE, I START TO BE SUSPICIOUS, HOW SAFE IS THAT. BASICALLY IT'S KIND OF THE LANGUAGE THAT IT WAS -- TRIED TO PROTECT THE PATIENT BUT THE PEOPLE FEEL IT, AND I THINK THAT AS HOW DO PEOPLE UNDERSTAND, DESPITE THAT YOU PUT IT IN SIMPLE WORDS, WHATEVER, BUT THE BACKGROUND HAS AN IMPACT. >> THAT'S A WONDERFUL -- THANK YOU VERY MUCH FOR THAT. I THINK THERE'S NO DOUBT THAT THERE ARE LOTS OF DIFFERENT CULTURAL APPROACHES TO HOW PEOPLE THINK ABOUT RESEARCH. THERE ARE ALSO CULTURAL APPROACHES TO HOW PEOPLE RECEIVE INFORMATION AND SEE INFORMATION, AND SO THE MOST IMPORTANT MESSAGE THERE IS THAT THE PEOPLE WHO ARE PLANNING THE CONSENT PROCESS SHOULD KNOW THEIR AUDIENCE, SHOULD KNOW WHO THEY'RE TALKING TO AND THINK CAREFULLY, AND MAYBE EVEN INVITE -- AND MANY TIMES THIS DOES HAPPEN -- INMEMBERS OF COMMUNITY TO HELP THEM, WHAT THE CONSENT PROCESS SHOULD LOOK LIKE LIKE. THAT'S A GREAT STORY. IT'S INTERESTING, THE THINGS WE DO EMPHASIZE SOMETIMES DO MAKE PEOPLE SUSPICIOUS, SO YOUR POINT IS VERY WELL TAKEN, THAT YOU SAY THIS IS YOUR CHOICE, YOU DON'T HAVE TO DO IT, YOU DON'T HAVE TO DO IT, YOU SAY IT ENOUGH TIMES, THE PERSON THINKS, WAIT A MINUTE, THERE'S SOMETHING THEY'RE NOT TELLING ME THAT THEY THINK I SHOULDN'T DO THIS. SO THERE'S THIS INTERESTING DYNAMIC THERE. ANY OTHER QEES? OKAY. THEN WE'RE MOVING ON TO OUR NEXT SESSION. ON THE ETHICS OF RANDOMIZED CLINICAL TRIALS AND CLINICAL EQUIPOISE. WE ARE PRIVILEGED TO HAVE BOB TRUEG, BOB HAS GRACIOUSLY GIVEN THIS LECTURE FOR THIS COURSE EVERY YEAR SINCE WE STARTED EXCEPT THE YEAR HE GOT HURRICANED OUT, AND IT'S A WONDERFUL LECTURE, SO YOU'RE IN FOR A TREAT. THANK YOU, BOB. >> GOOD MORNING, EVERYBODY. THANKS FOR BEING HERE. CHRISTINE SAID THIS IS SORT OF AN ANNUAL PILGRIMAGE TO WASHINGTON FOR ME EVERY OCTOBER. WHEN I FIRST STARTED TALKING ABOUT THIS CASE, IT WAS A RELATIVELY RECENT CASE. IT'S GOTTEN A LITTLE BIT DATED NOW BUT I DO THINK THAT THE ETHICAL ISSUES REALLY HAVE CHANGED VERY LITTLE IF AT ALL, AND WHERE THEY HAVE, I'LL POINT THOSE OUT FOR YOU. WE'RE GOING TO TALK ABOUT ETHICAL CONFLICTS AND RANDOMIZED CONTROL TRIALS AND I FEEL LIKE I'M GOING TO TELL YOU FIRST, I WANTED TO GIVE YOU AN OVERVIEW OF WHAT I WILL TELL YOU OVER AND OVER DURING THE ENTIRE PRESENTATION. SO HERE IS THAT OVERVIEW. WE BEGIN WITH TELLING YOU ABOUT A CASE, IN FACT, WE'RE GOING TO BUILD THE ENTIRE DISCUSSION ABOUT A PARTICULAR CASE INVOLVING A RANDOMIZED CONTROL TRIAL OF THE TECHNOLOGY KNOWN AS EXTRA CORPOREAL MEMBRANE OX JEMATION OR ECMO. THAT OF THE CLINICIAN VERSUS THE INVESTIGATOR. ONE WAY TO BAL BALANCE THOSE COMPETING OBL GAIGS IS A TECHNIQUE CALLED ADAPTIVE RANDOMIZATION, WHICH WE'LL DISCUSS, AND ONE WAY OF EASING THE PSYCHOLOGICAL BURDENS THAT EXIST IS AN APPROACH CALLED RANDOMIZED CONSENT, THEN FINALLY FINALLY, WE'LL EXPLORE THE QUESTION WITH YOU AS TO WHETHER RCTs ARE THE ONLY WAY TO LEARN. THE CASE I'LL BE DISCUSSING WITH YOU WAS THE ONE PUBLISHED HERE IN PEDIATRICS IN 1989, RANDOMIZED TRIAL OF ECMO VERSUS CONVENTIONAL MEDICAL THERAPY FOR NEWBORNS. LET ME START BY GIVING A LITTLE BIT ABOUT THE TECHNOLOGY OF ECMO. HOW MANY ARE FAMILIAR WITH ECMO IN YOUR CLINICAL PRACTICE? QUITE A FEW. LET ME GO OVER IT WITH YOU HOAR. SO WE HAVE A SICK BABY HERE, AND ECMO IS A FORM OF PROVIDING HEART AND LUNG BYPASS FOR PATIENTS WITH LIFE-THREATENING CARDIAC OR RESPIRATORY FAILURE. TO PUT A BABY ON ECMO, AN INCISION IS MADE IN THE NECK HERE, AND TWO CANNULAS ARE PLACED, ONE THROUGH THE CAROTID ARTERY DOWN TO THE ACOR TI ARCH, ONE THROUGH THE INTERNAL JUGULAR VEIN INTO THE RIGHT ATRIUM. BLOOD IS DRAINED BY GRAVITY OUT OF THE BODY INTO A RESERVOIR NEAR THE FLOOR WHERE HEPARIN IS ADMINISTERED TO ANTI-COAGULATE THE BLOOD, THEN THE ARTIFICIAL HEART, IF YOU WILL, PUMPS THAT BLOOD UP THROUGH A MEMBRANE OX GENET TORE. THIS IS ESSENTIALLY A LARGE SILICONE ENVELOPE WHICH HAS BEEN COILED OR WRAPPED UP INTO A CYLINDER, AND BLOOD FLOWS IN ONE DIRECTION THROUGH THE INSIDE OF THE ENVELOPE, GAS FLOWS IN THE OTHER DIRECTION THROUGH THE OUTSIDE OF THE ENVELOPE AND GAS EXCHANGE OCCURS ACROSS THAT SILICONE MEMBRANE. SO THIS IS WHERE YOU GET YOUR GAS EXCHANGE. THEN THE BLOOD FLOWS THROUGH A HEAT EXCHANGER WHICH WARMS IT BACK UP TO BODY TEMPERATURE AND THEN INTO THE BABY. SO WE'VE ESSENTIALLY REPLACED HEART AND LUNG FUNCTION. TO GIVE YOU A LITTLE MORE OF A FEEL OF WHAT IT LOOKS LIKE, THESE BABIES ARE TOO SICK TO GO DOWN TO THE OPERATING ROOM SO WE BRING THE OPERATING ROOM UP TO THE INTENSIVE CARE UNIT, WE CREATE A STERILE FIELD, THE SURGICAL TEAM, SCRUB NURSES COME UP FOR PLACEMENT OF THE CANNULAS AND INITIATION OF ECMO. THEN ONCE THE BABY IS ON ECMO, THIS IS WHAT THE BED SPACE LOOKS LIKE, AMAZING, THIS PICTURE WAS PROBABLY TAKEN 15 YEARS AGO AND IT LOOKS PRETTY MUCH IDENTICAL TODAY. YOU SEE THE BABY OBVIOUSLY. HERE IS WHERE THE BLOOD IS DRAINED DOWN TO AND MEDICATIONS ARE ADMINISTERED. HERE IS THE PUMP OR THE ARTIFICIAL HEART. HERE'S THE MEMBRANE OX GENET TORE HERE, AND THEN THE HEAT EXCHANGER, THE CYLINDER TUBE DOWN HERE WHERE THE BLOOD IS WARMED BACK UP, THEN BACK TO THE BABY. THIS IS WHAT THE BABY LOOKS LIKE ON ECMO. IF YOU USE YOUR IMAGINATION, PERHAPS YOU CAN CONVINCE YOURSELF THAT THE BLOOD DOWN HERE IS A LITTLE BIT DARKER THAN THE BLOOD UP HERE, SO THIS IS THE VERY NUSS BLOO VENUS BLOOD DRAINED OUT , THIS IS THE BLOOD GOING BACK IN. THE OTHER THING YOU'LL PROBABLY NOTICE ABOUT THIS PICTURE IS THAT THE ENDOTRACHEAL TUBE IS WAVING IN THE BREEZE HERE, IT'S NOT ATTACHED TO A VENTILATOR SORT OF MAKING THE POINT THAT YOU DON'T HAVE TO BREATHE WHEN YOU'RE ON ECMO. IN POINT OF FACT, WE DO KEEP THE BABIES ATTACHED TO A VENTILATOR JUST TO KEEP THE LUNGS EXPANDED SO THAT THIS WAS DONE JUST FOR THE PHOTO, BUT IT STILL MAKES THE POINT. LET ME GIVE YOU A LITTLE BACKGROUND TO THE TRIAL THAT I'M GOING TO BE TALKING ABOUT. SO AN NIH-FUNDED RANDOMIZED CONTROL TRIAL HAD BEEN DONE IN THE 1970s THAT HAD SHOWN THAT ECMO WAS NOT EFFECTIVE FOR TREATING ADULTS WITH SEVERE LUNG FAILURE ARDS. NOW ONE OF THE SURGEONS WHO WAS INVOLVED IN THAT STUDY, HIS NAME WAS BOB BARTLETT AT THE MASS GENERAL HOSPITAL, AND WHEN THIS WAS DONE, HE THOUGHT, YOU KNOW, WHY DIDN'T THIS WORK? AND MAYBE IT DIDN'T WORK BECAUSE THESE ADULTS ALREADY HAD A REVERSIBLE LUNG INJURY. THEY COULD STAY IN ECMO FOREVER AND IT WASN'T GOING TO CHANGE ANYTHING. THEIR LUNGS WERE ALREADY IRREVERSIBLY DAMAGED. SO IF WE COULD FIND A PATIENT POPULATION THAT HAD A LUNG DISEASE THAT COULD GET BETTER IN THE WEEK OR TWO WHERE WE CAN DO ECMO, MAYBE IT WOULD WORK. SO IT WAS KIND OF A THERAPY IN SEARCH OF A DISEASE, IF YOU WILL. SO BARTLETT, WHO WAS AN ADULT SURGEON, WENT TO MICHIGAN WHERE HE STARTED TO USE ECMO TO TREAT NEWBORNS WITH A DISEASE CALLED PPHN, PERSISTENT PULMONARY HYPERTENSION OF THE NEWBORN. THIS WAS A DISEASE WHERE RIGHT AFTER BIRTH, THE NEWBORNS EXPERIENCED A SPASM OF THEIR PULMONARY ARTERIES. AND SO WITH THAT SPASM, YOU'RE NOT GETTING ENOUGH BLOOD FLOW TO YOUR LUNGS, AND THAT'S LIFE-THREATENING. BUT THE NATURAL HISTORY OF THIS DISEASE IS THAT IF YOU CAN KEEP THE PATIENTS ALIVE FOR A FEW DAYS, THEN THAT SPASM STARTS TO RELAX, BLOOD FLOW RETURNS TO THE LUNG, AND YOU CAN HAVE A SURVIVOR. NOW THE MOST COMMON PRECIP TENT IS MECONIUM ASPIRATION, WHERE THE BABY INHALES MECONIUM MECONIUM DURING BIRTH, HE STARTS TO USE THIS THERAPY AND IT SEEMS MIRACULOUS. BABIES ARE COMING INTO THE UNIT THAT HE FEELS ALMOST CERTAINLY WOULD HAVE DIED, THEY GO ON TO ECMO, AND THEY SURVIVE. SO HE TALKS ABOUT THIS, BUT NOT VERY MANY PEOPLE BELIEVE HIM. SO PEDIATRICIANS ARE VERY RELUCTANT TO ADOPT ECMO. FOR ONE THING, IT'S AN INVASIVE SURGICAL PROCEDURE, IT'S NOT REALLY A PART OF THE NICU, NEWBORN ICU CULTURE, AND WE'VE CERTAINLY HAD MANY EXAMPLES IN MEDICINE WORE THINGS THAT LOOK UNBELIEVABLY PROMISING TURNED OUT TO BE WORTHLESS WHEN THEY WERE SUBJECTED TO A RANDOMIZED TRIAL. SO EVERYONE SAID WHY DON'T YOU DO AN RCT OF THIS? SO THE FIRST QUESTION I'D LIKE TO POST TO YOU IS IMAGINE YOU WERE BOB BARTLETT IN THIS SITUATION. WOULD YOU HAVE SOUTH TO PERFORM AN RCT TO DEMONSTRATE THE SUPERIORITY OF ECMO TO CONVENTIONAL MEDICAL THERAPY, AND WHY OR WHY NOT. SO THE DILEMMA FOR HIM HERE IS HE CAN STAY IN ANN ARBOR AND HE CAN SAVE LIVES AND DO ALL THE GOOD THINGS THAT WE DO AS DOCTORS AND CARE TEAMS, OR HE CAN DO AN RCT TO TRY TO CHANGE PRACTICE AROUND THE COUNTRY, AROUND THE WORLD, BUT IN DOING SO, HE'S GOING TO HAVE TO TAKE SOME BABIES AND PUT THEM INTO A CONTROL GROUP, AND HE'S GOING TO HAVE TO WATCH THEM NOT HAVE A THERAPY THAT HE THINKS COULD SAVE THEIR LIFE. SO IT MAY NOT BE ENTIRELY -- HOW MANY OF YOU, IF YOU WERE BOB BARTLETT, WOULD DO AN RCT VERSUS HOW MANY WOULD SAY, MY JOB IS TO JUST BE A DOCTOR FOR THE PATIENTS THAT ARE PARENNED T PRESENTED TO ME, I'M JUST TO CONTINUE TO DO WHAT I'M DOING IN ANN ARBOR. SO HOW MANY WOULD DO THE RCT OR PUSH TO DO AN RCT? HOW MANY WOULD CONTINUE TO DO WHAT YOU'RE DOING AND NOT WORRY ABOUT WHETHER OTHERS BELIEVE YOU OR NOT? SO THERE'S A LITTLE BIT OF A MIX. THERE'S A COUPLE PLACES I'D LIKE TO TAKE COMMENTS IF WE HAVE TIME. WOULD ANYBODY LIKE TO -- OR BE WILLING TO SHARE WHY THEY CHOSE ONE WAY OR THE OTHER? WHAT YOUR THINKING WAS ABOUT IT? IF YOU COULD COME DOWN TO THE MIC, THAT WOULD BE GREAT. >> IT WOULD BE HELPFUL TO KNOW WHAT THE NATURAL HISTORY OF THESE BABIES WERE. IF IT WERE 100% FATALITY BEEN DEFINED TIME FRAME AND HE WAS GIVEN SUCCESS, I MIGHT BE IN THE CAMP OF LET'S JUST KEEP DOING IT, LET THOSE PEOPLE WORRY ABOUT RCTs. >> GREAT B, INDEED IT WAS LIKE THAT. THE POPULATION HE WAS SEEING ROUGHLY HAD MAYBE AN 80% MORTALITY. IT WAS PRETTY CLEAR THAT THEY WERE SURVIVING. NOW THERE WERE SOME MORBIDITIES. THIS DOES INVOLVE USUALLY LIGATION OF THE CAROTID ARTERY AND THE INTERNAL JUGULAR VEIN, WHICH, OF COURSE, IS VERY CONCERNING. I CAN TELL YOU IN THE LONG TERM IT HAS TURNED OUT NOT TO INCREASE THE RISK OF NEUROLOGICAL INJURY THAT WAS CERTAINLY A RISK AT THE TIME. ANYBODY INSIST ON RCT, WILLING TO SHARE A THOUGHT? >> MY THOUGHT FOR THE RCT WAS JUST THAT HE'D BE ABLE TO HELP A BIGGER GROUP OF PEOPLE BY TRYING TO GET THE DATA, AND I MEAN, THESE CHILDREN WERE DYING AT OTHER FACILITIES. >> SO LET'S CONVINCE THEM. THANK YOU VERY MUCH FOR SHARING THAT. I THINK THAT'S A VERY GOOD REASON. SO BOB BARTLETT SAID OKAY, I'LL GIVE YOU AN RCT. THIS WAS A PAPER HE PUBLISHED, ECMO AND NEONATAL RESPIRATORY FAILURE, A PROSPECTIVE RANDOMIZED STUDY. LOOKS LIKE HE DID IT. IF YOU LOOK A LITTLE MORE CLOSELY, IT'S MORE COMPLICATED THAN THAT. HIS DESIGN INVOLVED WHAT'S CALLED A "PLAY THE WINNER" DESIGN. LET ME EXPLAIN TO YOU HOW IT WORKED. SO YOU START OFF WITH MARBLES OF TWO COLORS IN AN YOUR HONOR. SURN. SO LET'S SAY ECMO IS THE YELLOW MARBLE, CONVENTIONAL THERAPY IS THE BLACK MARBLE. YOU'RE GOING TO REACH IN AND YOU'RE GOING TO PULL ONE OF THOSE OUT, THAT'S GOING TO DETERMINE WHAT THAT BABY GETS. NOW LISTEN CAREFULLY. HERE EIGHTS THE CONFUSING PART. I'LL GO OVER IT TWICE. IF THAT BABY SURVIVED, THEN FOR THE NEXT DRAW, ANOTHER MARBLE OF THE SAME COLOR GOES INTO THE URN. IF THAT BABY DIES, THEN FOR THE NEXT DRAW, ANOTHER MARBLE OF THE OPPOSITE COLOR GOES INTO THE URN. SO LET ME SHOW YOU A SECOND TIME IN THE CONTEXT OF HOW IT ACTUALLY WENT. SO IN HIS TRIAL, THE FIRST BABY GOT ECMO AND SURVIVED. SO FOLLOWING THE RULE FOR THE NEXT DRAW, ANOTHER MARBLE OF THE SAME COLOR, YELLOW, WOULD GO BACK INTO THE YOUR HONOR. THE NEXT BABY DREW THE BLACK MARBLE, AND THAT BABY DIED. SO FOR THE NEXT DRAW, ANOTHER MARBLE OF THE OPPOSITE COLOR, NOW YELLOW, GOES INTO THE URN. SO YOU CAN SEE THAT THE RANDOMIZATION IS STARTING TO SHIFT TOWARDS THE THERAPY THAT'S LOOKING MORE SUCCESSFUL. IT FOLLOWED THIS STRATEGY UNTIL THERE WERE 11 BABIES ENROLLED, AND ONLY THE ONE DIED, 10 SURVIVED. AT THIS POINT, THE STUDY WAS STATISTICALLY SIGNIFICANT. P WAS LESS THAN .05, HE DETERMINED THE STUDY AND PUBLISHED IT AS A PROSPECTIVE RANDOMIZED CONTROLLED TRIAL. TO HIGHLIGHTS SOME OF THE ETHICAL TENSIONS HERE, THIS CHILD HERE, I'VE HAD AN OPPORTUNITY TO TALK TO DR. BARTLETT ABOUT THIS STUDY ON A NUMBER OF OCCASIONS. THAT CHILD WHO DIED WAS THE CHILD OF A WOMAN IN THEIR 40s WHO HAD GONE THROUGH INFERTILITY TREATMENTS FOR MANY YEARS. TO MAKE MATTERS WORSE DURING HER DELIVERY, SHE HAD TO HAVE A HIS HYSTERECTOMY, SO THIS WAS HER LAST CHANCE TO HAVE A CHILD SHE WOULD CONCEIVE AND DELIVER. THE CHILD CAME FROM KALAMAZOO, WHICH IS ACROSS THE STATE FROM ANN ARBOR. IT WAS THE FIRST REFERRAL FROM THERE THAT THEY'D HAD IN YEARS. THE DIRECTOR OF MEE OW DIRECTOR OF NEONATO LOGY CALLED UP BOB BARTLETT, HE SAID I KNOW YOU HAVE THIS AMAZING THERAPY AND YOU REALLY HAD TO MUTT PUT THIS BABY ON ECMO. BOB BARTLETT HAD TO SAY I'M SORRY, WE HAVE A TRIAL GOING, I CAN'T PROMISE THAT. THE BABY GOT CONVENTIONAL THERAPY. THE WAY BOB BARTLETT DESCRIBES IT AS INITIALLY GOT BETTER FOR A DAY OR TWO, THEY WERE VERY HOPEFUL, BUT THEN THINGS WENT SOUTH AND THE BABY ENDED UP DYING. TOWARDS THE END OF THE STUDY, THE DAUGHTER OF HIS BROTHER, HIS NIECE, WAS ACTUALLY REFERRED FROM INDIANA TO ANN ARBOR BECAUSE SHE ALSO HAD MECONIUM ASPIRATION AND PPHN. SHE DID NOT MEET CRITERIA FOR ECMO SO IT WAS NEVER A FIRM ISSUE, BUT HE DID SAY THAT HE WAS PREPARED TO RANDOMIZE HER AS WELL. SO AS THIS IS ACTUALLY LIVED, THESE ETHICAL TENSIONS ARE VERY REAL AND VERY HARD. LET'S GO BACK JUST TO THE RESULTS OF THE STUDY. SO YOU READ THIS PAPER, YOU ARE A NEONATOLOGIST IN BOSTON OR LOS ANGELES OR ATLANTA. YOU'VE HEARD A LITTLE BIT ABOUT BOB BART LESS' WORK. WHEN YOU READ THE ARTICLE, WOULD YOU HAVE SAID, OKAY, WE'VE GOT WHAT WE NEED, AND TELL YOUR HOSPITAL ADMINISTRATOR THAT YOU'D NEED TO START AN ECMO PROGRAM. SO YOU'RE A NEONATOLOGIST. HOW MANY OF YOU FEEL THIS IS THE EVIDENCE THAT YOU ARE WAITING FOR AND NOW YOU'RE GOING TO START THE PROGRAM? NOT MANY, JUST A COUPLE. HOW MANY FEEL THAT THIS IS STILL INADEQUATE, THAT THIS WAS NOT A CONVINCING STUDY? DEFINITELY THE MAJORITY. ANY ONE OF THOSE WHO THOUGHT THAT WAS NOT CONVINCING, SOMEBODY WILLING TO COME TO THE MICROPHONE? COME ON NOW, PLEASE PARTICIPATE. YOU MUST HAVE HAD A REASON FOR RAISING YOUR HAND. OKAY. AM I HEARING SOMEBODY? OH, GREAT. THANK YOU. >> I DON'T KNOW IF IT'S GOOD OR BAD. I DON'T HAVE ENOUGH EVIDENCE THAT IT'S GOING TO BE SUPERIOR TO THE STANDARD THAT YOU HAVE TO COMPARE. >> OKAY. >> AND THAT IS NOT IN THE STUDY, RIGHT? SO YOU ARE NOT COMPARING THE TWO -- >> WELL, YOU ARE COMPARING IN THE SENSE THAT THIS ONE BABY GOT CONVENTIONAL THERAPY. SO THAT WAS THE COMPARISON TO ECMO. AND THAT TENDS TO BE THE PROBLEM. PEOPLE SAY HOW COULD THIS POSSIBLY BE CONVINCING IF THERE WAS ONLY ONE BABY IN THE CONTROL GROUP? >> THAT'S MY REASON. >> GOOD. THANK YOU VERY MUCH. I APPRECIATE YOUR SPEAKING UP. AND INDEED, THIS WAS THE VIEW THAT WAS SHARED BY SOME COLLEAGUES OF MINE IN BOSTON. IN AN EDITORIAL ON THIS ARTICLE, SAID THE ISSUES REMAIN UNDEFINED. FURTHER RANDOMIZED CONTROL TRIALS WILL BE DIFFICULT BUT REMAIN NECESSARY. SO IN THE TRADITION OF ACADEMIA, THEY CRITICIZED THE STUDY AND THEN PROPOSED TO DO THEIR OWN. SO THAT WAS THE ARTICLE THAT WAS PUBLISHED HERE WITH JIM WARE AND MIKE EPSTEIN AS AUTHORS. LET ME TELL IT YOU A LITTLE BIT ABOUT THE TRIAL, BECAUSE IT HAS SOME INTERESTING AND IMPORTANT ETHICAL FEATURES. SO A NUMBER OF DECISIONS WERE MADE HERE. FIRST WAS THAT CONVENTIONAL THERAPY, THE CONTROL ARM, IS GOING TO BE DELIVERED IN A DIFFERENT PLACE FROM ECMO. SO CONVENTIONAL THERAPY WOULD HAPPEN IN THE NEONATAL ICU ON THE SEVENTH FLOOR OF THE HOSPITAL, ECMO IN THE PEDIATRIC ICU ON THE FIFTH FLOOR. PART OF THE REASON, NOT THE ONLY REASON BUT PART OF THE REASON WAS NOT TO HAVE THE PARENTS OF BABIES WITH A VERY SIMILAR CONDITION BEING TREATED IN VERY DIFFERENT WAYS NEXT TO EACH OTHER. BUT IT WAS MORE THAN THAT. THE NICU WAS STAFFED BY NEONATOLOGISTS WHO ARE VERY SKEPTICAL ABOUT THE USE OF THIS SURGICAL THERAPY. WHEREAS THE PEDIATRIC ICU, WHERE I WAS WORKINGS WAS STAFFED BY ANESTHESIOLOGISTS AND SURGEONS MORE WITH THE PHILOSOPHY, A CHANCE TO CUT IS A CHANCE TO HEAL KIND OF THING, MORE FAVORABLY DISPOSED TOWARDS ECMO. AND I WAS AN ANESTHESIA FELLOW AT THE TIME THAT THIS TRIAL WAS DONE, WORKING IN THIS ICU. THIRD DOWN HERE, THIS IS IMPORTANT, NO PATIENTS AT OUR HOSPITAL WITH THIS CONDITION HAD EVER BEEN OFFERED ECMO SO THAT THEY WERE NOT BEING DENIED A TREATMENT THAT HAD BEEN PREVIOUSLY AVAILABLE BEFORE THE STUDY STARTED, WAS DIFFERENT FROM BOB BARTLETT'S SITUATION. HE'D BEEN DOING IT WITH GREAT SUCCESS, THEN WHEN HE STARTS THE STUDY, SUDDENLY PATIENTS WHO PREVIOUSLY WOULD HAVE GOTTEN IT, CAN'T GET IT ANYMORE. WE HAVE NEVER USED ECMO FOR THIS DISEASE. SO I THINK THAT IT WAS AN ETHICAL ADVANTAGE. WE WEREN'T PULLING SOMETHING AWAY THAT HAD BEEN PREVIOUSLY BEEN AVAILABLE. ON THE OTHER HAND, ON THE FIFTH FLOOR, WE HAD BEEN USING ECMO FOR A DIFFERENT DISEASE, CONGENITAL HERNIA, WHERE THE DIAPHRAGM DOES NOT FORM ON ONE SIDE OF THE CHEST. SO A DIFFERENT DISEASE, SIMILAR PHYSIOLOGY IN SOME WAYS, BUT THE ADVANTAGE HERE WAS THAT WE WERE ALREADY PRETTY GOOD AT DOING ECMO AS A TECHNOLOGY. WHEN ECMO PROGRAMS FIRST START UP IN A NEW PLACE, THE FIRST FEW PATIENTS DON'T TYPICALLY DO VERY WELL, GOT A PRETTY STEEP LEARNING CURVE. WE WERE ALREADY PAST THAT STEEP PART OF THE LEARNING CURVE, WE KNEW THAT TECHNOLOGY. SO THIS WAS GOING TO BE A REALLY GOOD TEC TECHNOLOGY FOR US TO COMPARE, AND THEN THERE WAS THE SORT OF ANTIECMO/PRO ECMO SENTIMENTS THAT WERE PRESENT. SO THIS WAS THE SETUP FOR THE TRIAL. THE OTHER THING, JUST TO GO OVER THE STUDY DESIGN WITH YOU, IS THAT NEWBORNS WHO WERE ELIGIBLE WITH THE STUDY HAD TO HAVE PPHN AND THE PREDICTED MORTALITY OF 85% BASED ON THE MOST RECENT RETROSPECTIVE DATA FROM OUR HOSPITAL. I WANT YOU TO REMEMBER THAT NUMBER. 85%. THE STUDY WAS DIVIDED INTO TWO PHASES. DURING PHASE 1, THERE WOULD BE 50/50 RANDOMIZATION BETWEEN ECMO AND CONVENTIONAL THERAPY, UNTIL THERE WERE FOUR DEATHS IN ONE OF THE ARMS. AND AT THAT POINT, THE STUDY WOULD ENTER PHASE TWO, WHERE ALL OF THE PATIENTS WOULD BE ASSIGNED TO THE MORE SUCCESSFUL THERAPY AND THE TRIAL WOULD CONTINUE UNTIL THERE WERE FOUR DEATHS IN THAT ARM OR UNTIL STATISTICAL SIGNIFICANCE WAS ACHIEVED. THE STATISTICIAN WAS THE ONLY ONE WHO KNEW ABOUT THIS TWO-PHASED PLAN. FOR INVESTIGATORS, IT WAS JUST GOING TO BE A MATTER OF OPENING ENVELOPES AND SEEING WHAT THE ASSIGNMENT WAS. FINALLY, THERE WAS A DECISION TO SEEK CONSENT FROM THE PARENTS ONLY OF THOSE WHO WERE RANDOMIZED TO BE EXPERIMENTAL THERAPY, NOT TO THOSE ASSIGNED TO THE CONTROL GROUP. AND WE'LL TALK MORE ABOUT THAT. BUT BEFORE GOING ON, I DO WANT TO JUST MAKE A COMMENT HERE ABOUT THIS NUMBER FOUR, AS I'VE TAUGHT THIS CASE OVER THE YEARS, PEOPLE TEND TO ASK WHERE DOES THAT NUMBER FOUR COME FROM? SEEMS RATHER ARBITRARY. SO I DIDN'T KNOW THE ANSWER TO THAT, SO I WENT BACK TO THE ARTICLE, TO JIM WARE THAT HAD WRITTEN ABOUT THIS STUDY DESIGN AND I LOOKED IT UP. HERE'S THE ANSWER TO THAT QUESTION. THIS IS THE PAGE FROM THE ARTICLE, NOTICE THERE'S A 4 RIGHT HERE. THERE'S A 4 DOWN HERE. HONESTLY THAT'S THE BEST EXPLANATION THAT I COULD GIVE YOU. I TEACH THIS CASE WITH JIM QUITE A BIT, I ALWAYS CHUCKLED WITH THAT BUT HE, OF COURSE, READS THIS LIKE WE READ THE NEWSPAPER. BUT IT ALSO SHOWS THAT THE STATISTICS BEHIND THESE KIND OF TRIALS ARE VERY, VERY COMPLEX. ALL RIGHT. SO HOW DID IT TURN OUT? SO DURING PHASE 1, THERE WERE NINE BABIES ASSIGNED TO ECMO. YOU CAN SEE ALL OF THEM SURVIVED. NONE DIED. THERE WERE 10 ASSIGNED TO CONVENTIONAL THERAPY, SIX SURVIVED, FOUR DIED. WHEN THE FOURTH DEATH OCCURRED HERE, IN THE CONTROL GROUP, BY DESIGN, THE STUDY ENTERED PHASE 2, 20 MORE BABIES WERE ASSIGNED TO ECMO, 19 SURVIVED, ONE DIED, STATISTICAL SIGNIFICANCE WAS ACHIEVED. THE STUDY WAS TERMINATED AND IT WAS WRITTEN UP. I'M GOING TO GO ON NOW AND TALK ABOUT THE ETHICS, BUT BEFORE I DO SO, ANY QUESTIONS ABOUT THE TRIAL IT SELF? OKAY. LET'S GO ON THEN. I WANT TO TALK ABOUT THE MOST IMPORTANT THING. IF YOU COME AWAY WITH ONE TAKE-HOME FROM THIS TALK, IT SHOULD BE THE FUNDAMENTAL CON FLECT BETWEEN THE ROLES OF HEALER AND INVESTIGATOR. THE SUBJECT OF THE FIRST QUESTION THAT CAME UP TO CHRISTINE'S EARLIER TALK. I THINK THIS IS A FUNDAMENTAL CONFLICT, I THINK IT GOES ALL THE WAY TO THE BONE, I DON'T THINK THAT THERE'S ANY REAL WAY OF RESOLVING IT. THE DILEMMA IS AS FOLLOWS: PHYSICIAN INVESTIGATORS, PHYSICIANS ARE DEDICATED TO CARING FOR THEIR PATIENTS, INVESTIGATORS ARE DEDICATED TO CARING FOR THEIR RESEARCH. THESE TWO COMMITMENTS CONFLICT WHENEVER AN INDIVIDUAL, PHYSICIAN/INVESTIGATOR, COMES FACE TO FACE WITH AN INDIVIDUAL PATIENT/SUBJECT. THE PUBLIC IS AWARE OF THIS, THIS IS A CARTOON FROM "THE NEW YORKER," A MEMBER OF THE PLACEBO GROUP. I THINK THAT THERE'S A CERTAIN SKEPTICISM AND WARINESS THAT MAYBE IF YOU PARTICIPATE IN RESEARCH, YOU ARE NOT GOING TO BE TREATED LIKE A PATIENT. SO I'M GOING TO GIVE YOU THREE POSSIBLE SOLUTIONS TO THIS. ONE IS TO HAVE A FULL SEPARATION OF ROLES. REBECCA DRESSER HAS WRITTEN ABOUT THIS. SHE SAYS RESEARCHERS MUST GIVE PATIENTS STARK, BOLD AND DRAMATIC SIGNS THAT RESEARCH IS DIFFERENT FROM CLINICAL CARE. INSTEAD OF THE WHITE COATS ASSOCIATED WITH MEDICAL CARE, INVESTIGATORS COULD WEAR RED ONES. SO, YOU KNOW, YOU'RE AT THE NIH, WHEN SOMEBODY WALKS INTO THE ROOM, YOU KNOW EXACTLY WHAT ROLE THEY'RE PLAYING. ARE THEY HERE TO TAKE CARE OF ME, OR ARE THEY HERE TO DO THEIR RESEARCH? AND AS THE QUESTION POINTED OUT, IT'S OFTEN NOT CLEAR. NOW I DO THINK THAT THIS IS THE IDEAL WAY TO MANAGE THE CONFLICT WHENEVER IT'S POSSIBLE. BUT IN MANY CASES, IT'S NOT POSSIBLE, AND I THINK THE NIH IS PROBABLY ONE OF THE BEST EXAMPLES OF THAT, PEOPLE COME HERE BECAUSE THEY'RE SOMEBODY WHO IS THE WORLD'S EXPERT AT RARE DISEASE X AND AS A PATIENT, YOU ABSOLUTELY WANT THEM TO BE TAKING CARE OF YOU. THEY KNOW MORE THAN ANYBODY ELSE ABOUT THE DISEASE YOU HAVE. BUT NO SURPRISE, THEY'RE ALSO THE PERSON THAT'S DOING THE RESEARCH ON THE DISEASE. AND SO WE CAN'T ALWAYS SEPARATE THESE TWO ROLES. SO POSSIBLE SOLUTION 2 IS WHAT'S BEEN CALLED PERSONAL EQUIPOISE. THIS WAS A STANDARD FOR MANY YEARS. IT REQUIRES THAT THE INVESTIGATOR BE PERSONALLY UNBIASED BETWEEN THE TREATMENT ARMS. PERFECTLY BALANCED ON THE EDGE OF THE SWORD. THE PEOPLE SAID IF YOU'RE GOING TO DO RESEARCH AND YOU'RE GOING TO ENROLL SOMEBODY, YOU HAVE TO BE PERSONALLY UNDECIDED ABOUT WHICH OF THOSE TWO ARMS IS BETTER. THE PROBLEM IS THIS IS ALMOST NEVER THE CASE. RESEARCHERS BELIEVE IN THE TREATMENTS THEY STUDY. BOB BARTLETT CERTAINLY BELIEVED IN ECMO. FOR THOSE OF YOU ENGAGED IN YOUR OWN RESEARCH HERE, YOU'RE GOING TO SPEND THE NEXT THREE, FOUR, FIVE YEARS OF YOUR LIFE DOING A CLINICAL TRIAL ON SOMETHING, YOU KNOW, YOU BET YOU BELIEVE IN IT. YOU WOULDN'T BE DOING THE RESEARCH IF YOU DIDN'T BELIEVE IN IT. SO THIS IS A VERY AWKWARD REQUIREMENT, AND REQUIRING PERSONAL EQUIPOISE LEAVES INVESTIGATORS FEELING EITHER GUILTY LIKE, OH, I'M NOT LIVING UP TO MY ETHICAL OBLIGATIONS, OR FEELING CYNICAL, LIKE, WELL, IF THOSE ARE THE OBLIGATIONS, THEN ETHICS IS A BUNCH OF HOOEW. THAT'S NOT GOOD. SO IN 1987, CANADIAN BIOETHICIST BENJAMIN FRIEDMAN CAME UP WITH A THIRD APPROACH, CALLED CLINICAL EQUIPOISE, AND THIS IS THE ONE YOU SHOULD KNOW. IT REQUIRES UNCERTAINTY WITHIN THE MEDICAL COMMUNITY AS A WHOLE, OKAY? SO IMAGINE YOU'RE DOING A TRIAL OF AN ANTIHYPERTENSIVE, YOU'RE SEEING SOMEBODY IN YOUR CLINIC, AND SO YOU WANT TO ENROLL THEM IN THE TRIAL, YOU SAY, YOU KNOW, WELL, I PERSONALLY BELIEVE THAT PILL A IS BETTER, BUT HONESTLY, MY COLLEAGUE DOWN THE HALL WOULD HAVE RECOMMENDED PILL B. SO GIVEN THAT IT'S RANDOM WHO YOU ARE SEEING TODAY, WOULD YOU AGREE TO HAVE YOUR TREATMENT DETERMINED BY A COIN FLIP? SO THAT WE CAN LEARN FROM THIS EXPERIENCE? THAT'S THE IDEA BEHIND CLINICAL EQUIPOISE. WHAT MAKES YOUR TRIAL ETHICAL IS THAT THERE IS GENUINE UNCERTAINTY WITHIN THE MEDICAL COMMUNITY AS A WHOLE. SO IT'S INTERESTING WITH SITUATIONS LIKE THE HARVARD ECMO TRIAL, IT'S LIKELY THAT NO SINGLE INVESTIGATOR INVOLVED WITH THE TRIAL WAS IN PERSONAL EQUIPOISE. WE HAD THE BELIEVERS AND NON-BELIEVERS, BUT WE COULD ARGUE THAT WE DID HAVE CLINICAL EQUIPOISE BECAUSE THROUGHOUT THE INSTITUTION AND ARGUABLY THROUGHOUT THE COUNTRY, THERE WAS DISAGREEMENT ABOUT WHAT WAS THE BEST TREATMENT. SO THAT'S A CONCEPT YOU SHOULD COME AWAY WITH, CLINICAL EQUIPOISE. LET ME TALK A LITTLE ABOUT ADAPTIVE RANDOMIZATION. THIS IS BECOMING PARTICULARLY MORE RELEVANT FOR THE GENERATION OF CLINICAL INVESTIGATORS THAT ARE COMING ALONG, AND I'LL EXPLAIN WHY. THE IDEA BEHIND ADAPTIVE RANDOMIZATION IS THAT YOU DEVIATE FROM BALANCED OR 50/50 RANDOMIZATION WITH MORE PATIENTS ASSIGNED TO THE THERAPY THAT IS LEADING DURING THE TRIAL. IT'S KIND OF LIKE BETTING ON THE HORSE WHO WAS OUT IN FRONT. BEFORE WE KNOW HOW THE RACE IS GOING TO END. THERE'S A NUMBER OF ADVANTAGES TO THIS. GOING BACK TO THE MOST IMPORTANT POINT I WANTED YOU TO GET, IT DOES ATTEMPT TO MITIGATE THIS CONFLICT BETWEEN THE HEALER AND THE INVESTIGATOR BY MINIMIZING THE NUMBER OF PATIENTS WHO END UP GETTING ASSIGNED TO THE LESS SUCCESSFUL THERAPY. NOW, YOU KNOW, AS MUCH AS THE HARVARD GROUP CRITICIZED THE MICHIGAN GROUP, IN FACT, THOSE TRIALS WERE REALLY VERY SIMILAR. THE DIFFERENCE WAS THAT IN THE BARTLETT TRIAL, 50/50 RANDOMIZATION WAS GUARANTEED ONLY FOR THE IT FIRST PATIENT. WHEREAS IN THE HARVARD TRIAL, 50/50 RANDOMIZATION WAS GUARANTEED UNTIL THERE WAS A FOURTH DEATH IN ONE ARM. BUT FUNDAMENTALLY BOTH FELT CONSTRAINED NOT TO HAVE ANY MORE PATIENTS THAN NECESSARY ASSIGNED TO THE TREATMENT THAT WAS GOING TO BE LESS SUCCESSFUL. THAT WAS WHAT DROVE THAT STUDY DESIGN. IT MUST BE ONLY ONE OUT COME OF INTEREST AND THE OUTCOME MUST BE APPARENT WITHIN A SHORT PERIOD OF TIME BECAUSE YOU ARE ADJUSTING THE RANDOMIZATION RANDOMIZATION SCHEME IN REALTIME. I'LL SAY IT IN A MOMENT BUT SOME OF THE CURRENT CANCER TRIALS THAT USE THIS ARE UPDATING THEIR RANDOMIZATION TRIALS HOUR BY HOUR, SO IT IS A REALTIME THING, SO THE NUMBERS THAT YOU'RE FOLLOWING HAVE TO BE APPARENT IN A FAIRLY SHORT PERIOD OF TIME. THIS WAS TRUE FOR THE ECMO TRIAL, SURVIVAL OR DEATH, AND WE KNEW PRETTY QUICKLY. IT MAY SUFFER FROM ACCRUAL BIAS, BECAUSE VOLUNTEERS WHO HAVE A CHOICE MAY WANT TO BE RECRUITED INTO THE TRIAL LATER, WHEN IT BEEN SHIFTED TOWARDS THE MORE SUCCESSFUL THERAPY. NOT AN ISSUE IN THE ECMO TRIAL BECAUSE THE BABIES HAD A LIFE-THREATENING PROBLEM. IN THE LITERATURE, THE TRIAL WAS CRITICIZED IN BOTH DIRECTIONS. THERE WAS THE ENTIRE ISSUE OF THE STATISTICS JOURNAL, THERE WERE THOSE THAT SAID NO PATIENTS SHOULD HAVE BEEN ASSIGNED TO CONVENTIONAL THERAPY. BARTLETT HAD ALREADY SHOWN CONVINCING EVIDENCE THAT THIS WAS A SUPERIOR THERAPY, YOU DIDN'T NEED TO DO THE RANDOMIZED CONTROL TRIAL, AS ONE OF OUR PARTICIPANTS SAID THERE. OTHER PEOPLE SAID YOU MISSED A GOLDEN OPPORTUNITY. HERE YOU COULD HAVE DONE A TRIAL THAT WOULD HAVE CONVINCED EVERYBODY AND YOU END UP WITH THIS CLOCK MAEMI DESIGN, IT'S NOT ALL THAT CONVINCING, THE TRIAL IS STILL OPEN, IT WAS A WASTE OF EFFORT. PERHAPS THIS WAS A GOOD BALANCE. NOT ONLY BECAUSE OF THE VIEW THAT THE STATISTICIANS WHO USED IT BUT WE ALSO SAW IT WITHIN THE CLINICIANS THEMSELVES, SO YOU KNOW, ICU NURSES ARE OFTEN LIKE THE CANARIES IN THE COAL MINE THIS WAS TRUE FOR THE NEONATAL ICU NURSES WHO WERE WATCHING THESE BABIES DIE IN THE NEONATAL ICU, AND OF COURSE THEY'RE HAVING LUNCH WITH THE NURSES IN THE PEDIATRIC ICU AND THE BABIES ARE ALL DOING FINE, AND THERE'S SKEPTICISM THAT STARTED TO GO UP. BY THE TIME THERE WAS A FOURTH DEATH IN THE NICU, THERE WAS BEGINNING TO BE A LITTLE BIT OF A REVOLT AS TO WHETHER THEY WERE GOING TO CONTINUE TO WITHHOLD ECMO FOR THESE BABIES, CONTINUE OH GTO GO ALONG WITH THEM. THE RANDOMIZATION SCHEME THEN SWITCHED OVER THAT ALL THE BABIES GOT ECMO. BUT THAT NUMBER FOUR MAY HAVE BEEN MAGICAL FOR MORE THAN ONE REASON. THESE ARE A COUPLE ARTICLES FROM JAMA THAT SPEAK TO THE INCREASING USE OF ADAPTIVE DESIGNS, IN FACT, AT HARVARD MEDICAL SCHOOL, WE JUST RECENTLY HAD AN ALL-DAY SYMPOSIUM ON THESE. THE HERO OF ALL OF THIS RIGHT NOW IS DON BARRY, USING THESE DESIGNS FOR A LARGE NUMBER OF CLINICAL TRIALS MOSTLY INVOLVING CHEMO THERAPEUTIC AGENTS. THEY'RE GAINING A LOT OF TRACTION SO I THINK THIS IS SOMETHING TO BE AWARE OF. THE THIRD SORT OF UNUSUAL STUDY DESIGN HERE IS RANDOMIZED CONSENT. LET ME EXPLAIN TO YOU A LITTLE BIT ABOUT THIS. LET'S LOOK AT A CONVENTIONAL RCT WITHOUT INFORMED CONSENT. YOU DETERMINE YOUR PATIENT IS ELIGIBLE, THEN YOU RANDOMIZE BETWEEN THE TWO TREATMENTS, A AND B. REALLY CLEAN, REALLY STRAIGHTFORWARD. PROBLEM IS, UNLESS YOU'RE DEALING WITH LAB RATS, IT'S UNETHICAL. BECAUSE WHAT'S MISSING HERE IS INFORMED CONSENT. SO IF WE INSERT INFORMED CONSENT INTO THE PROCESS, WE RANDOMIZE THOSE WHO SAY YES AND WE DROP THOSE WHO SAY NO AND AS ALL OF YOU KNOW, THE DIFFICULTY NOW IS YOU'VE GOT TO BE SURE THAT THIS IT GROUP DOESN'T DIFFICULTER IN ANY SYSTEMATIC WAYS FROM THESE PEOPLE. BUT THAT'S THE PRICE WE PAY TO DO ETHICAL RESEARCH. SO THEN MARVIN ZAELEN CAME ALONG, STILL A PROFESSOR AT THE SCHOOL OF PUBLIC HEALTH AT HARVARD, AND HE PROPOSED THIS NEW DESIGN. WHICH IS CALLED RANDOMIZED CONSENT OR ZELEN RANDOMIZATION AND IT LOOKS LIKE THIS. WHEN A PATIENT IS ELIGIBLE, THE FIRST THING YOU DO IS RANDOMIZE THEM. THEN IF THEY AGREE TO BE RANDOMIZED, YOU ASK THEM WILL YOU ACCEPT THE EXPERIMENTAL THERAPY? IF THEY SAY YES, THEY GET IT. IF THEY SAY NO, THEY GET THE CONVENTIONAL THERAPY. IF THEY'RE RANDOMIZED WITH THE CONVENTIONAL GROUP, YOU DON'T GIVE THEM CONSENT, YOU SIMPLY GIVE THEM THE CONVENTIONAL THERAPY. SO THIS IS HOW IT LOOKED FOR THE ECMO TRIAL. BABIES -- NO BABIES WERE BORN AT CHILDREN'S HOSPITAL, WE DON'T HAVE A DELIVERY SERVICE, SO THEY WERE ALL BORN ELSEWHERE. THEY MET ECMO CRITERIA, THEY WERE TRANSPORTED IN, AND WHILE THEY WERE IN THE AMBULANCE ON THE WAY IN TO CHILDREN'S, THE ENVELOPE IS OPENED AND WE FIND OUT DO THEY GO TO THE SEVENTH OR THE FIFTH FLOOR? THESE WERE REALLY SICK BABIES, THEY WOULD HAVE BEEN COMING TO CHILDREN'S ANYWAY, AND THERE WAS NO OTHER ECMO CENTER WITHIN NEW ENGLAND WHERE THEY COULD HAVE GONE, SO THEIR ONLY CHANCE FOR GETTING ECMO WAS TO COME TO CHILDREN'S HOSPITAL. SO THEY'RE RANDOMIZED ON THE WAY IN. AND THEN IF THEY'RE RANDOMIZED TO ECMO, THEN THEY'RE APPROACHED FOR CONSENT, AND IF THEY SAY YES, THEY GET IT, IF THEY SAY NO, THEY GET CONVENTIONAL THERAPY. IF THEY'RE RANDOMIZED TO CONVENTIONAL THERAPY, THEY GO TO THE SEVENTH FLOOR AND GET CONVENTIONAL THERAPY. NOW, THERE WERE 29 BABIES THAT WENT ON THIS PATHWAY. SO ASK YOURSELF IN YOUR HEAD, I WON'T ASK YOU TO RAISE YOUR HANDS OR ANYTHING, HOW MANY OF YOU THINK THEY SAID YES TO ECMO? THE ANSWER WAS, ALL 29 SAID YES TO ECMO. THAT'S A LITTLE ODD, ISN'T IT? WE NORMALLY DON'T EXPECT 100% ENROLLMENT IN OUR CLINICAL TRIAL, BUT I THINK IT SHOWS ONE OF THE FEATURES OF THIS DESIGN IS THAT IT CHANGES THE NATURE OF THE CONVERSATION THAT YOU HAVE HERE. IF NOT, WOULD YOU BE WILLING TO HAVE US FLIP A COIN TO DETERMINE WHAT KIND OF TREATMENT YOU'RE GOING TO GET? IT'S A LITTLE BIT LIKE THIS IS YOUR LUCKY DAY. WE ALREADY KNOW YOU CAN HAVE ECMO IF YOU WANT IT. ALL YOU HAVE TO DO IS SAY YES. SO WHEN PRESENTED WITH THE CHOICE IN THAT WAY, 100%, ALL 29 OF THE PARENTS, SAID YES TO ECMO. DID YOU HAVE A QUESTION? REAL QUICKLY, RUN DOWN TO THE MICROPHONE, THOUGH, PLEASE. >> WHAT WAS THE CONTENT OF THAT CONSENT? WERE THEY TOLD THAT ANOTHER GROUP HAD BEEN RANDOMIZED BUT THEY WEREN'T BEING ASKED? >> I WOULD SAY THAT THE CONSENT FORM LOOKED IDENTICAL TO WHAT YOU WOULD HAVE SEEN WITH TRADITIONAL CONSENT. I'M ONLY IMPLYING THAT I THINK THAT THERE -- I WAS A FELLOW, I WASN'T INVOLVED IN THOSE CONVERSATIONS, MY ATTENDINGS WERE. BUT I SUSPECT THAT THERE WAS A CHANGE IN TONE. THAT'S ALL I CAN SAY, AND I DON'T WANT TO SAY THAT THERE WAS ANYTHING UNETHICAL THAT WENT ON, I THINK IT'S JUST HUMAN NATURE, THAT KNOWING HOW THE RANDOMIZATION CAME OUT IS GOING TO AFFECT THE WAY THAT YOU TALK ABOUT IT WITH THE FAMILY, AND I THINK THE EVIDENCE FOR THAT WAS 100% ENROLLMENT. ALL RIGHT. NOW IMAGINE YOU WERE ON THE IRB AT BOSTON CHILDREN'S HOSPITAL WHEN THIS STUDY WAS PERFORMED. WOULD YOU HAVE APPROVED THIS ZELEN RANDOMIZATION SCHEME, WHY OR WHY NOT? HOW MANY OF YOU ARE GOING IT TO APPROVE THIS STUDY DESIGN? I'M SEEING MAYBE A HALF. HOW MANY WOULD SAY, NO, THERE'S AN ETHICAL PROBLEM HERE? I'M SEEING MAYBE A LITTLE LESS THAN HALF. CAN WE TAKE ONE MORE MINUTE JUST TO HAVE A VOICE FROM EACH SIDE? WOULD SOMEBODY BE WILLING TO SAY WHY THIS IS UNETHICAL? >> I AM NOT SURE IF IT'S ETHICAL NOT TO SEEK CONSENT OF INFORMED PEOPLE, THE GROUP OF PARENTS, ABOUT -- INTERVENTION AND GIVE THEM THE OPTION TO DECIDE THAT -- THAT'S MY MAIN PROBLEM. >> SO A LOT OF PEOPLE SAY YOU'RE DOING RESEARCH ON PEOPLE WITHOUT THEIR CONSENT, RIGHT? SOMEBODY WHO THINKS THIS IS AN ACCEPTABLE STRATEGY, WOULD YOU -- PLEASE. >> I GUESS I WOULD TEND TO THINK THAT THE -- YOU KNOW, IF THE PATIENT HAS REASON TO CARE ABOUT IS WHAT KIND OF TREATMENT THEY'RE GOING TO GET, AND WHETHER OR NOT SOMEBODY ELSE IS OR ISN'T GOING TO GET A KIND OF TREATMENT DOESN'T REALLY MAKE A DIFFERENCE TO THE SORT OF REASONABLE INTEREST THAT THEY HAVE AT STAKE IN THE CASE. >> ALL RIGHT. GOOD. THANK YOU. YOU KNOW, I THINK -- LET ME JUST GIVE A LITTLE MORE TO SAY ABOUT WHY THIS MIGHT BE ETHICAL. THESE BABIES ARE GETTING EXACTLY, EXACTLY THE SAME CARE THAT THEY WOULD HAVE GOTTEN IF THERE HAD BEEN NO STUDY. IF THERE WAS NO STUDY, THEY GO TO THE NICU, THEY GET CONVENTIONAL TREATMENT. SO THEIR TREATMENT IS NOT BEING ALTERED IN ANY WAY. LET ME COME BACK TO THAT IN A MOAM. MOMENT. [INAUDIBLE] >> NO, THERE WAS NOT. SO THE ONLY THING THAT WAS DONE HERE WAS THAT INFORMATION WAS TAKEN FROM THEIR CHARTS, PARTICULARLY WHETHER THEY LIVED OR DIED, AND AS YOU KNOW, YOU COULD DO THIS AS A CHART REVIEW WITHOUT THE INFORMED CONSENT OF THE FAMILY. SO IN THAT SENSE, IT FITS VERY WELL WITH OUR TRADITIONAL RULES THAT YOU'RE NOT GOING TO EVOLVE CARE, THE INFORMATION YOU'RE GOING TO GET IS HIPPA-COMPLIANT. IN TERMS OF TELLING THE PARENTS, MANL WHAIMAGINE WHAT THIS CONVERSATION MIGHT HAVE LOOKED LIKE, IT WOULD HAVE BEEN SOMETHING ALONG THE LINES OF I HAVE SOMETHING I NEED TO TELL YOU, WE'RE DOING THIS STUDY OF ECMO AT THE HOSPITAL HERE WITH BABIES WITH YOUR CONDITION. SOME PEOPLE THINK IT WILL WORK, SOME PEOPLE THINK IT WON'T BUT IT DOESN'T REALLY MATTER BECAUSE WE'VE ALREADY DECIDED THAT YOU CAN'T HAVE IT. YOU CAN ASK FOR IT OR DO WHATEVER YOU WANT BUT YOU CAN'T HAVE IT, BUT I JUST THOUGHT I WOULD TELL YOU THAT. PEOPLE FELT THAT THAT WOULD JUST BE A MEANINGLESS AND CRUEL CONVERSATION. SO THAT WAS ONE OF THE OTHER REASONS, AND INDEED, THERE WAS DISCUSSION THAT WHAT IF ONE OF THE KENNEDY BABIES SHOULD SHOW UP AT THE HOSPITAL, YOU KNOW, THE VIEW WAS THEY WOULD BE RANDOMIZED LIKE EVERYBODY ELSE. THIS WAS NOT GOING TO BE ANY FAVORITISM. ONE MORE COMMENT FROM THE BACK THERE. NAID NAW[INAUDIBLE] >> I'M SO GLAD YOU MENTIONED THAT BECAUSE IT'S A POINT THAT I FORGOT TO MENTION MYSELF. THANK YOU. SO THE QUESTION WAS, LISTEN, WE HAD THIS HISTORIC -- IF I UNDERSTOOD YOU CORRECTLY, WE HAD THIS HISTORICAL DATA FROM RIGHT BEFORE WE STARTED THE STUDY, AND WE KNEW THAT THE MORTALITY OF BABIES WHO MET THESE CRITERIA WAS 85%. SO WHY COULDN'T WE HAVE USED THIS RECENT HISTORICAL DATA FROM OUR OWN HOSPITAL AND THEN DONE THE COMPARISON TO THE ECMO GROUP GROUP? SO THE MORTALITY WE WOULD HAVE PREDICTED IN THE CONTROL GROUP WAS 80%. DO YOU RECALL FROM THE RESULTS WHAT THE MORTALITY WAS THAT WE ACTUALLY SAW? 40%. 40%. NOW, IT'S ONLY 10 PATIENTS. I DON'T KNOW THAT OVER THE LONG HAUL, IT WOULD HAVE BEEN 80%. OR 85%. BUT IT IS INTERESTING, ISN'T IT? IT SHOWS THAT EVEN HISTORICAL DATA FROM THE SAME INSTITUTION AS RECENT AS YOU CAN POSSIBLY GET MAY NOT BE RELIABLE. THAT, I THINK, IS A PRETTY COMPELLING REASON WHY YOU NEED CONTEMPORANEOUS CONTROL GROUP GROUP. ONE MORE, THEN I'M GOING TO GO ON. [INAUDIBLE] >> UP THEIR GAME A LITTLE BIT, RIGHT. SO THE QUESTION HERE IS, MAYBE THE REASON WE SAW LOW MORTALITY WAS BECAUSE PEOPLE KNEW THEY WERE BEING WATCHED, THE HAWTHORNE EFFECT. OH, BOY, A TRIAL IS GOING ON HERE. I AGREE WITH YOU, I'M SURE THEY COME IN EVERY DAY TRYING THEIR HARDEST NO MATTER WHAT. BUT THERE IS A LITTLE MORE OF AN INCENTIVE AND THAT'S ACTUALLY KIND OF A GOOD THING. THEY'RE TRYING TO DO THE BEST THEY CAN. IF THAT EXPLAINS THE LOW MORTALITY RATE, THAT'S ALL THE MORE REASON WHY YOU'D NEED TO HAVE A CONTEMPORANEOUS CONTROL ARM. SO HOW DOES THIS WORK OUT? WHAT HAPPENED WAS, I'LL TELL YOU JUST BRIEFLY BECAUSE I REMEMBER IT SO WELL, I WAS HAVING BREAKFAST AT MY HOME ONE MORNING WITH MY WIFE AND MY LITTLE KIDS AT THE TIME, AND THERE IN THE "BOSTON GLOBE" WAS AN ARTICLE BY RICHARD KNOX, REPORTER FOR "THE BOSTON GLOBE," HE NOW REPORTS FOR NPR SO YOU'LL HEAR HIS REPORTS ON THE RADIO, AND HE TALKED ABOUT THE STUDY. I THOUGHT THIS WAS SO COOL, I WAS AWARE OF THE STUDY, INVOLVED IN THE STUDY, BUT APPARENTLY SOMEBODY CLIPPED THAT OUT OF THE NEWSPAPER AND THEY SENT IT TO THE NIH. THE NIH WAS APPALLED THAT RESEARCH WAS BEING DONE WITHOUT EXPLICIT INFORMED CONSENT, SO THEY WROTE A LETTER TO CHILDREN'S HOSPITAL SAYING CAN YOU PLEASE EXPLAIN HOW YOUR IRB APPROVED THIS STUDY? SO IRB GOT BACK TO THEM, SAYING, WELL, FIRST OF ALL THE CONTROL PATIENTS WERE NOT REALLY RESEARCH SUBJECTS. I THINK THIS IS PROBABLY THE BEST EXPLANATION. THAT THEY GOT THE SAME CARE THAT THEY WOULD HAVE GOTTEN REGARDLESS OF WHETHER A STUDY WAS GOING ON. SECONDLY THEY ARGUE THAT THE PARENTS OF THE CONTROL PATIENTS WERE NOT REALLY BEING OFFERED A CHOICE, AS I TRIED TO SAY WITH THAT MOCK CONVERSATION. THERE'S NO CHOICE HERE. SO WHY SUBJECT THEM TO THE STRESS OF KNOWING THAT THEIR BABY DID NOT GET THE THERAPY, AND FINALLY, THAT THE PRESSURE IT TO CROSS OVER FROM CONVENTIONAL THERAPY TO ECMO WOULD HAVE BEEN UNBEARABLE, THAT IF BABIES WERE DYING AND THE PARENTS KNEW IT AND KNEW THAT AN ALTERNATIVE TREATMENT WAS AVAILABLE, THEY WOULD HAVE PRESSURED TO GO ON TO ECMO LATE IN THE GAME WHERE IT REALLY PROBABLY WOULDN'T HAVE BEEN A GOOD IDEA. SOMEBODY ASKED ABOUT WHETHER ANY OF THE PARENTS IN THE CONTROL GROUP WERE AWARE THAT THEY WERE IN THE CONTROL GROUP, WHEN THE ARTICLE WAS PUBLISHED IN THE GROAB, I WAGLOBE, I WAS SURE THIS WAS GOIN G TO COME OUT THAT SOMEBODY WAS GOING TO READ ABOUT THE STUDY AND SAY, OH, GEE, OUR BABY WAS AT CHILDREN'S DURING THAT TIME AND HAD THIS DISEASE AND WE DIDN'T GET ECMO. I'VE OFTEN WONDERED ABOUT THAT. TO MY KNOWLEDGE, NO PARENT HAS EVER COME FORWARD AND SAID WE WERE IN THE CONTROL GROUP, WHY DIDN'T SOMEBODY ASK OUR CONSENT. BUT I THINK IT DOES SPEAK A LITTLE BIT TO THE PROBLEMS WITH TRANSPARENCY AROUND THIS DESIGN. SO THE CHILDREN'S IRB GOT BACK TO THE NIH AND THE RESPONSE WAS NOT VERY POSITIVE. THE OFFICE FOR PROTECTION FROM RESEARCH RISKS REPRIMANDED THE HOSPITAL. CHARLES MCCARTHY, DIRECTOR OF OPR AT THAT TIME, SAID THE HOSPITAL IRB MADE DECISIONS THAT RIGHTFULLY BELONG TO THE PARENTS, THEY REALLY BLEW IT. I'M NOT REALLY SURE I UNDERSTAND THIS, TO BE HONEST WITH YOU, I'M NOT SURE WHAT DECISIONS THE PARENTS COULD HAVE MADE THAT BELONGED TO THEM. I MEAN, THEY COULD HAVE SAID WE DON'T WANT TO BE IN A TRIAL BUT THEY WOULD HAVE GOTTEN EXACTLY THE SAME CONVENTIONAL THERAPY THAT THEY GOT. SO I'M NOT REALLY SURE WHAT HE'S REFERRING TO THERE. GEORGE AT BOSTON UNIVERSITY, HARSH, DOCTORS ARE DOING EXACTLY WHAT PHYSICIANS DID BEFORE WE HAD A DOCTRINE OF OF INFORMED CONSENT, MAKING DECISIONS FOR PARENTS. I AGAIN, I THINK THIS KIND OF MISSES THE MARK, ALTHOUGH I DO AGREE THAT THERE'S SOMETHING SORT OF SHADY HERE THAT RAISES CONCERNS. IN CLOSING, I JUST WANT TO SAY A FEW WORDS ABOUT THE REVERENCE THAT WE HAVE FOR RANDOMIZED CONTROL TRIAL. IF YOU THINK ABOUT HOW WE LEARN IN MEDICINE, THERE'S A GRADATION OF EVIDENCE. DOWN HERE WAS ANECDOTAL CASE REPORTS, VARIOUS KINDS OF CASE SERIES, GOING UP TO THE RANDOMIZED CONTROL TRIAL WHICH ACTUALLY IS NOT EVEN AT THE TOP OF THE PILE. WE DO METAANALYSES OF MULTIPLE RCTs. NOW ALL OF THESE ARE WAYS OF LEARNING, WE CAN LEARN FROM ALL OF THESE. WHAT MAKES THEM DIFFERENT IS THAT WE HAVE DIFFERENT DEGREES OF COMPETENCE. IN THE INFORMATION THAT THEY CONTAIN. BUT THERE'S BEEN SOME CONCERN THAT WE HAVE AN IRRATIONAL REVERENCE FOR THE RCT. SO A COUPLE COMMENTS, THE BRILLIANCE HAS BECOME A FORM OF INTELLECTUAL TYRANNY. INDEED THERE HAVE BEEN A NUMBER OF ARTICLES LIKE THIS ONE IN THE NEW ENGLAND JOURNAL THAT LOOKED AT CAREFULLY CONDUCTED OBSERVATIONAL STUDIES AND RANDOMIZED CONTROL TRIALS, AND SAID THAT 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 RANDOMIZED CONTROLLED TRIALS. INDEED AT THE TIME OF THE ECMO TRIALS, WE DID HAVE AN ECMO DATABASE. THERE WERE NO CONTROL PATIENTS IN THIS DATABASE, IT WAS JUST ECMO PATIENTS, AND 715 OF THEM, THE PATIENTS HAD AN 81% SURVIVAL OVERALL, AND IF YOU DID THE MATH, IT WOULD HAVE MEANT THAT ECMO WAS STATISTICALLY SUPERIOR TO ANY OTHER TREATMENT WITH THE SURVIVAL RATE THAT WAS LESS THAN 78%. SO AGAIN THERE'S NO CONTROLS HERE SO YOU CAN'T DRAW ANY FIRM CONCLUSIONS BUT I THINK PEOPLE AT THE TIME WOULD HAVE LOOKED AT THESE DATA AND SAID IT'S REALLY UNLIKELY THAT WHAT WE'RE CURRENTLY DOING COME CLOSE TO A SURVIVAL RATE OF 78% FOR THIS COHORT. SOME PEOPLE WOULD HAVE ARGUED THAT THIS DATABASE SHOULD HAVE BEEN SUFFICIENT. THAT THE OTHER TRIALS WERE NOT NECESSARY. BUT LET ME JUST ASK YOU A QUICK SHOW OF HANDS, GIVEN ALL YOU'VE SEEN, THE DATABASE, BARTLETT STUDY, HARVARD STUDY, IS THERE ANYONE THAT STILL WOULD HARBOR DOUBTS THAT ECMO IS A SUPERIOR THERAPY TO CONVENTIONAL THERAPY? SO SEEING NO HAND, I WILL GO ON BECAUSE IT WAS RELEVANT ACTUALLY IN THE UNITED KINGDOM. IN THE MID 1990s, THE UNITED KINGDOM WAS CONSIDERING STARTING ECMO PROGRAMS. THEY LOOKED AT THE ECMO DATABASE WHICH BY NOW WAS LARGER, THEY LOOKED AT THE BARTLETT TRIAL, THEY LOOKED AT THE HARVARD TRIAL AND THEY SAID, NOT GOOD ENOUGH. NOT SUFFICIENT EVIDENCE. WE NEED TO DO OUR OWN RCT. THEY SAID THAT THE EXISTING RCTs OF NEONATAL ECMO SUGGESTED REDUCTIONS OF NEONATAL MORTALITY BUT ARE NOT CONCLUSIVE BECAUSE THEY USED -- THEY COULDN'T QUITE BITE THE BULLET, SO WE'RE GOING TO DO A GOOD TRIAL. SO BETWEEN 93 AND 95, THEY INVOLVED -- THE TRIAL WAS STOPPED EARLY BY THE DSMB WITH THE SURVIVAL DIFFERENCES THAT YOU SEE THERE, P .0005. NOW THEY PUBLISHED THIS AS A SUCCESS. MY COLLEAGUE JOHN LANTOS WROTE A VERY CRITICAL ARTICLE IN THE LANCET SAYING YOU SHOULD HAVE BEEN CONVINCED BY THE AVAILABLE EVIDENCE, THIS TRIAL DID NOT NEED TO BE DO DONE AND THERE WERE 22 BABIES THAT DIED THAT DID NOT NEED TO DIE. SO I'LL LEAVE IT TO YOU, WHETHER YOU BELIEVE THE EVIDENCE THAT PRECEDED THIS WAS CONVINCING OR NOT, I'LL LEAVE TO YOU. BUT I DO THINK THIS TRIAL WAS ETHICALLY PROBLEMATIC. MY CONCLUSIONS HERE WOULD BE THAT RCTs ARE USUALLY THE BEST APPROACH FOR EVALUATING NEW THERAPIES. I DON'T WANT YOU TO LEAVE HERE SAYING THAT I THINK WE SHOULD ABANDON THE RCT, AS I THINK SOME PEOPLE DO SOMETIMES. I'M NOT SAYING THAT AT ALL. BUT I DO THINK THAT WE NEED TO CONSIDER ALTERNATIVES WHEN THEY'RE APPROPRIATE, THAT THE CONFLICT BETWEEN CL NICHE AND INVESTIGATOR IS PROFOUND AND CAN NEVER BE ENTIRELY ELIMINATED THAT, ADAPTIVE RANDOMIZATION IS ONE WAY TO BALANCE COMPETING OBLIGATIONS, INCREASINGLY POPULAR, THAT ZELEN RANDOMIZATION REDUCES PSYCHOLOGICAL BURDENS OF THE INVESTIGATORS BUT IS PROBABLY UNACCEPTABLE. I THINK THE ZELEN APPROACH WILL NOT BE LOOKED ON KINDLY BY THE NIH, ALTHOUGH WE COULD DEBATE THE ETHICS OF IT HERE. SO I'LL CLOSE WITH A COMMENT FROM BENJAMIN FRIEDMAN, THE CANADIAN BIOETHICIST AGAIN WHO GAVE US THE CONCEPT OF CLINICAL EQUIPOISE, PASSED AWAY UNFORTUNATELY AT A VERY EARLY AGE. HE WROTE THAT THE USE OF STATISTICS IN MEDICAL RESEARCH HAS BEEN COMPARED TO A RELIGION, IT HAS ITS HIGH PRIEST, THE STATISTICIANS, ITS SUM CAN'TS, THE JOURNAL EDITORS AND RESEARCHERS, AND IT'S OR DOCKS EE THAT P LESS THAN .05 IS SIGNIFICANT. I FINK THIS HE WERE ALIVE TODAY, HE WOULD ALSO WARN US NOT TO FOLLOW THE ADVICE OF THOSE WHO TELL US TO NEVER, THINK OUTSIDE OF THE BOX. SO WITH THAT, I'LL CLOSE. I DON'T KNOW WHERE WE'RE AT FOR TIME, IF WE HAVE TIME FOR A QUESTION OR TWO OR NOT. COMMENTS? THANK YOU VERY MUCH. [APPLAUSE] >> WE HAVE TIME FOR QUESTIONS. >> OKAY. >> GREAT TALK. I WAS A NEONATAL NURSE DURING 1985 AND 1992, AND THE REALLY BAD MECONIUM ASPIRATION BABIES, WE STABILIZED THEM, TRANSFERRED THEM TO THE LEVEL 3 AND THEY WENT ON ECMO. AND SO I HAVE A PROBLEM WITH THE RANDOMIZATION TO CONSENT BECAUSE MAYBE THOSE PARENTS COULD HAVE BEEN TOLD ANOTHER HOSPITAL DOWN THE ROAD IS DOING ECMO, AND THEY WEREN'T TOLD THAT. >> RIGHT. SO THAT'S A REALLY GOOD POINT. THE NEAREST OTHER CENTER THAT WAS DOING ECMO AT THIS TIME WAS IN PHILADELPHIA. THE VIEW WAS THAT THESE BABIES WOULD BE TOO SICK FOR TRANSPORT, THAT EVEN IF WE WEREN'T DOING ECMO, THAT WE WOULDN'T BE TRANSPORTING BABIES TO PHILADELPHIA TO GET ECMO. IT WOULD HAVE INTRODUCED TOO MUCH RISK. >> ONE MORE QUESTION. AND AGAIN, I DON'T KNOW THE TRIAL DESIGN, BUT IT SEEMS LIKE NOW, IF THE TRIAL WERE BEING DONE, MAYBE THERE WOULD BE A RESCUE POINT? >> THEY EXPLICITLY DID NOT WANT TO HAVE RESCUE BECAUSE THE CONCERN WAS THAT RESCUE WOULD OCCUR AFTER THESE BABIES WERE ALREADY IRREVERSIBLY ILL. NOW YOU'RE PUTTING BABIES ON ECMO WHO WEREN'T GOING TO SURVIVE EITHER WAY, AND YOU'D BE DOING A DISSERVICE TO THE CHILD AS WELL AS TO THE STUDY. >> I WAS WONDERING IF YOU COULD SPEAK BRIEFLY ABOUT WHAT SOME OF THE U.K. COLLABORATORS, WHAT ARE SOME OF THE BIAS THEY WERE CONCERNED ABOUT WITH THE ADAPTIVE DESIGN? >> I CAN'T, ALL I CAN TELL YOU IS WHAT THEY PUT IN THE INTRODUCTION TO THEIR STUDY, WHICH IS WHY THEY FELT A TRADITIONAL RCT NEEDED TO BE DONE. I THINK THAT ADAPTIVE DESIGN THE HAVE JUST NOT BEEN TRUSTED. PART OF IT HAS TO DO, YOU SAW, WITH THE COMPLICATED STATISTICS. YOU'RE NOT LOOKING AT STRAIGHTFORWARD STATISTICAL ANALYSIS. BUT WHETHER THAT'S A SUFFICIENT REASON TO SAY YOU'RE NOT GOING TO TRUST THE RESULT, I DON'T KNOW. >> THANKS FOR THIS, IT WAS A VERY INTERESTING TALK. I WAS ACTUALLY REALLY SHOCKED WHEN YOU PUT UP THE DATABASE SLIDE AT THE VERY END, WHAT WAS IT, SOMETHING LIKE 180-SOME NEONATES HAD ALREADY GONE ON ECMO BEFORE THE HARVARD TRIAL STARTED. IS THAT TRUE? >> NO, THAT'S NOT EXACTLY TRUE. THE DATABASE WAS SMALLER AT THE TIME THE HARVARD TRIAL WAS STARTED. WHAT I SHOWED YOU WERE THE NUMBERS IN THE DATABASE AT THE TIME IT WAS PUBLISHED, WHICH WAS SOMETIME AFTER. YOUR POINT IS VERY WELL TAKEN, AND I SHOULDN'T IMPLY THAT EVERYBODY HAD ACCESS TO THOSE NUMBERS IN THE DATABASE. THAT WAS ACCUMULATING DURING THE TIME, I THINK AT THE IT TIME OF THE HARVARD TRIAL, THERE MAYBE WOULD HAVE BEEN A COUPLE HUNDRED BABIES AT MOST. I DON'T KNOW WHAT THE NUMBERS WERE. >> I GUESS MY QUESTION, THOUGH, STILL STANDS WHICH IS, I WOULD BE REALLY INTERESTED IN HEARING YOUR COMMENT ON THE ROLE OF ANECDOTAL EVIDENCE AND WHEN WH IT ACTUALLY BECOMES SORT OF UNETHICAL TO NOT HAVE DONE A TRIAL AND WHEN YOU'RE JUST PUTTING PEOPLE ON THIS NEW THERAPY SORT OF ANECDOTALLY, THEN I THINK YOU END UP IN THE SITUATION WHERE YOU GET RESULTS THAT ARE VERY CONVINCING AND NO ONE HAS NEVER DONE A TRIAL SO YOU'RE IN AN ETHICAL BIND. >> THAT IS A GREAT QUESTION, THAT IS A HUGE DILEMMA. DON CHALMERS IS A STATISTICIAN, HAS WRITTEN ARTICLES CALLED "RANDOMIZE THE FIRST PATIENT," SPECIFICALLY TO TRY TO AVOID THAT. IN OTHER WORDS, YOU GOT A NEW THERAPY, RANDOMIZE THE FIRST PATIENT. I THINK THAT'S RATHER NAIVE. I THINK THAT MOST THERAPIES HAVE TO GO THROUGH A CERTAIN PROCESS OF DEVELOPMENT IN ORDER TO GET REASONABLY CLEAR ABOUT HOW TO DO THEM, BUT I WOULD COMPLETELY AGREE WITH YOU THAT ONCE WE'RE THERE, THAT'S WHERE WE NEED TO START THE RANDOMIZED TRIAL, BECAUSE SEVERAL HUNDRED PATIENTS INTO IT, IT'S MUCH MORE DIFFICULT. AND, YOU KNOW, WE COULD GIVE COUNTLESS EXAMPLES OF WHERE THAT HAS HAPPENED IN AMERICAN MEDICINE. THANK YOU. >> IN RANDOMIZED TRIALS, IF YOU WAIT TO RANDOMIZE PEOPLE AFTER THE CONSENTING, THE PEOPLE WHO ARE NOT OPTING IN TO THE TRIAL, THEN HAVE YOU SEEN ANY GOOD METHODS THAT WOULD ENABLE YOU TO COMPARE SOMETHING FROM THE PEOPLE WHO ARE DECLINING VERSUS THE PEOPLE WHO ARE INCLUDED THAT GIVE YOU ANY KIND OF INFORMATION INFORMATION? >> YOU MEAN IN THAT BOTTOM ARM THERE WHERE EVERYBODY WAS SAYING YES? >> RIGHT. WELL, YEAH, IF YOU WAITED TO RANDOMIZE AFTER THE CONSENTING, SO YOU HAVE PEOPLE WHO SAY -- >> OH, THE TRADITIONAL APPROACH. >> YES. >> OKAY. SORRY. >> SO THE NO'S, YOU KNOW, YOU DON'T HAVE PROBABLY TOO MUCH MEDICAL INFORMATION BECAUSE THEY'RE NOT CONSENTING, RIGHT? >> YEAH. >> IS THERE ANYTHING YOU COULD DO TO TRY TO PULL IN ANY INFORMATION FROM THEM, LIKE A SECOND ROUND OF THIS IS A LIMITED THING, WE JUST WANT TO COMPARE YOU TO THE OTHER GROUP? HAVE YOU SEEN ANY COMPARISON YOU CAN DO? >> NOT OFF THE TOP OF MY HEAD. CHRISTINE, MAYBE YOU HAVE -- LOOKING AT PEOPLE WHO DON'T CONSENT AND -- I DON'T KNOW. ALL RIGHT. >> I JUST WANTED TO TRY TO TIE TOGETHER CHRISTINE'S TALK ON INFORMED CONSENT AND YOUR TALK. WONDERFUL TALKS, BOTH OF YOU, THANK YOU. THE 100% OF PARENTS WHO AGREED TO THIS STUDY, OF COURSE THEY WOULD, BUT WERE THEY UNDER SOME SORT OF DURESS? I IMAGINE YOU SAID THEIR CONSENT WAS TAKEN, THEY'RE IN THE BACK OF AN AMBULANCE, THERE ARE SIRENS, THEY HAVE A SICK BABYSITTING IN FRONT OF THEM, AND HOW MUCH OF THE CONSENT WAS IN THE FORM OF DO WHATEVER IT TAKES TO MAKE MY BABY BETTER, AND DOES THAT COMPROMISE ANYTHING? I THINK OF IN THE SUPPORT TRIAL, WHICH RECENTLY THE TOWN HALL ON THE SUPPORT TRIAL, ONE MOTHER SHARED THE STORY ABOUT HOW WHEN SHE HEARD THE ACRONYM "SUPPORT," SHE THOUGHT, OH, WELL, THIS IS GOING TO BE WONDERFUL, THEY'RE GOING TO HAVE THIS FOLLOW-UP AND HELP ME TAKE CARE OF MY SICK BABY AND -- I MEAN, YOU KNOW, THE NAME "SUPPORT," THAT'S SO CARING AND WONDERFUL AND LOVING, AND COMPLETELY MISSED THE POINT. SO HOW MUCH OF THAT SORT OF BIAS IS IN THIS SORT OF CONSENT-TAKING SITUATION? >> YEAH. GREAT POINT. JUST TO CLARIFY, THOUGH, THE CONSENT WASN'T OBTAINED IN THE AMBULANCE. IT WAS AFTER THEY ARRIVED IN THE ICU. >> OKAY. THANK YOU. A VERY CALMING ENVIRONMENT, I'M SURE. >> WE ALL SUFFER -- YOUR BABY IS REALLY SICK, OUR DATA SHOWS 85% CHANCE OF DYING. 85% CHANCE OF DYING. WE DO HAVE THIS PROMISING NEW THERAPY AND WE KNOW YOU CAN HAVE IT. IT'S NOT SURPRISING THAT PARENTS RESPOND, GEE, OF COURSE. OF COURSE. THEY DON'T IMMEDIATELY THINK ABOUT THE POTENTIAL RISKS. SO I THINK THAT THAT BIAS IS THERE. I DON'T THINK YOU CAN CAN GET RID OF IT. BUT THANK YOU VERY MUCH. CHRISTINE, THANK YOU. >> ROUND OF APPLAUSE. >> OH, THANK YOU. [APPLAUSE] >> WONDERFUL AS USUAL. WE'RE GOING TO TAKE A BREAK. AFTER THE BREAK WE HAVE A PANEL OF PARTICIPANTS AND INVESTIGATOR AND THE PATIENT REP, SO PLEASE COME BACK AT 10:35. >> I THINK WE'LL BEGIN. IF ANYBODY'S OUTSIDE, COME BACK IN. WE'RE GOING TO START THE PANEL. SO EVERY YEAR THAT WE'VE HAD THIS COURSE, WE'VE HAD A PANEL OF PEOPLE WHO PARTICIPATE IN RESEARCH, AND IN THE LAST COUPLE OF YEARS, I'VE HAD A PANEL OF INVESTIGATORS AS WELL. NOW THIS YEAR, SINCE OUR TIME GOT ALL SCREWED UP BECAUSE OF THE SHUTDOWN, I DECIDED TO HYBRIDIZE IT, SO TO SPEAK. SO WE HAVE THE HONOR OF, WITH US TODAY, A ANTOINETTE, A LONG TERM PARTICIPANT IN THE NIH, AND THE INVESTIGATOR WHO IS THE P.I. OF THE STUDY THAT ANTOINETTE IS ENROLLED IN, MIKE SNELLER, AND THEY'RE BOTH GOING TO TALK A LITTLE ABOUT THAT STUDY, ANTOINETTE IS GOING TO TALK ABOUT HER OWN EXPERIENCE, MIKE IS GOING TO TALK ABOUT THAT STUDY AND MAYBE CONTRAST IT WITH ANOTHER STUDY OR MORE THAN ONE THAT HE' HE'S DONE. BOTH OF THEM WITH THE IDEA THAT HERE'S THE SORT OF WAY THEY SEE THTHE ETHICS FROM THEIR PERSPECTIVE. THEN LAURA, PATIENT REPRESENTATIVE FOR THE INTRAMURAL PROGRAM WHO SEES LOTS OF PEOPLE ACROSS LOTS OF STUDIES, AND HER HEARS SOMETIMES THE COMPLAINT SIDE OF THINGS BUT FROM HER PERSPECTIVE OVER THE YEARS, SHE HAS SOME LESSONS TO SHARE WITH YOU AS WELL. SO WITH THAT, TO START, FIRST THEY'RE EACH GOING TO TALK FOR ABOUT FIVE OR 10 MINUTES, THEN YOU GUYS CAN ASK QUESTIONS AND IF YOU DON'T, I WILL, WE'RE GOING TO HAVE A CONVERSATION. SO ANTOINETTE, IF YOU WOULD LIKE TO BEGIN. >> THANK YOU, DR. GRADY, FOR INVITING ME TO PARTICIPATE AGAIN THIS YEAR. LIKE MANY PATIENTS THAT ARE SEEN HERE AT NIH, MY HEALTHCARE JOURNEY BEGAN ELSEWHERE. I'M NOT GOING TO DIVULGE ANY OF THE NAMES OF THOSE FACILITIES, BUT I WILL REFER TO TWO OF THEM AS HOSPITAL A AND B. WELL, SINCE CHILDHOOD, MY MAIN HEALTH PROBLEMS HAVE BEEN SEVERE ANEMIA, COUPLED WITH AN INABILITY TO GAIN WEIGHT, WHICH WAS LATER TERMED FOR MY CASE AS MALMALABABSORPTION SYNDROME. THESE PROBLEMS LED TO A NEED FOR MANY BLOOD TRANSFUSIONS, AND THEN LATER, TO OTHER CHRONIC HEALTH CONDITIONS. ONE IN PARTICULAR IS BEING DIAGNOSED HIV-POSITIVE. IT WAS FOR THAT MAJOR HEALTH COMPLICATION THAT HOSPITAL A WITH DESPERATELY TRYING TO GET ME TREATMENT THROUGH DRUG COMPANY TRIALS, BUT THEY WERE UNSUCCESSFUL TIME AND TIME AGAIN DUE TO MY SEVERE ANEMIA ANEMIA. IN THE MEANWHILE, I WAS GETTING WEAKER AND WEAKER. THESE PHYSICAL WEAKNESSES WERE FOLLOWED BY MANY HOSPITALIZATIONS. DURING ONE OF MY INPATIENT STAYS, THE GOOD LORD SENT ME AN ANGEL IN HUMAN FORM NAMED DR. LAURA O'BRIEN. AT THAT TIME, SHE WAS A CLINIC PHYSICIAN FELLOW FROM NIH OF THE NIAID DIVISION DURING HER CLINICAL ROTATION THERE AT HOSPITAL A. DR. O'BRIEN TOOK 30 MINUTES OUT OF HER VERY BUSY SCHEDULE TO TELL ME ABOUT NIH AND THEIR INVOLVEMENT IN CLINICAL TRIALS. BUT I SAID TO HER, TO BE PERFECTLY HONEST, I'M REALLY GETTING TIRED EMOTIONALLY AS WELL AS YOU CAN SEE PHYSICALLY OF GIVING SOME TUBES OF MY WELL-NEEDED BLOOD AWAY, AND THEN LATER DENIED PARTICIPATION IN TRIALS BY THE DRUG COMPANIES. SHE ASSURED ME THAT WOULD NOT BE THE CASE AT NIH. AFTER I WAS RELEASED, AN APPOINTMENT WAS MADE BY MY PRIMARY CARE PHYSICIAN AT HOSPITAL A TO BE SEEN HERE. THUS BEGAN A NEW JER KNEE FOR ME. IT WAS ON FEBRUARY 10TH OF 1999 AT 7:00 A.M. IN THE SKEPTICAL BY FOCUSING ON MY PREVIOUS EXPERIENCES, AND THE EXPECTATION HAD BEEN TURNED DOWN TO PARTICIPATE IN AN NIH CLINICAL TRIAL, BUT AT THE END OF MY APPOINTMENT THAT MORNING WITH MY NEW HEALTHCARE TEAM INCLUDING DR. ALICE POWELL, THE CLINIC PHARMACIST, THE NURSE SAID TO ME, YOU CAN GO TO THE OUTPATIENT PHARMACY AND PICK UP YOUR MEDICATION. I WAS AMAZED AND EXTREMELY SHOCKED TO HEAR THAT. OH, AND BY THE WAY, MY FIRST PHYSICIAN FELLOW SEEN HERE AT NIH WAS DR. O'BRIEN. FOLLOWED BY MANY OTHER GREAT ONES LIKE DR. CARUSO AND PALMORE, JUST TO NAME A FEW. OF COURSE MY JOURNEY DIDN'T JUST STOP THERE AT THAT POINT. BECAUSE I'VE HAD MANY OTHER HOSPITALIZATIONS HERE AT NIH AND OTHER HOSPITALS THAT ARE LOCAL SINCE FEBRUARY OF 1999. HERE IS AN INCIDENT THAT I WOULD LOVE TO SHARE WITH YOU. IT WAS LATER THAT YEAR IN DECEMBER OF 1999 I BEGAN HAVING BACK PAINS. SO I WENT TO THE EMERGENCY ROOM AND A FACILITY CLOSE TO MY HOME REFERRED TO AS HOSPITAL B. AFTER THE DOCTORS THOUGHT MY PROBLEM WAS UNDER CONTROL, I WAS DISCHARGED FROM THEIR E.R. THEN THE NEXT DAY I ENDED UP BACK IN THE EMERGENCY ROOM, BUT THIS TIME RETURNED TO HOSPITAL A, SCREAMING AT THE TOP OF MY LUNGS IN EXCRUCIATING PAIN. THAT E.R. VISIT RESULTED IN A 2 1/2 WEEK COMA COUPLED WITH A 2 1/2 MONTH INPATIENT STAY FOR ME. WHILE IN THERE, I RECALL AT LEAST TWO OCCASIONS A THAT THE HEALTHCARE TEAM MEMBERS AT HOSPITAL A WOULD VERBALIZE IN MY MY COMA TOES PRESENCE THAT I WAS BRAIN DAMAGED AND A QUADRIPLEGIC TO MY LOVED ONES IN THE HOSPITAL ROOM WHEN THEY ASKED HOW I WAS DOING. IT WAS UNKNOWN TO THAT HEALTHCARE TEAM THAT ALTHOUGH MY EYES WERE CLOSED, I WAS ABLE TO SOAK UP MY SURROUNDINGS LIKE A SPONG. AS YOU CAN SEE, I DID WAKE UP OUT OF THAT COMA. BUT MY LEFT ELBOW WAS CONTRACTED, I HAD AN INABILITY TO MOVE, WALK, TALK, OR EAT, PLUS I HAD MANY TUBES ATTACHED TO ME, AND A TRACH IN PLACE. IT WAS DURING MY LAST GRAND ROUNDS FROM DOCTORS AT HOSPITAL A, I WAS ABLE TO ASK QUESTIONS WITH MY FINGER ON MY TRACH AND ONE WAS, WHAT CAUSED ME TO GO INTO THAT COMA? THE DOCTORS WERE STILL A BIT CLUELESS BUT DID ADMIT THAT SOON AFTER GIVING ME ONE OF MANY MEDICATIONS IN THEIR E.R., I HAD A REACTION. MY DISCHARGE SUMMARY FROM HOSPITAL A STATES SPINAL MENINGITIS/ENCEPHALITIS OF UNKNOWN ORIGIN. OF COURSE WHEN I ASKED FOR MORE DOCUMENTATION REGARDING THE MEDICATION, THE STORY HAD CHANGED MAJORLY OVER TIME. AND I TRULY EXPECTED THAT TO BE THE CASE. I THOUGHT I WAS GOING TO BE SENT TO A REHAB FACILITY OR HOME UPON RELEASE FROM THAT LONG HOSPITAL STAY AT HOSPITAL A. HOWEVER, I WAS PLACED PER MY TEAM'S REQUEST IN A HOSPICE FACILITY. WHILE AT HOSPICE, I WAS STILL RECEIVING MY MEDICAL CARE FROM HOSPITAL A, ALTHOUGH MY MOTHER AND MY FRIEND MR. LARRY HOLMAN WERE VISITING ME THERE, THEY WERE NOT AT EASE WITH MY PROGRESS. OF COURSE THERE WAS NOT GOING TO BE ANY PROGRESS BECAUSE I WAS IN HOSPICE. AND THEN IT REALLY OCCURRED TO ME AND IT REALLY GOT ME INTO WHAT THEY CALL SURVIVE MODE, THAT MY MOTHER WAS APPROACHING HER 70s AT THAT TIME, AND WOULD EVENTUALLY NEED MORE OF MY ASSISTANCE. PLUS I WAS NOT GETTING STRONGER BUT WEAKER JUST BY LAYING IN THE BED AND NOT BEING PROVIDED IN ANY EXERCISES. SO AFTER TWO WEEKS OF BEING IN THE HOSPICE, I CALLED MY MOTHER AND FRIEND LARRY AND REQUESTED THEY TAKE ME HOME. WITHIN TWO HOURS, THEY WERE THERE, GATHERED MY ITEMS, AND WE LEFT AMA AGAINST MEDICAL ADVICE. FOR A SHORT PERIOD OF TIME WHILE I WAS STILL UNDER THE CARE OF HOSPITAL A, IN MY OPINION, I WAS STILL TAKING TOO MANY UNNECESSARY MEDICATIONS, SO I CONTACTED MY NURSE CASE MANAGER, PAMELA STALL, AND SAID I WOULD LIKE TO HAVE MY CARE CONTINUED AT NIH. SHE MENTIONED MY REQUEST TO DR. JOANNE MIKENS, THE PRINCIPAL INVESTIGATOR AT THAT TIME, AND WITHOUT A BEAT, AN APPOINTMENT WAS SET. I WAS AGAIN UNDER THE EXCELLENT CARE OF MY HEALTHCARE TEAM AND PHYSICIAN FELLOW DR. O'BRIEN. SHE REVIEWED ALL OF MY MEDICATIONS FROM THE INPATIENT STAY AT HOSPITAL A AND SAID SHE COULD NOT BELIEVE WHY THEY WERE STILL PRESCRIBING HOW MANY OF THEM TO ME. SO DR. O'BRIEN HAS SCALED BACK MY MEDICATION FROM 15 DIFFERENT MEDICATIONS TO JUST FIVE OF THE ONES THAT WERE ABC LOWTLY NEEDED FOR MY CONDITION. PLUS SHE HAD THAT FEEDING TUBE REMOVED FROM ME. ALSO SOMETHING ELSE THAT HAS CHANGED OVER THE YEARS JUS BEING BACK UNDER THE CARE OF AN EXCELLENT TEAM HERE AT NIH, MY PROGNOSIS WENT FROM QUADRIPLEGIC TO PARAPLE PARAPLEGIC, AND NOW JUST SPASTIC PARAPERESIS. I AM CURRENTLY RECEIVING ACUPUNCTURE AND PHYSICAL THERAPY HERE AS WELL. BOTH OF THOSE DISCIPLINES HAVE ASSISTED ME IN BEING PRODUCTIVE IN MOVING MY LEGS, STANDING, AND THE ABILITY TO TAKE A FEW STEPS IN A PARALLEL BAR OR WITH A WALKER. FURTHERMORE, MY COUNT IS NOW 562 WITH A -- OF LESS THAN 40. I DID HAVE THE HONOR TO SERVE AS MY MOTHER, MRS. HADDY BOYS IS E'S CAREGIVER UNTIL HER DEATH OF HEART FAILURE ON APRIL 15TH OF THIS YEAR. I ALSO WITNESSED HER ON MANY OCCASIONS BEING OF SERVICE TO OTHERS AS WELL. SHE WAS TRULY A BLESSING AND AN INSPIRATION IN MY LIFE. IT WAS JUST A FEW YEARS EARLIER THAT SHE ENCOURAGED ME TO SERVE AS A COCAREGIVER ALONGSIDE HER TO PROVIDE QUALITY OF LIFE FOR HER LAST LIVING BROTHER, MR. ALBERT MOODY GLOVER, UNTIL HIS DEATH IN DECEMBER OF 1999. AS A RESULT OF THOSE EXPERIENCES, I AM CURRENTLY SERVING AS A CAREGIVER TO MY FRIEND, MR. LARRY HOLMAN, STEPPING UP TO THE PLATE JUST LIKE MY MOTHER WOULD HAVE DONE WITHOUT HESITATION. ALTHOUGH MR. HOLMAN IS NOT IN ATTENDANCE TODAY, HE HAS AUTHORIZED ME TO BRIEFLY JUST HIS RECENT EXPERIENCES HERE AT THIS FACILITY. HE WAS REFERRED TO NIH AND BEGAN HIS PARTNERSHIP IN RESEARCH ON SEPTEMBER 9TH OF THIS YEAR. HIS CLINIC COORDINATOR SAID TO HIM IF YOU DID NOT COME IN FOR TREATMENT TODAY, YOU WOULD HAVE DIED WITHIN THE NEXT SIX MONTHS. DUE TO THE CONDITION HE WAS IN, I THOUGHT TO MYSELF, I DON'T THINK HE WOULD LAST PAST OCTOBER OCTOBER 1ST. TO MAKE A LONG STORY VERY SHORT, A DIAGNOSIS WAS GIVEN FOR HIS DECLINE IN CONDITION, HE WAS TREATED WITH THE RIGHT COMBINATION OF MEDICATIONS AND VITAMINS. AS A RESULT, HE IS MAKING A TREMENDOUS RECOVERY IN A VERY, VERY SHORT PERIOD OF TIME. WITHOUT THE EXCELLENT TREATMENT BY THE NIH, HIS LIFE EXPECTANCY WAS GRIM, AS WAS MINE. AND BY THE WAY, LAST THURSDAY OCTOBER 24TH WAS HIS 54TH BIRTHDAY, SO HE DID MAKE IT PAST THAT OCTOBER 1ST DATE THAT I THOUGHT MAY HAVE BEEN THE END OF HIM. IN CLOSING, MY EXPERIENCES HERE HAVE PROVEN TO ME THAT IF YOU WANT TO REAP A GOOD MEDICAL HARVEST, NIH IS THE SOIL TO PLACE YOUR SEED -- TO PLANT YOUR SEEDS. YOU MAY BE TAKING THIS BIOETHICS COURSE BY FORCE OR BY CHOICE, BUT THE TAKE-HOME LESSONS ARE THAT EACH CLINICIAN, RESEARCHER, PATIENT, EMPLOYEE, CONTRACTOR ARE ALL CONSIDERED PARTNERS AT THIS HEALTHCARE FACILITY. IN OTHER WORDS, THE OIL THAT KEEPS THIS ENGINE RUNNING. NUMBER TWO, IT'S OKAY TO BE OF SERVICE TO ANOTHER. IT WILL NOT DEVALUE YOU AS A PERSON. THANK YOU. [APPLAUSE] >> THANK YOU, ANTOINETTE, FOR SHARING YOUR STORY WITH US. SO AS DR. GRADY INDICATED, I'M CURRENTLY THE PRINCIPAL INVESTIGATOR ON THE CLINICAL RESEARCH STUDY THAT ANY TIME NET IS PARTICIPATING IN. AND THE STUDY IS DIFFERENT FROM PROBABLY MOST OF THE STUDIES YOU HEARD ABOUT THIS MORNING IN ITS DESIGN AND SCOPE, SO LET ME JUST BRIEFLY DESCRIBE WHAT THE STUDY IN THIS CURRENT FORM BASICALLY IS. SO THIS PROTOCOL STUDY HAS TWO MAIN PURPOSES. THE FIRST IS SO THAT WE CAN MAINTAIN A COHORT OF HIV-INFECTED INDIVIDUALS WHO ARE WELL CHARACTERIZED CLINICALLY, WHO WE SEE AT THE MINIMUM OF TWO TO THREE TIMES OR TWO TO FOUR TIMES A YEAR. WE CAN SEE THEM MORE OFTEN IF IT'S CLINICALLY INDICATED. DURING THOSE VISITS, WE COLLECT CLINICAL DATA ON THEM, OTHER ILLNESSES THEY MAY HAVE, HOW THEY'RE DOING. WE COLLECT EXTENSIVE LABORATORY DATA RELATED TO THEIR HIV INFECTION, AND WE STORE CELLS AND SERUM, SO WE'VE BEEN DOING THIS FOR MANY YEARS NOW, SO WE HAVE REALLY ABOUT A TWO, 300 PATIENT COHORT OF WHICH WE HAVE DETAILED LONGITUDINAL CLINICAL DATA AND ALSO BANKED SPECIMENS LONGITUDINALLY. THIS IS A VERY VALUABLE RESOURCE TO MANY OF OUR LABORATORY AND ALSO CLINICALLY-BASED INVESTIGATORS. THIS IS ALL MAINTAINED IN THE DATABASE, AND IF A RESEARCHER WANTS TO FIND 50 PATIENTS WHO HAVE SUCH AND SUCH A CD4 COUNT, SUCH AND SUCH A VIRAL LOAD TO LOOK AT SOME ASPECT OF HIV PATHOGENESIS, THEY QUERY THE DATABASE, GET THE LIST, THEY COME TO ME, I REVIEW WHAT THEY WANT TO DO WITH IT, AND ALMOST 100% OF THE TIME, THEY GET THE SAMPLE. SO THE PRIMARY PURPOSE IS TO MAINTAIN THIS WELL CHARACTERIZED GROUP OF PATIENTS TO SUPPORT ONGLG LABORATORY RESEARCH AND ALSO WE SERVE AS A POSSIBLE REFERRAL BASIS FOR OTHER STUDIES THAT ARE GOING ON IN OUR CLINIC, THERAPEUTIC TRIALS, OTHER SORTS OF MORE CLEAR RESEARCH TRIALS. SO AS PART OF THE STUDY, WE PROVIDE ALL THE HIV-RELATE THE CAR-RELATED CARETO THE PARTICIPANTS AT NO COST, SO WE TREAT ANY COMPLICATIONS OF THE HIV INFECTION COMPLICATIONS THEY HAVE, WE PROVIDE RETROVIRAL AND ALL THE MONITORING ASSOCIATED WITH THAT, SO ALL THE MEDICAL CARE, ALL THE INTERVENTIONS, ALL THE MEDICATIONS ARE ALL STANDARD OF CARE, STANDARD MEDICAL CARE. WE DON'T DO ANY -- THE ONLY EXPERIMENTAL COMPONENT OF THIS PROTOCOL IS A LITTLE BIT OF EXTRA BLOOD WE DRAW, ANYWHERE FROM TWO TO THREE TIMES A YEAR, THAT ARE USED FOR RESEARCH PURPOSES. SO IN HE ENS, IT'S PROBABLY DIFFERENT FROM THE TRIALS YOU HEARD THIS MORNING IN THAT THERE'S A LOT OF BENEFICIAL BENEFITS TO THE PATIENTS, THEY GET ACCESS TO OUR CLINIC, OUR PHARMACY AND MEDICAL CARE, BUT WE HAD -- BY ME NECESSITY HAVE TO PUT SOME RESTRITIONS ON WHAT WE WILL AND WILL NOT PROVIDE IN THIS PROTOCOL, SO WE USED TO TAKE CARE OF BASICALLY ANY MEDICAL PROBLEM OF ANY KIND, EITHER HIV-RELATED, INFECTIOUS DISEASE-RELATED OR ANYTHING FOR THESE PATIENTS. THAT OVER THE YEARS BECAME UNSUSTAINABLE BECAUSE THE TREATMENTS FOR HIV INFECTION HAVE IMPROVED DRAMATICALLY SUCH NOW THAT WE HAVE VERY IESKTTIVE DRUGS TO TREAT HIV. AND WHAT BEGAN TO HAPPEN IS THAT MANY OF OUR PATIENTS LIVING LONGER AND LONGER BEGAN TO DEVELOP OTHER PROBLEMS THAT WERE LIKE HYPERTENSION OR DIABETES OR DEGENERATIVE ARTHRITIS, THINGS LIKE THAT. AND IT BECAME JUST IMPOSSIBLE LOGISTICALLY FOR US TO CARE FOR ALL OF THOSE ASPECTS, GENERAL INTERNISTS, AS WELL AS THEIR INFECTIOUS DISEASE DOCTOR. SO SEVERAL YEARS AGO, I WROTE A NEW PROTOCOL TO TRY TO INCORPORATE JUST THE INFECTIOUS DISEASE COMPONENT, SO THAT'S THE PROTOCOL THAT I DID DESCRIBE, SO WE PROVIDE ALL THE HIV-RELATED CARE, THE INFECTIOUS DISEASE AND ANYTHING THAT'S WITHIN THE SPECIALTY OF INFECTIOUS DISEASES OR HIV MEDICINE, WE PROVIDE STANDARD OF CARE FOR THAT. BUT WE DO NOT PROVIDE CARE THAN NON-HIV CONDITIONS, AGAIN, LIKE DIABETES OR HYPERTENSION, AND WE MAKE THIS VERY CLEAR TO THE PATIENTS, THE CONSENT FORM SPELLS THAT OUT ABSOLUTELY CLEARLY. ONE OF THE INCLUSION CRITERIA FOR THE STUDY IS THAT THE PARTICIPANT HAS A GENERAL PRACTITIONER OR INTERNIST WHO WILL DEAL -- OR SOME PHYSICIAN WHO WILL DEAL WITH NOBOD NON-HIV RELATED PROBLEMS SO THEY CAN'T ENROLL IN THE STUDY UNLESS THEY DOCUMENT THEY HAVE OUTSIDE CARE. THERE'S ALSO THE PROVISION IN THE STUDY THAT PATIENTS, IF THEY SEVERAL YEARS INTO THE STUDY DROP THEIR -- STOP GOING TO THEIR INTERNIST, DROP THEIR PRIMARY CARE PROVIDER, THAT THAT'S A CRITERIA IN THEORY OF REMOVING A PATIENT FROM THE STUDY, AGAIN BECAUSE MANY OF THE PATIENTS WE TREAT TEND TO BE UNDERINSURED OR UNINSURED, AND THEY HAVE DIFFICULTY FINDING PRIMARY CARE ANYWHERE. BUT IT REALLY WASN'T POSSIBLE LOGISTICALLY TO CONTINUE DOING THIS PROTOCOL AND CONTINUE TO PROVIDE BASICALLY GLOBAL MEDICAL CARE FOR THESE PATIENTS. SO NOW THIS IS HOW WE HANDLE IT. WE JUST TREAT HIV-RELATED PROBLEMS AND PROVIDE TREATMENT FOR THAT. SO I WAS ASKED TO SORT OF COMMENT ON SOME OF THE ETHICAL DILEMMAS THAT I FACE IN A STUDY LIKE THIS. IT'IT'S REALLY JUST A STANDARD OF CARE TRIAL AND THE ONLY RESEARCH AGAIN IS DRAWING A LITTLE BIT OF BLOOD FROM THE PATIENT. THE SECOND PURPOSE THAT I MENTIONED THIS PROS KOL SERVES IS THAT IT SUPPORTS THE INFECTIOUS DISEASE TRAINING PROGRAM, WHICH WE HAVE HERE WHICH HAS A REQUIREMENT FOR INFECTIOUS DISEASE FELLOWS TO HAVE A LONGITUDINAL CLINIC IN WHICH THEY FOLLOW HIV OUTPATIENTS. SO THAT IS ALSO A PURPOSE AS DR. O'BRIEN AND MANY OF THE OTHERS AND ANTOINETTE MENTIONED WERE FORMER INFECTIOUS DISEASE FELLOWS WHO PARTICIPATED IN OUR PROGRAM, WHO PARTICIPATED IN HER CARE, WE HAD CLINICS SEVERAL TIMES A WEEK. THE MAIN PURPOSE IS REALLY TO HAVE THIS COHORT OF PATIENTS THAT WE FOLLOW LONGITUDINALLY. THE STUDY HAS KIND OF TWO ARMS. ONE IS A LONGITUDINAL ARM, WE FOLLOW ROUGHLY 200 PATIENTS WHICH IS ABOUT ALL WE CAN HANDLE WITH THE RESOURCES WE HAVE, BASICALLY FOR MANY YEARS. SOME OF THEM, WE FOLLOW ANTOINETTE FOR 15 EVEN ALMOST CLOSE TO 15 YEARS. THE OTHER ARM OF THE STUDY IS WHAT WE CALL THE CONSULT ARM. THAT IS A SHORT-TERM ARM WHICH PATIENTS THAT LIVE WITHIN 100 MILES OF THE NIH, WE HAVE TO HAVE THAT GEOGRAPHIC RESTRAINT BECAUSE WE CAN'T PAY FOR TRAVEL FOR PATIENTS FROM DISTANT CITIES, BUT IF THEY'RE REFERRED BY AN INFECTIOUS DISEASE D THEY CAN COME HERE AND BE EVALUATED FOR A PARTICULAR COMPLICATION OF HIV ON A SHORT-TERM BASIS, SO THEIR REQUIREMENTS FOR THAT ARE THAT THEY HAVE AN HIV-RELATED CONDITION AND THAT THEY ARE REFERRED BY A PHYSICIAN WHO IS WILLING TO CONTINUE THEIR MANAGEMENT OF HIV ONCE WE ADDRESS THEIR PROBLEM, AND WE THEN SEE THEM TRY TO ADDRESS WHATEVER THE COMPLICATION OR PROBLEM IS, AND ONCE IT'S EITHER TAKEN CARE OF OR DONE ALL WE CAN, WE TURN THEM BACK OVER TO THEIR REFERRING PHYSICIAN, AND THERE'S A TIME LIMIT ON THAT PARTICULAR ARM OF THE PROTOCOL OF ONE YEAR. SO WE'LL PROVIDE FOLLOW-UP AND THE TREATMENT IS ALL STANDARD OF CARE, AND THAT PART MAINLY SUPPORTS THE INFECTIONTIOUS DISEASE TRAINING PROGRAM AS A WAY FOR OUR FELLOWS TO SEE HIV COMPLICATIONS. AND WE LARGELY DRAW OUR PATIENTS FROM THE COMMUNITY CLINICS IN THE D.C. METRO AREA, AND THEY'RE LARGELY UNDERINSURED OR UNNICHED PATIENT POP LAYINGS WHO ARE SEEN IN THESE CLINICS BUT BECAUSE THESE CLINICS ARE SO OVERBURDENED, TO GET AN MRI SCAN TAKES TWO MONTHS AND AN ACT OF GOD TO BE PAID FOR SO HERE WE CAN OFTEN DO IT MUCH QUICKER THAN THAT. SO THAT'S THE PROTOCOL. SO TWO SORT OF ETHICAL ISSUES THAT I'M FACED WITH IN THIS TYPE OF PROTOCOL, IN THIS PARTICULAR PROTOCOL, IT HAD TO DO WITH THOSE FACTORS. SO ONE IS, OBVIOUSLY THERE ARE MANY PATIENTS WHO HAVE HIV-RELATED -- VERY COMPLICATED HIV PROBLEMS IN THE D.C. METRO AREA. THOUSANDS OF THEM. AND WE SIMPLY -- UNLESS WE WERE GOING TO DEDICATE OUR WHOLE RESEARCH CLINIC TO TAKING CARE OF THOSE PATIENTS, WE CAN'T TAKE EVERYONE WHO NEEDS TO BE SEEN. SO I'VE CALLED MULTIPLE TIMES A MONTH BY PHYSICIANS IN THESE CLINICS ASKING IF I CAN HELP THEM OUT WITH THE PATIENT SUCH AND SUCH, AND BY NECESSITY, I HAVE TO CHOOSE WHO I TAKE ON THE PROTOCOL AS I CAN. THEY'RE ALL ELIGIBLE BECAUSE THE ELIGIBILITY CRITERIA ARE PRETTY OPEN-ENDED, YOU HAVE THAT HIV INFECTION, YOU HAVE A PROBLEM THAT NEEDS ADDRESSING. SO I OBVIOUSLY CAN'T TAKE EVERY PATIENT IN THE 100-MILE RADIUS OF BETHESDA WHO DOESN'T HAVE GOOD INSURANCE AND GOOD CARE, AND STILL HAVE WITHOUT GREETLY OVERWHELMING OUR CAPACITY AND OUR RESEARCH PLAN. SO I HAVE TO PICK AND CHOOSE. THAT'S AN ETHICAL DILEMMA, I TRY TO DO THE BEST I CAN CAN, I TRY TO LOOK AT AS MUCH INFORMATION FROM THE PHYSICIAN AS I CAN AND PICK THOSE PATIENTS WHO ARE REALLY SICK AND WE CAN CAN REALLY IMPACT ON AND BRING THEM IN AND TRY TO DO THAT. SO THAT'S ONE TYPE OF ETHICAL DILEMMA. A SECOND HAS TO DO WITH THE -- LIMITING THE MEDICAL CARE THAT WE CAN PROVIDE ON THIS STUDY. AS I INDICATED, WE WILL PROVIDE THE MEDICATIONS TO TREAT THE HIV AND COMPLICATIONS BUT WE REALLY CAN'T TREAT ANY OTHER PROBLEMS THAT ARE COMPLETELY UNRELATED TO THE HIV. AND THIS OFTEN CAUSES PROBLEMS. SO WE'LL SEE A PATIENT IN CLINIC AND NOTICE THEIR BLOOD PRESSURE IS NOT SO WELL CONTROLLED ANYMORE. ASK THEM, YOU NEED TO TALK TO YOUR INTERNIST, WHOEVER'S PRESCRIBING YOUR BLOOD PRESSURE MEDICINE. AND THEN IT COMES OUT, WELL, THEY HAVEN'T SEEN THEIR INTERN IN TWO YEARS. UNBEKNOWNST TO US. AND WE'VE BEEN SENDING RECORDS ALL THIS TIME, BECAUSE THEY CAN'T AFFORD THE CO-PAY OR THEY MOVED TO VIRGINIA FROM M.D. AND THEY'RE NOW -- THEY NOW HAVEN'T APPLIED FOR VIRGINIA MEDICAID AND WHATEVER. SO IT BECOMES VERY TEMPTING TO JUST PRESCRIBE THEM ANTIHYPERTENSIVE AND TAKE OVER THE MANAGEMENT OF THEIR HYPERTENSION, BUT AGAIN, IF WE DO IT FOR ONE PATIENT, WE HAVE TO DO IT FOR THEM ALL AND THEN AGAIN, WE CAN'T SUPPORT THAT CLINIC UNLESS WE COMPLETELY DEDICATE OUR CLINIC AWAY FROM DOING THE RESEARCH AND DRUG TRIALS THAT WE DO TO TREATING UNINSURED PATIENTS, WE CAN'T DO THAT. SO THAT'S ANOTHER SOURCE OF SORT OF ETHICAL TENSION THAT I'M CONFRONTED WITH ALMOST ON A WEEKLY OR A MONTHLY BASIS. THE WAYS -- AND THEN SORT OF THE FLIP SIDE IS WHEN YOU FIND OUT THAT THE INDIVIDUAL NO LONGER SEES THEIR PRIMARY CARE PROVIDER BECAUSE OF EITHER THEY CAN'T AFFORD THE CO-PAYS OR THEY MOVE JURISDICTIONS OR THE INSURANCE CHANGED PROVIDERS, THEY JUST HAVEN'T GOT AROUND TO FINDING A NEW PROVIDER, AND THE PROTOCOL STIPULATES THAT THEY NEED -- THEY NEED TO BE REMOVED FROM THE STUDY. OF COURSE THAT'S HARD TO DO, BECAUSE IT'S HARD TO ARGUE THAT THAT'S IN THE PATIENT'S BEST INTEREST AT THAT TIME, SO THAT'S ANOTHER PROBLEM, HOW DO I DEAL WITH THAT. YOU'RE TEMPTED, THE DOCTOR IN YOU, TO START TREATING THE PATIENT IF YOU KNOW THEIR HYPERTENSION IS NOT BEING MANAGED. SO THE WAY WE DEAL WITH THOSE PATIENTS IS TO TRY TO HELP AS MUCH AS WE CAN WITHIN THE CONTEXT OF THE STUDY. FOR EXAMPLE, THE PATIENT HASN'T SEEN THEIR INTERN IN TWO YEARS AND CAN'T GET BLOOD PRESSURE MEDICINE, WE HAVE THEM SEE THE SOCIAL WORKER, WE HAVE A FABULOUS SOCIAL WORKER IN OUR CLINIC, THEY'RE VERY KNOWLEDGEABLE ABOUT RESOURCES IN THE AREA, CAN CALL DIFFERENT CLINIC, MAKE APPOINTMENTS FOR PATIENTS, HELP THEM GET THE PAPERWORK FOR MEDICAID, STEER THEM THROUGH THE PROCESS, AND I THEN USUALLY GIVE THEM SOME GRACE PERIOD OF MONTHS TO RE-ESTABLISH CARE WITH AN INTERNIST, AND THE NURSE CASE MANAGERS THAT ARE INVOLVED WITH THE PATIENTS ARE ALSO FABULOUS, THEY WILL HELP AS MUCH AS THEY CAN, THEY WILL CALL CLINICS, THEY WILL MAKE APPOINTMENTS FOR THE PATIENT, THEY WILL DO EVERYTHING, PUSH THE PATIENT TO GO OUT AND DO IT, AND EVEN THOUGH THIS COMES UP VERY FREQUENTLY, THIS PROBLEM, I'VE YET TO HAVE HAD TO REMOVE A PATIENT FROM A STUDY BECAUSE THEY DIDN'T FIND AN INTERNIST. WE CAN ALMOST ALWAYS WORK WITHIN THE SYSTEM, AGAIN WE'RE FORTUNATE TO HAVE THESE RESOURCES, SOCIAL WORKERS, TO DO SO. SO AT LEAST SO FAR, I'VE BEEN ABLE TO KIND OF TREAD THAT ETHICAL LINE ABOUT NOT ABANDONING A PATIENT EVEN THOUGH THE PROTOCOL REQUIREMENTS WOULD SEEM TO SAY THAT I SHOULD DO SO. SO THAT'S SORT OF THE STUDY THAT ANTOINETTE'S ON, IF I GET YOU TO CALL IT A NATURAL HISTORY STUDY, A COHORT STUDY, WHATEVER, BUT I THINK IT PRESENTS THE MAIN ETHICAL ISSUES THAT IT I'M CONFRONTED WITH AS PRINCIPAL INVESTIGATOR, LARGELY HAD TO DO WITH WHO I TAKE ON THE STUDY, I'M LIMITED BY RESOURCES, HOW DO I PROVIDE STANDARD MEDICAL CARE BASICALLY. THERE ARE REALLY NO RESEARCH ETHICAL -- DRAWING SOME EXTRA TUBES OF BLOOD RARELY POSTS A DANGER TO THE PATIENT, THOSE ARE NEVER REALLY ETHICAL ISSUES, AND IF THEY ARE, THEY'RE USUALLY INCREDIBLY EASY, IF SOMEONE'S HEMOGLOBIN IS LOW, IT'S VERY SIMPLE, WE DON'T DRAW. SO THAT'S ONE SORT OF TYPE OF PROTOCOL THAT I'M INVOLVED WITH. I'M ALSO INVOLVED IN SORT OF MORE STANDARD DRUG TRIALS, THERAPY TRIALS AND HAVE BEEN FOR MANY YEARS, AND YOU PROBABLY KNOW I'M PROBABLY -- YOU SPENT MOST OF YOUR TIME TALKING THIS MORNING, THEY POSE A DIFFERENT SORT OF ETHICAL QUESTION. I'LL BRIEFLY GO THROUGH ONE OF THEM THAT WAS A RECENT STUDY THAT I THINK I CAN GIVE YOU EXAMPLES OF HOW I DEALT WITH THESE PROBLEMS. IT WAS A STUDY THAT'S NOW COMPLETED BUT IT WAS A STUDY OF -- JUST VERY BRIEFLY, A TYPE OF VAS VASCULITIS, THE BREAST TREATMENT FOR IT WOULD BE IF YOU COULD CURE THE HEPATITIS C INFECTION IN INDIVIDUALS, THAT TENDS IN MOST PATIENTS TO MAKE THEM IMPROVE OR COMPLETELY GO AWAY. THE REASON WE WERE DOING THE STUDY WAS THAT THE THERAPIES WE HAD FOR HEPATITIS B WERE NOT THAT GOOD AND LESS THAN HALF THE PATIENTS COULD BE CURED WITH WHAT WAS STANDARD THERAPY FOR HEPATITIS C SO FOR PATIENTS WHO HAD THIS UNUSUAL COMPLICATION OF HEPATITIS C AND COULDN'T BE TREATED WITH ANTIVIRAL THERAPY OR THE ANTIVIRAL THERAPY WAS NOT SUCCESSFUL, THEIR ONLY OPTION WAS TO BE TREATED WITH STANDARD FORMS OF IMMUNOSUPPRESSANT MEDICATION SUCH AS CORTICOSTEROIDS, AND THAT'S HOW THEY WERE TREATED FOR MANY YEARS. I THINK ANY FAIR READING OF THE LITERATURE SHOWED THAT THAT TREATMENT REALLY DIDN'T WORK BECAUSE IT TENDED TO MAKE THE UNDERLYING HEPATITIS VIRUS INFECTION WORSE, AND IT ONLY TRANSIENTLY SUPPRESSED THE INFLAMMATION OF THE AUTOIMMUNE PROCESS, SO THERE WAS REALLY NO GOOD TREATMENT. WE BEGAN LOOKING AT AN ANTIBODY WHICH YOU MAY BE FAMILIAR WITH, IT'S STILL A LICENSED DRUG FOR THE TREAT M OF LYMPHOMA, BUT THERE ARE REASONS TO THINK IT MIGHT WORK IN THIS DISEASE WHICH I WON'T GO INTO. THERE WERE SOME ANECDOTAL REPORTS AFTER SMALL CASE THEORIES OF PROMISING CLINICAL EFFECTS WITH THIS PARTICULARLY MONO CLONAL. BUT AGAIN, THEY WERE NON-CONTROLLED, THEY WERE VARIOUS DOSES IN SLIGHTLY DIFFERENT PATIENT POPULATIONS SO IT REALLY DIDN'T SHOW THAT THAT WAS AN EFFECTIVE TREATMENT BUT IT SUGGESTED IT MIGHT BE. ONE OF THE STUDIES WAS OPEN LABEL, HAD ABOUT 20 PATIENTS IN IT, SUGGESTED THAT THE DRUG, WHILE IT MIGHT IMPROVE THE CLINICAL -- IT MIGHT WORSEN THE HEPATITIS C INFECTION BY SUPPRESSING RESPONSE TO THAT. THEY DIDN'T HAVE A CONTROL GROUP, THERE WERE A NUMBER OF REASONS WHY IT WAS IMPORTANT, WE FELT, TO DO A RANDOMIZED CONTROL TRIAL AND PATIENTS WOULD BE RANDOMIZED TO EITHER STANDARD TREATMENT, WHICH I'VE ALREADY TOLD YOU DOESN'T WORK VERY WELL AT ALL, OR THE MONOCLONAL ANTIBODY. OF COURSE WHEN YOU DESIGN THE TRIAL, I PERSONALLY FELT THAT IT HAD A PRETTY GOOD CHANCE OF WORKING AND PROBABLY WOULD BE EFFECTIVE AS SOON AS WE DEFINED THE RISKS OF IT, WHAT THE BEST DOSE WAS, ET CETERA. I THOUGHT IT WOULD WORK. SO OBVIOUSLY RIGHT UP FRONT -- AND I KNEW STANDARD THERAPY, I WAS PRE P TI SURE, DIDN'T OFFER MUCH. PROBABLY VERY TOXIC WITH LITTLE BENEFIT, SO THEN IT BECOMES HARD, HOW DO YOU RANDOMIZE, THE THINGS YOU TALKED ABOUT THIS MORNING, A TRIAL IN WHICH YOU'RE COMPARING A POTENTIALLY EFFECTIVE DRUG AGAINST NOT A VERY GOOD STANDARD OF CARE. SO I THINK THE WAY -- FROM STUDY DESIGN, SO ONE THING ABOUT THIS DISEASE WHICH MADE IT A LITTLE EASIER FOR ME WAS THAT IT'S NOT -- IT CAUSES A LOT OF MORBIDITY AND OCCASIONALLY MORTALITY, THIS VASCULITIS ASSOCIATED WITH HELP TIES C, IT CAUSES MORBIDITY AND MORTALITY OVER MANY YEARS. SO THAT MAKES IT A LITTLE EASIER. SO IT'S NOT THE SAME AS THE THE ECMO THING YOU TALKED ABOUT THIS MORNING. BUT NONETHELESS, IT CAUSES PEOPLE TO SUFFER. SO THAT WAS MADE ACTUALLY THE DESIGN SOMEWHAT EASIER, SO WE RANDOMIZED PATIENTS WHO USED STANDARD THAIRM IT, WE SPECIFICALLY WROTE EXCLUSION CRITERIA FOR PATIENTS WHO HAD RAPIDLY PROGRESSING DISEASE, POTENTIAL OF GOING INTO ORGAN FAILURE, WE EXCLUDED THEM FROM THE STUDY, FELT IT BEST THEY TRY TO GET OPEN LABEL TREATMENT IF THAT WAS THE CASE, AND THE OTHER WAY IS WE MADE OUR END POINT OF SIX MONTHS, HOW MANY PATIENTS ARE IN REMISSION AT SIX MONTHS. SO FOR THOSE IN THE CONTROL GROUP WHO DIDN'T GET EFFECTIVE THERAPY, THEY HAD THE ABILITY TO CROSS OVER AND GET ON OPEN LABEL, SO EVERYBODY GOT AN OPPORTUNITY TO GET THE EFFECTIVE DRUGS, SOME PEOPLE GOT IT SOONER THAN OTHERS. SO THAT'S HOW IN THE TRIAL DESIGN BEFORE WE ENROLL THE PATIENT HOW WE ADDRESS THAT ISSUE. THERE WAS A COUPLE OF TIMES IN WHICH PATIENTS SCREEN TO -- WOULD HAVE MET THE ELIGIBILITY CRITERIA, INCLUDING THE -- DIDN'T QUITE MEET THE CRY TIER WHY FOR EXCLUSION FOR DISEASE BUT WHO I FELT WOULD BE BETTER SERVED BY NOT ENTERING OUR TRIAL BECAUSE THEY MIGHT GET IN THE STANDARD OF TREATMENT ARM AND THAT THEY WOULD BE BETTER SELFED BY TRYING TO GET IT ON A COMPASSIONATE BASIS BY MAKING A PLEA TO THEIR INSURANCE TO PAY FOR IT, A LICENSED DRUG FOR A DIFFERENT INDICATION. I HAD NO PROBLEM WITH THAT. THE LAST THING I WANTED TO DO WAS HARM A PATIENT, DENY THEM WHAT I THOUGHT MIGHT BE EFFECTIVE THERAPY. SO THAT'S A SUMMARY OF THAT TRIAL, YOU SEE IT'S A VERY DIFFERENT SET OF ETHICAL ISSUES THAN THE PREVIOUS TRIAL THAT ANTOINETTE IS ON, WHICH REALLY INVOLVES THE BEST STANDARD CARE THAT WE HAVE, GIVEN THIS PART OF THE STUDY. SO I THINK I'LL END THERE. [APPLAUSE] >> HE TALKED ABOUT THE COMPLEXITIES OF SEEING A RESEARCHER HERE, ALMOST OVERWHELMED BY IT. I'M ALWAYS IN YOU A TO HEAR ANTOINETTE'S STORY. I'VE HEARD IT A NUMBER OF TIMES, HER EXPERIENCES OF BEING A PATIENT AND BEING A RESEARCH PARTICIPANT HERE AT THE NIH. ONE THING SHE DIDN'T MENTION TO YOU, BUT I WILL, IS THAT SHE WAS VERY HELPFUL TO US WHEN WE FIRST MOVED TO THE NEW BUILDING POINTING OUT PLACES THAT MET THE CRITERIA OR MET THE LAW, ACTUALLY, FOR DISABILITIES, THE ADA LAW, MET THE SPECIFICATIONS BUT WERE NOT REALLY USEFUL FOR PEOPLE THAT ARE DISABLED SUCH AS IN A WHEELCHAIR, AND WE WERE ABLE TO FORCE THE HAND OF THOSE WHO HAVE TO FIX THESE THINGS TO PUT IN AUTOMATIC DOORS ON THE BATHROOMS AND SOME OF THE -- DIDN'T HAVE THEM, AND TO ACTUALLY MOVE THE LIBRARY BECAUSE YOU COULDN'T GET A WHEELCHAIR IN THERE TO THE COMPUTERS, AND REALLY HELPED TO POINT OUT THINGS THAT THOSE OF OF US NOT IN WHEELCHAIRS ARE BLIND TO SOMETIMES. SO GOOD WORK. SO YOU HEARD ALREADY THAT I'M THE PATIENT REPRESENTATIVE HERE IN THE CLINICAL CENTER, AND I DO HEAR FROM PEOPLE IN ALL THE DIFFERENT INSTITUTES FROM INPATIENTS, OUTPATIENTS, FORMER PATIENTS, PROSPECTIVE PATIENTS, FAMILIES OF PATIENTS, STAFF WHO ARE HERE TAKING CARE OF PATIENTS, AND I COULD TALK ALL AFTERNOON ABOUT DIFFERENT HORROR STORIES TO TELL BUT, BUT THERE ARE A COUPLE THINGS I THOUGHT ABOUT THAT I WANTED TO MENTION. ONE IS RELATED TO WHAT THE DOCTOR WAS TALKING ABOUT ABOUT PATIENTS NOT ALWAYS GETTING IT, THE DIFFERENCE BETWEEN CLINICAL CARE AND RESEARCH. THEY COME HERE, SOME VERY DESPERATE FOR HELP, THEY LEFT OTHER PLACES, WHATEVER THEY TRIED HASN'T HELPED, SO THEY COME HERE WITH THE EXPECTATION THAT THIS IS THE ANSWER FOR THEM, THEY'RE GOING TO BE ABLE TO SORT OF LAND HERE, AND EVEN THOUGH THEY MAY BE TOLD A NUMBER OF TIMES THAT IF THIS HAPPENS, YOU WON'T BE IN THE STUDY ANY LONGER, THEY DON'T NECESSARILY HEAR THAT. THEY TUNE IT OUT BECAUSE THEY WANT THIS SO BADLY TO BE THE ANSWER FOR THEM. AND I THINK PEOPLE WHO WERE RESEARCH STAFF NEED TO BE ESPECIALLY ATTENTIVE TO THAT AND BE LOOKING FOR THAT AND CLARIFY FOR PEOPLE AGAIN AND AGAIN, SO THEY REALLY GET -- SO THEY HAVE A PLAN B, YOU KNOW, A PATIENT BEING TOLD FRIDAY AFTERNOON, BEFORE A WEE WEEKEND, THAT YOUR DISEASE HAS PROGRESSED SO YOU WON'T BE IN THE STUDY ANYMORE. I HAVE SUCH A PATIENT I TALKED TO, LOOKING FOR STUDY, FRANTICALLY SEARCHING AND SEARCHING. I THINK KEEPING IN MIND NOT NECESSARILY TRYING TO FARM THEM OUT SOMEPLACE BUT KEEPING IN MIND THAT THAT'S ALWAYS GOING TO BE THERE FOR VERY SICK PATIENTS, THAT THEY NEED TO UNDERSTAND THE COMMITMENT HERE IS BASED ON A PROTOCOL AND DECISION-MAKING IS BASED ON WHAT'S IN THE PROTOCOL, SO A DECISION THAT MIGHT BE MADE FOR ME LAYING IN A HOSPITAL BED IS GOING TO BE BASED ON WHAT'S WRONG WITH ME, WHAT DO THEY HAVE TO TREAT ME WITH, WHAT WILL MY INSURANCE COVER, THINGS LIKE THAT. HERE IT'S BASED ON WHAT'S NEXT IN THE PROTOCOL? YOU MIGHT ALSO CONSIDER SOME OF THOSE OTHER THINGS, BUT THE PRIMARY REASON THEY'RE HERE IS THE PROTOCOL. THE OTHER THING I WANTED TO HIGHLIGHT, PATIENTS COME HERE FROM EVERYWHERE, SOME ARE VERY SOPHISTICATED ABOUT THEIR ILLNESS, THEY KNOW MORE THAN MANY OF US DO ABOUT WHAT'S OUT THERE, WHAT THEY'VE TRIED ALREADY, WHAT'S POSSIBLE HERE, WHAT IT MEANS, ET CETERA, AND THEN WE HAVE -- THEY REALLY DON'T UNDERSTAND THEIR ILLNESS AT ALL, OR MAYBE WE DON'T KNOW WHAT THEIR ILLNESS IS, AND THEY ARE COMING HERE SORT OF LOOKING TO US TO SOMEHOW SOLVE THE PUZZLE THAT THEY'VE BEEN TO THEIR OWN DOCTORS AT HOME AND NONE OF THEM SEEM TO KNOW -- NEVER SAW A PATIENT LIKE THIS BEFORE, DON'T KNOW WHAT TO DO ABOUT THIS. I'LL JUST DESCRIBE A DYNAMIC TO YOU ABOUT WHAT A PATIENT TOLD ME. HE WAS SITTING IN A ROOM AT A CONFERENCE TABLE, HAD BEEN HERE THREE OR FOUR DAYS, GETTING LABS AND SCANS AND THE VARIOUS STUFF WE DO TO EVALUATE PATIENTS. ABOUT EIGHT PEOPLE CAME INTO THE ROOM, ALL WEARING WHITE COATS, ALL TALKING TO EACH OTHER, CAME IN, SAT DOWN AND SORT OF DECLARED TO THE PATIENT, YOU KNOW, WHAT THE RESULTS WERE OR WHAT THE FINDINGS WERE. AND THINKING OF ONE'S SELF IN THAT PATIENT'S SEAT, THAT'S TERRIFYING. IN THINKING ABOUT IT, ONE PIECE THAT'S MISSING AND THAT'S MISSING VERY OFTEN NOW IN RESEARCH SITUATIONS IS A PERSON, SOMEBODY, IF THERE'S ONE PERSON IN THAT GROUP OF EIGHT WHO'S THAT PATIENT'S PERSON, THEY KNOW THAT'S THEIR GO-TO PERSON, THEY CAN CALL THAT PERSON, THEY KNOW THAT THAT PERSON KNOWS ABOUT THEM, AND SMILES WHEN THEY COME IN THE ROOM. THAT'S THE PERSON THEY CAN CALL FROM HOME IF THEY FORGET WHEN THEY'RE SUPPOSED TO BE COMING HERE OR WHEN THEIR NEXT TEST IS OR ANYTHING. IT MAKES ALL THE DIFFERENCE, AND THAT THEY HAVE NO PERSON, THEY'LL CALL MY NUMBER AND THE FIRST THING I ASK THEM AS WELL, WHO'S YOUR PERSON. THAT'S WHAT I'M TRYING TO GET TO. WHO DO WE GO TO? HOW DO WE FIND OUR WAY BACK TO THERE? SOMETIMES IT'S LIKE TRYING TO FIGURE OUT A PATH BACK TO WHOEVER IT IS THAT'S ON THE RESEARCH TEAM TO ANSWER THE QUESTIONS. I THINK THAT'S A VERY IMPORTANT THING TO THINK ABOUT AND CAN MAKE A BIG DIFFERENCE IN THE EXPERIENCE PATIENTS HAVE, AND THEY'RE FEELING ABOUT PARTICIPATING ABOUT BEING A PART OF WHAT'S GOING TO HAPPEN, WITHOUT THAT, WE CAN'T SEE WHAT WE'RE DOING, RIGHT? THEY COME AND NEED TO BE ACKNOWLEDGED FOR THAT PIECE. I'M GOING TO LEAVE IT THERE. >> THANK YOU ALL THREE OF THE SPEAKERS. AS YOU GUYS ARE COMING TO THE MIC, I'M GOING TO MAKE A FEW COMMENTS. I THINK TWO THINGS THAT I THINK ARE VERY IMPORTANT FROM WHAT YOU'VE JUST HEARD IS THAT IN THIS COURSE, WE TALK ABOUT THIS DISTINCTION, THIS ETHICAL DISTINCTION BETWEEN CLINICAL CARE AND CLINICAL RESEARCH. IT'S REAL. IT'S THERE. BUT THE REALITY IS MUCH MESSIER THAN THAT, AS YOU PROBABLY KNOW, AND AS YOU'VE JUST HEARD. THERE IS A LOT OF CLINICAL CARE GOING ON HERE, THERE'S A LOT OF PEOPLE WHO HAVE DISEASES WHO COME HERE HOPING THAT THEY'RE GOING TO GET TREATED, AND MANY OF THEM DO GET TREATED. THEY'RE STILL PARTICIPATING IN RESEARCH, AND SO BEING CLEAR ABOUT WHICH IS WHICH, AND THE FACT THAT SOMETIMES THERE'S BOTH GOING ON IS TRICKY, AND IT'S TRICKY FOR A NUMBER OF DIFFERENT PERSPECTIVES. IT'S TRICKY FROM THE PERSPECTIVE OF THE PATIENT PARTICIPANT, WHO'S HOPING FOR TREATMENT BUT WILLING TO BE IN RESEARCH, IF THEY UNDERSTAND THOSE TWO THINGS. IT'S TRICKY FROM THE PERSPECTIVE OF THE INVESTIGATOR, AS MIKE DESCRIBED IN TERMS OF WHAT ARE THE LIMITS IF OUR JOB HERE IS TO DO RESEARCH, WHAT ARE THE LIMITS, HOW DO WE DECIDE HOW MUCH CLINICAL CARE WE CAN AND CANNOT GIVE IN THE CONTEXT OF OF A RESEARCH STUDY AND HOW DO WE COMMUNICATE THAT TO SOMEBODY ELSE. IT'S TRICKY IN THE DESIGN OF THE STUDY ITSELF. HOW DO WE SET UP THE STUDY, HOW MUCH DO WE BUILD IN THIS CARE, WHAT ARE THE PARAMETERS, WHAT'S THE DESIGN? IS IT A RANDOMIZED CONTROL TRIAL, IS IT A NATURAL HISTORY STUDY, IS IT -- DO PEOPLE GET STANDARD OF CARE AND THEN A LITTLE BIT OF RESEARCH ON THE SIDE? OR IS THE CENTRAL THING THE RESEARCH? AND IT'S TRICKY FROM THE INSTITUTIONAL PERSPECTIVE. SOMETHING WE HAVEN'T TALKED ABOUT MUCH IN THIS COURSE AND THAT IS THE GOAL OF THIS INSTITUTION IS RESEARCH. SO EVERYTHING WE DO THAT DOESN'T LOOK LIKE RESEARCH HAS TO BE JUSTIFIED AND LIMITED. AND THAT'S A REALITY TOO. THE REALITY THAT WITH ALL THOSE OTHER THINGS GETS ALL MIXED UP AND SOMETIMES PRETTY MESSY. I WANT TO HIGHLIGHT SOMETHING THAT ANTOINETTE SAID, I WON'T GET YOUR EXACT WORDS BUT IT WAS SOMETHING LIKE THE PATIENTS, THE NURSES, THE INVESTIGATORS, THE INSTITUTION, EVERYBODY ARE ALL OIL IN THE SAME MACHINE OR I FORGET YOUR VERY NICE ANALOGY, BUT IT'S SO TRUE. AND SO THE STORY THAT MIKE TOLD ABOUT HAVING TO MAKE DECISIONS ABOUT WHICH THINGS TO DO AND WHICH NOT TO DO, AND THE STORY THAT LAURA TOLD ABOUT THE PERSPECTIVE OF THE PERSON WE'RE INVITING IN TO HELP US. THAT SEEMS SO OBVIOUS, YOU KNOW, WHEN YOU SAY IT, BUT IN THE DAY TO DAY BUSYNESS THAT WE ALL GET OURSELVES INVOLVED IN, SOMETIMES WE FORGET, WE FORGET TO SIT DOWN AND SAY, OKAY, LET ME THINK ABOUT THE PERSPECTIVE OF THIS PERSON THAT MIGHT BE DIFFERENT THAN MY PERSPECTIVE, AND HOW DO WE WORK TOGETHER TO DO THE BEST THING THAT WE CAN IN ALL CASES? SO WITH THOSE EMOTIONS THAT I JUST EMOTED BASED ON WHAT PEOPLE SAID HERE ON THE PANEL, I'D LOVE TO HEAR YOUR QUESTIONS AND COMMENTS FOR ANY AND ALL THE PANELISTS. PLEASE. >> THANK YOU. SO I HAVE A QUESTION ABOUT THE HIV STUDY, THE FIRST ONE THAT YOU MENTIONED THAT BEFORE GAVE COMPREHENSIVE CARE, AND I WONDER IF I MISSED WHETHER OR NOT YOU STILL GIVE THE PATIENT WHO ENROLLED WHILE YOU WERE GIVING THE GLOBAL CARE, DO YOU STILL OFFER THAT TO THEM? >> NO, WE ACTUALLY -- IT'S REALLY TWO SEPARATE PROTOCOLS, SO THE OLD ONE THAT DID ALL THAT -- >> OH, IT ENDED. >> -- IT TERMINATED, BUT WE OFFERED ROLLOVER ENROLLMENT TO THE NEW ONE TO EVERYONE WHO WAS CURRENTLY ON THE OLD ONE. AND WE GAVE NEARLY A YEAR'S NOTICE THAT WE WERE GOING TO DO THIS. WE HAD SEVERAL WRITTEN DOCUMENTS EXPLAINING THE REAP FOR THAT AND EXACTLY WHAT -- THE REASON FOR THAT AS WELL AS THE CONSENT FORM. I THINK ALL BUT ONE OF 200 ELECTED TO ROLL OVER TO THE NEW STUDY, SO THEY HAD PLENTY OF TIME TO FIND A PRIMARY CARE PROVIDER IF THEY DIDN'T ALREADY HAVE ONE. THEY WERE -- IT WAS ALL REVIEWED WITH THEM, THEY HAD RESIGNED -- THE NEW CONSENT FORM, WHICH IS A COMPLETELY NEW PROTOCOL THAT SPELLED EVERYTHING OUT IN DETAIL. SO THAT WAS ACTUALLY, YOU KNOW, AT THE TIME, WE WERE VERY CAREFUL ABOUT HOW WE MADE THE TRANSITION, SO ANTOINETTE IS ON OR WAS ON THE EARLIER PROTOCOL AND IS NOW ON THE NEW PROTOCOL, AND YOU CAN EXPLAIN HOW THE -- IF YOU WANT TO COMMENT ON THE TRANSITION, HOW WE DID IT, HOW WELL IT WORKED OR DIDN'T WORK. >> I WAS REALLY KIND OF SCARED TO TAKE THAT NEXT STEP FROM THE OLD PROTOCOL TO THE NEW PROTOCOL BECAUSE THAT MEANT I WOULD HAVE TO BASICALLY DO A LOT OF PAPER CHASING FROM ONE -- FROM HERE TO MY PRIMARY CARE PHYSICIAN, AND COME TO FIND OUT IT ROLLED OVER JUST AS SMOOTH, SO IT WORKS VERY WELL. VERY, VERY WELL. >> AND MY SECOND ONE IS MORE OF A COMMENT FOR THE PATIENT REPRESENTATIVE AND I'M WONDERING -- AND THAT'S DR. GRADY AS WELL, I'M WONDERING IF IT WOULD IMPROVE THE FUZZINESS THAT PATIENTS HAVE BETWEEN YOU'RE INVITING ME TO HELP YOU HERE AT THE NIH AND YOU'RE REALLY OFFERING ME THE CARE I NEED, AND, YOU KNOW, THEY'RE BOTH ONE AND THE SAME SOMETIMES. MAYBE IF PATIENTS WERE ASKED, AT THE END OF THIS, OR, YOU KNOW, IF YOU ARE EVER -- IF YOU EVER MEET THE CRITERIA THAT WOULD DISALLOW YOUR PARTICIPATION, WHAT WILL YOU DO? WHAT WOULD BE A PLAN, YOU KNOW, DO YOU HAVE ANY OTHER OPTIONS, CAN WE HELP YOU FIND THOSE NOW OR POINT -- YOU KNOW, I KNOW THAT CLINICAL TRIALS -- THEY VACILLATE AND SOMETIMES IT TAKES YEARS, YOU KNOW, BUT STILL, IF YOU JUST PUT THAT BUG IN THE PATIENT'S EAR, IF YOU WILL, I WONDER IF THAT MIGHT HELP. >> THAT'S WHY I WAS TALKING ABOUT A PLAN B. IT'S A DELICATE THING, THOUGH, BECAUSE YOU HAVE SOMEBODY THERE PARTAKING OF THE STUDY, ALL KINDS OF THINGS RELATED TO THAT STUDY, AND TO GO IN AND SAY, BY THE WAY, WHEN THIS DOESN'T WORK, WHAT ARE YOU GOING TO DO. IT HAS TO BE DONE IN A WAY THAT DOESN'T UNDERMINE THE PARTICIPATION IN THE STUDY THEY'RE IN. THAT'S WITH THEY'RE HERE, WHY WE WANT THEM TO BE HERE. SO IT HAS TO BE DONE DELICATELY, BUT ALSO, I THINK IT SHOULD BE ROUTINE. THIS IS PART OF DISCHARGE PLANNING, THIS IS WHAT WE DO WITH EVERYBODY, IN REGULAR HOSPITALS WE'RE DOING THIS, SO WE DO THIS HERE TOO. THANK YOU VERY MUCH FOR YOUR COMMENT. >> I WAS VERY IMPRESSED AND TOUCHED BY ANTOINETTE'S STORY, AND SO I WAS THINKING THAT THOSE KIND OF STORIES SHOULD BE SHARED IN THE MEDIA, AS LONG AS THE PATIENT AGREES WITH IT, AND ESPECIALLY DURING THE SHUTDOWN, THERE COULD BE A VERY IMPRESSIVE STORY THAT COULD -- I KNOW NIH WAS IN THE NEWS A LOT OF TIMES DURING TH THE SHUTDOWN, BUT I THINK THOSE KINDS OF STORIES COULD BE SHARED AND IF THE PATIENT AGREES WITH THAT, IN OTHER WORDS, THOSE SHOULD BE SHARED AND NOT ONLY TO INCREASE FUNDING FOR NIH, BUT ALSO TO -- I REMEMBER IN THE TOWN HALL MEETING, ONE OF THE SUGGESTIONS FOR THE AUDIENCE WAS WHY DOES NIH JUST HAVE A YEARLY FUNDING, UNLIKE OTHER AGENCIES LIKE EPA OR ENERGY THAT HAS MULTIPLE YEARS OF FUNDING. BECAUSE IF YOU HAVE CLINICAL TRIALS LIKE THIS THAT COULD BE INTERRUPTED BECAUSE OF THE SHUTDOWN, YOU KNOW, THAT'S A JUSTIFICATION TO SAY -- AND I SHOULD PROBABLY HAVE MULTIPLE YEAR FUNDING. THE OTHER POINT I WANTED TO MAKE WAS THE PROTOCOL, I LIKE THE PROTOCOL YOU HAVE THAT'S MORE OPEN-ENDED BECAUSE THEN YOU'RE ABLE TO BRING IN PATIENTS LIKE ANTOINETTE, ALTHOUGH IT'S EXPENSIVE AND IT'S A DILEMMA ON WHICH PATIENTS TO CHOOSE, BUT -- AND ALSO -- AND RESEARCH. BUT THE OTHER ISSUE I WANT TO BRING UP IS THE ISSUE OF TRAINING, BECAUSE OBVIOUSLY IT'S LIMITED IN TERMS OF RESEARCH AND CARE WE PROVIDE HERE, BUT IF THERE'S SOME KIND OF TRAINING, SHORT TERM TRAINING, IT DOESN'T HAVE TO REALLY -- BY TRAINING, IT DOESN'T REQUIRE THAT WE PAY -- BUT THEY COME TO NIH FOR X NUMBER OF TIMES, BASED ON THE SCHEDULE THAT THEY COME TO NIH, LIKE IT'S NOT REALLY THEY COME HERE ALL -- THE WHOLE YEAR OR THE WHOLE -- BUT THEY STILL PRACTICE IN THEIR CLINIC BUT THEY JUST COME HERE LIKE EXTRAMURALLY, THEY JUST COME HERE X NUMBER OF TIMES A WEEK OR A YEAR. THOSE ARE THE TWO COMMENTS I HAVE ABOUT PATIENT PERSPECTIVES AND ALSO THE TRAINING. >> THANK YOU. BOTH OF THOSE ARE GOOD IDEAS FOR THE INSTITUTION TO THINK ABOUT. CERTAINLY WE DO HAVE SHORT TERM TRAINING PROGRAMS AS WELL AS LONGER TERM TRAINING PROGRAMS, BUT -- >> ALSO AT LEAST FOR OUR INSTITUTE AT NAID, WE HAVE AGREEMENTS WITH GEORGETOWN AND GEORGE WASHINGTON WHERE THEIR SECOND AND THIRD YEAR MEDICAL RESIDENTS DO ROTATIONS ON OUR INPATIENT SERVICE. SO AT ANY ONE TIME, THERE ARE PROBABLY TWO OR THREE GEORGETOWN AND TWO OR 3G.W. RESIDENTS WHO ARE ON OUR WARDS, AND WE ALSO OFFER THE CONSULT INFECTIOUS DISEASE TRAINING PROGRAM FOR RESIDENTS AND FELLOWS THAT COME HERE FOR ROTATION ROTATION. GLG THE OTHER THING ANTOINETTE DID NOT TELL YOU IS SHE'S A MEMBER OF THE PATIENT ADVISORY BOARD, SO PEOPLE LIKE HER, WHO HAVE GOOD IDEAS AND ARE WILLING TO TAKE THE TIME AND ENERGY TO COME TO MEETINGS AND TALK ABOUT NOT ONLY HER EXPERIENCE BUT SUGGEST WAYS THAT THE NIH CAN DO BETTER AT A NUMBER OF THINGS, SO HER STORY GETS UTILIZED ALL OVER THE PLACE, RIGHT? DO YOU WANT TO SAY ANYTHING ABOUT THAT EXPERIENCE? >> LAST THURSDAY, DR. JOHN GALLEN AND MS. LAURA COLONEL INVITED ME TO PARTICIPATE IN THE SCIENTIFIC MANAGEMENT REVIEW BOARD, AND THAT BASICALLY GAVE A SPEECH SIMILAR TO THIS ONE TO THAT GROUP OF FOLKS, AND I REALLY, REALLY HOPE THAT THEY GOT THE PICTURE THAT THE FUNDING AT NIH IS REALLY -- IT REALLY IS NEEDED THAT PEOPLE'S LIVES ARE BEING SAVED AS A RESULT OF THE FUNDING BEING PROVIDED HERE AT NIH, AND IF YOU KNOW THAT THE SCIENTIFIC MANAGEMENT REVIEW BOARD IS A BOARD APPOINTED BY CONGRESS TO MAKE SURE THAT NIH I GUESS USES THE MONEY LIKE THEY SHOULD USE IT, IN OTHER WORDS. IT WAS ME AND ANOTHER PATIENT ADVISORY GROUP MEMBER BY THE NAME OF JERRY SAX THAT WAS ON THE PANEL LAST THURSDAY. THANK YOU. >> PLEASE JOIN ME IN THANKING THE PANELISTS AGAIN. [APPLAUSE] THANK YOU VERY MUCH FOR BEING HERE AND SHARING YOUR EXPERIENCES AND PERSPECTIVES. REMEMBER THAT FOR NEXT WEEK, IN ADDITION TO TALKING ABOUT STORED SAMPLES, GENETICS, WE'RE GOING TO HAVE A MOCK IRB, SO READ THE PROTOCOL. IT'S A STUDY OF TRAUMATIC BRAIN INJURY, RANDOMIZED CONTROL