>>I'M HOLLY TAYLOR ON THE FACULTY IN THE DEPARTMENT OF BIOETHICS AT THE CLINICAL CENTER AT THE NIH, I WANT TO WELCOME YOU TO THE ETHICAL AND REGULATORY ASPECTS OF CLINICAL RESEARCH DAY 1. TODAY'S THE -- THIS SESSION IS GOING TO BE THE 24th OFFERING, AND THERE ARE OVER A THOUSAND OF YOU WHO HAVE PRE-ENROLLED FOR THE COURSE. I'LL JUST QUICKLY MENTION THAT YOU ALL OUT THERE SEEM TO BE AN ESPECIALLY FRIENDLY GROUP. I APPRECIATE THE E-MAILS, BUT THERE ARE A THOUSAND OF YOU. SO JUST KEEP THAT IN MIND WHEN YOU E-MAIL YOUR NOTES. OUR GOAL TOGETHER IS TO SPEND ABOUT, WELL, TO SPEND SEVEN WEEKS TO DISCUSS THE MAJOR ETHICAL CONSIDERATIONS INVOLVED IN DESIGNING, CONDUCTING, AND REVIEWING CLINICAL RESEARCH WITH HUMAN BEINGS, AND OUR GOAL IS TO LEAVE YOU WITH SOME KNOWLEDGE AND SKILLS SO THAT IN WHATEVER JOB, CLASS, ENGAGEMENT YOU HAVE, YOU HAVE THE ABILITY TO APPLY ETHICS, TO BE THOUGHTFUL, AND IMPORTANTLY TO BE ABLE TO GIVE REASONS AND JUSTIFICATIONS FOR WHAT YOU'RE BRINGING TO THE TABLE. SO, WE HAVE A TOTAL OF SEVEN WEEKS, AND LET ME SEE WHERE MY SLIDES BEGIN. THIS IS A SLIDE THAT YOU WILL BE -- YOU WILL SEE OFTEN. THOSE OF US ON THE FACULTY NEED TO LET YOU KNOW THAT WE'RE NOT SPEAKING ON BEHALF OF NIH, THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, OR THE U.S. GOVERNMENT. AND THESE ARE THE COURSE OBJECTIVES. I'M NOT GOING TO SPEND A LOT OF TIME GOING THROUGH THESE. YOU HAVE THEM ON YOUR SYLLABUS. BUT THE GOAL HERE AS I MENTIONED IS TO SHARE WITH YOU SOME IMPORTANT INFORMATION AND SKILLS SO THAT YOU CAN THEN ENGAGE IN CONVERSATIONS ABOUT ALL OF THESE IMPORTANT ISSUES. SO, HERE'S AN OVERVIEW OF THE COURSE. AS I SAID, WE'LL BE MEETING SEVEN TIMES. WE'LL ALWAYS MEET AT THIS ADDRESS, THE NIH VIDEOCAST, FROM 8:30 IN THE MORNING TO 11:30 IN THE MORNING, ON WEDNESDAYS. THE EXCEPTION TO THAT IS OCTOBER 5, WHEN WE'LL BE TAKING A BREAK FOR THE YOM KIPPUR HOLIDAY. SO WE'LL START TODAY AND THE LAST DAY OF CLASS WILL BE THE 9th OF NOVEMBER. OH, I WANTED TO MENTION THE BOOK. SO, THIS IS THE COVER OF THE BOOK THAT YOU'RE ALL WELCOME TO PURCHASE IF YOU WOULD LIKE. THAT SAID, ALL OF THE READINGS ARE POSTED IN CANVAS, AND I'LL TALK A LITTLE ABOUT CANVAS IN A MOMENT. SO, YOU'RE WELCOME TO GET THE BOOK, BUT DON'T FEEL LIKE YOU HAVE TO GET THE BOOK BECAUSE ALL OF THE READINGS FROM THE BOOK AND ALL THE OTHER READINGS ARE POSTED AND AVAILABLE ON CANVAS. SO, A COUPLE OF THINGS ABOUT MANY OF YOU. IF YOU'RE TUNED IN, IT'S LIKELY THAT ALL OF YOU HAVE ALREADY SELF-ENROLLED, WHICH IS GREAT. THAT MEANS YOU HAVE ACCESS TO ALL THE COURSE MATERIALS ON CANVAS. AND THAT INCLUDES THE READINGS, WE'RE GOING TO BE POSTING THE -- THE POWERPOINT SLIDES ARE POSTED AT 8 A.M. IN THE MORNING. IF THAT'S ALL YOU WANT, TUNE IN AND DO THE READINGS, ALL YOU NEED TO DO IS SELF-ENROLL. IF YOU WANT TO GET A CERTIFICATE OF PARTICIPATION, YOU HAVE TO SELF-REGISTER, AND THERE IS A PLACE ON THE WEBSITE WHICH I'M GOING TO SHOW YOU IN A MINUTE WHERE YOU NEED TO SELF-REGISTER. THIS IS REALLY EASY. IT'S BASICALLY YOUR NAME AND WHY YOU'RE IN THE COURSE, BUT WE NEED THAT IN ORDER TO THEN TRACK YOU TO SEE WHETHER YOU'VE COMPLETED ENOUGH OF THE SESSIONS IN ORDER TO GET THE CERTIFICATE. THE WAY THAT WE'RE GOING TO TRACK WHETHER OR NOT YOU'VE ATTENDED CLASS IS THAT EACH SESSION HAS A QUIZ. IN EACH OF THE MODULES, THE LAST ITEM IN THE MODULE WILL BE THE QUIZ. THERE ARE THREE QUESTIONS, TWO OF THEM ARE ABOUT THE CONTENT FROM TODAY, AND THE THIRD IS WHAT THE WORD OF THE DAY IS. THE WORD OF THE DAY TODAY IS "NUREMBERG." SO, THAT'S THE WAY THAT WE'LL KNOW THAT YOU HAVE TUNED IN, EITHER LIVE OR REVIEWED THE VIDEO THAT WE WILL POST. THE VIDEOS OF OUR SESSIONS ARE POSTED BOTH IN CANVAS AND IN THE DEPARTMENTAL WEBSITE 24 TO 4 HOURS AFTER CLASS. THOSE OF YOU NOW VIEWING AT A REASONABLE TIME BECAUSE YOU LIVE ON THE OTHER SIDE OF THE GLOBE, THAT'S -- YOU CAN ALWAYS TUNE IN TO THOSE TO GET CREDIT, AND/OR IF YOU MISS A SESSION YOU CAN ALWAYS GO TO ONE OF THE WEBSITES, CANVAS OR THE COURSE WEBSITE, AND WATCH THE VIDEO. WE ALSO SEND YOU AN EVALUATION AT THE END OF EACH SESSION. THERE'S A LOT OF QUIZZING AND FILLING OUT OF FORMS, BUT THIS REALLY HELPS US IN FINDING OUT HOW YOU'RE DOING, WHAT YOU THINK ABOUT THE PRESENTATIONS, WHETHER YOU THINK WE'RE GIVING YOU THE INFORMATION WE PROMISED, AND IT'S JUST REALLY GREAT. THOSE WILL COME TO YOU BY E-MAIL, AND IT'S SURVEY MONKEY SURVEY, FOR THOSE WHO ARE FAMILIAR WITH THE TECHNOLOGY. AGAIN, IT SHOULD BE REALLY STRAIGHTFORWARD. YOU'LL CLICK THE LINK AND FILL OUT THE FORM. THE LAST THING I'M GOING TO MENTION IS THAT I SENT EVERYONE WHO PRE-ENROLLED THE PRE-COURSE ASSESSMENT. THE GOAL THERE WAS TO BASICALLY SEE WHERE IS YOUR UNDERSTANDING TODAY, AND THEN AT THE END OF THE COURSE WE'RE GOING TO SEND THAT OUT AGAIN. I'VE CLOSED THE PRE-COURSE ASSESSMENT THIS MORNING BECAUSE WE'RE NOW IN THE COURSE. SO IF YOU DIDN'T COMPLETE IT, DON'T WORRY. I DON'T KNOW WHO COMPLETED IT OR NOT. IT'S ANONYMOUS. BUT PLEASE DO THE POST-ASSESSMENT WHEN THAT COMES ALONG. AGAIN, WE'RE NOT COMPARING INDIVIDUALS PRE AND POST. WE'RE MEASURING THE GENERAL KNOWLEDGE OF THE GROUP AND THE POST-GENERAL KNOWLEDGE OF THE GROUP. LET ME QUICKLY SAY A COUPLE THINGS ABOUT CANVAS. SOY, -- SO THIS IS A PICTURE OF WHAT I CALL THE CANVAS HUB, LISTS THE MODULES FOR THE COURSE. AT THE VERY TOP YOU SEE KEY DOCUMENTS. I ACTUALLY ADDED A COUPLE OF DOCUMENTS THERE THIS MORNING, BUT THERE YOU'LL SEE A ONE-PAGER THAT GIVES YOU THE PRINCIPLES AND BENCHMARKS DR. GRADY WILL TALK ABOUT MOMENTARILY. THERE'S A LINK TO BIOS OF ALL THE DEPARTMENT FACULTY WHO YOU'LL MEET AND SELF-REGISTRATION IS ALSO CONNECTED THERE. THE SELF-REGISTRATION IS ALSO UNDER THE QUIZ TAB, BUT ALL YOU NEED TO DO IS GO TO THE FRONT PAGE AND COMPLETE THAT SELF-REGISTRATION. IF YOU LOOK DOWN, YOU'LL SECESSION 1, AND I ALSO UPLOADED THE POWER POINTS FOR THIS MORNING, SO THOSE ARE ALSO THERE. SO, FOR EVERY DAY THERE'S A SPECIAL PLACE YOU CAN GET ALL THE INFORMATION YOU NEED. SO, FOR TODAY, FOR EXAMPLE, AND FOR EVERY OTHER DAY, THERE IS A SESSION SUMMARY. SO IF YOU OPEN THAT UP, YOU'LL SEE WHAT THE PLAN IS FOR THE DAY. THIS IS BASICALLY CUT AND PASTED FROM THE SYLLABUS. IT GIVES YOU THE OBJECTIVES, THE SCHEDULE, AND THE READINGS. YOU'LL SEE THAT THERE ARE READINGS AND THEN SOMETIMES WE HAVE OPTIONAL READINGS. ALL OF THE READINGS ARE OPTIONAL, BUT THE ONES WE'VE LISTED AS NON-OPTIONAL ARE THE ONES WE THINK ARE THE SORT OF BEST COMPLEMENT OR SUPPLEMENT TO THE MATERIAL THAT WE'RE COVERING TODAY. I WILL ALSO OCCASIONALLY INCLUDE ADDITIONAL RESOURCES THERE, SO A LINK TO A PARTICULAR DOCUMENT OR SOMETHING THAT COMES UP IN CLASS, DR. GRADY MENTIONS AN ARTICLE, AND WE SAY, OH GOSH, LET'S POST THAT IN THE SESSION. WE WILL POST THAT THEN IN THE MODULE WHERE THE SESSION IS. AS I MENTIONED, THE POWER POINTS FOR THIS SESSION, FOR ALL THE SESSIONS TODAY, ARE POSTED IN A MODULE AT 8 A.M. ON THE DAY OF CLASS. SO FOR THOSE WHO LIKE TO PULL THOSE UP AND TAKE NOTES, THOSE WILL ALWAYS BE THERE AT 8 A.M., HALF HOUR BEFORE CLASS. SO, AS I MENTIONED, THERE ARE READINGS, AND YOU'LL SEE HERE TEXT BOOK, TEXT BOOK, TEXT BOOK, THOSE ARE LINKS TO THE READINGS IN THE MODULE. AND THEN HERE I WANT TO MAKE A POINT ABOUT HOW YOU CAN REACH OUT TO US AND WHEN I SAY "US" I MEAN MYSELF AND CONOR, WHO MANY OF YOU HAVE MET ONLINE. HE'S GOING TO BE HELPING ME ADMINISTER THE COURSE. SO, THERE'S TWO WAYS YOU CAN ASK QUESTIONS DURING THE SESSIONS. ONE WAY IS TO GO TO THE DISCUSSIONS IN CANVAS AND OPEN UP THE DISCUSSION AND POST A QUESTION. NOW, I MENTIONED THAT ALL OF YOU ARE SUPER FRIENDLY. MANY OF YOU HAVE GONE IN THERE ALREADY AND INTRODUCED YOURSELF TO EACH OTHER. SO, I CREATED A SECOND PLACE THAT SAYS, SESSION 1 SUBSTANTIVE QUESTIONS. SO IF YOU GO INTO DISCUSSIONS, YOU'LL SEE THERE ARE TWO. PLEASE USE THE ONE THAT SAYS SESSION 1 QUESTIONS. I'LL BE SITTING OVER THERE, YOU CAN'T TELL, BUT I'LL BE SITTING OVER THERE, THAT'S WHERE I'LL BE ABLE TO SEE THE QUESTIONS. THE OTHER WAY TO ASK QUESTIONS, BECAUSE AS I MENTIONED SOME OF YOU ARE JUST GOING TO PRE-ENROLL OR JUST ENROLL; YOU DON'T REALLY CARE ABOUT BEING ON CANVAS WHICH IS TOTALLY FINE. BUT BECAUSE YOU AREN'T IN CANVAS, THE OTHER WAY YOU CAN ASK QUESTIONS IS TO SEND AN E-MAIL TO THIS E-MAIL, BIOETHICSINQUIRIES, THEY GO TO CONOR WHO WILL SEND THEM TO ME. MY GOAL IS TO COLLECT QUESTIONS AS EACH SPEAKER IS SPEAKING, I WILL BRING THOSE QUESTIONS TO THE GROUP. NOW, YOU GUYS MAY HAVE MANY MORE QUESTIONS THAN WE CAN COVER IN THE IN-PERSON SESSION. I WILL GO IN LATER AND ANSWER QUESTIONS THERE. SO, IF YOU DON'T HEAR YOUR QUESTION ASKED, IT JUST MEANS WE DIDN'T HAVE ENOUGH TIME. BUT I WILL TRY TO ANSWER THOSE. IF YOU HAVE ADMINISTRATIVE QUESTIONS ABOUT THE COURSE, I HAVE POSTED IN CANVAS IN THAT FIRST BLOCK A DOCUMENT THAT HAS COURSE BASICS, AND ANOTHER THAT HAS INFORMATION ABOUT THE CERTIFICATES WHICH I'M GOING TO SAY JUST A LITTLE BIT MORE IN THE LAST COUPLE OF MINUTES. THOSE ARE PLACES YOU SHOULD GO FIRST, IF YOU HAVE A QUESTION, BECAUSE, YOU KNOW, WE WANT YOU TO BE ABLE TO GET QUICK ANSWERS TO YOUR QUESTIONS. GO THERE FIRST, IF YOU CAN'T GET AN ANSWER TO YOUR QUESTION FEEL FREE TO REACH OUT. THIS WAS JUST A REMINDER THAT THE QUIZZES, YOU CAN EITHER GET IT UP IN SESSION 1 OR GO TO THE QUIZ PAGE. NOW, FOR THOSE OF YOU WHO WANT TO GET A CERTIFICATE OF PARTICIPATION, YOU NEED TO ATTEND THREE SESSIONS. THE WAY YOU'RE GOING TO TELL ME YOU'VE ATTENDED IS BY COMPLETING THOSE QUIZZES. IF YOU'RE FROM THE NIH AND YOU WANT TO GET A CERTIFICATE, THE CLINICAL RESEARCH CURRICULUM CERTIFICATE, YOU NEED TO COMPLETE SIX OF THE SEVEN SESSION QUIZZES, AND THOSE OF YOU WHO ARE SEEKING MARYLAND NURSING ASSOCIATION CREDIT ALSO NEED TO COMPLETE SIX OF THE SEVEN -- SORRY, SIX OF THE SEVEN SESSIONS. THOSE WHO COMPLETED THE REGISTRATION QUIZ KNOW THAT WE ASKED YOU ABOUT THAT AND WE, ON THE BACK END, WILL BE SORTING THROUGH THAT INFORMATION. REALLY QUICK, ADMINISTRATIVELY, IF ANYONE OUT THERE NEEDS AN INTERPRETER, WE CAN HAVE ONE COME HERE AND DO, FOR THOSE WHO ARE HEARING IMPAIRED. IF ANYBODY NEEDS THAT, PLEASE -- WELL, I GUESS THEY WON'T BE ABLE TO HEAR IT, BUT I WILL POST A MESSAGE. I'LL SEND OUT A MESSAGE IF ANYONE NEEDS A HEARING IMPAIRED INTERPRETER. WITH THAT, WE'LL MOVE ON TO THE CONTENT OF THE COURSE. SO, IT'S MY GREAT PLEASURE TO INTRODUCE OUR FIRST SPEAKER, CHRISTINE GRADY, WHO IS CURRENTLY THE CHAIR OF THE DEPARTMENT OF BIOETHICS HERE AT THE NIH. DR. GRADY IS A NURSE BIOETHICIST AND SENIOR INVESTIGATOR HERE AT THE CLINICAL CENTER. SHE HAS A RƒSUMƒ THAT IS VERY LONG, AND HAS MADE CONTRIBUTIONS BOTH IN CONCEPTUAL AND EMPIRICAL WORK ACROSS A WHOLE BUNCH OF DIFFERENT TOPICS, INFORMED CONSENT, STUDY DESIGN, RECRUITMENT, MORE RECENTLY AROUND COVID, AROUND ESPECIALLY THE EFFECT OF COVID ON NURSING PROFESSIONALS, SERVED AS COMMISSIONER ON THE PRESIDENT'S COMMISSION FOR THE STUDY OF BIOETHICAL ISSUES FROM 2010 TO 2017, THAT WAS UNDER PRESIDENT OBAMA. SO, WITHOUT FURTHER ADO I'M GOING TO HAND IT OVER TO CHRISTINE AND THEN YOU'LL HEAR -- I'LL BE HERE EVERY DAY, I'LL BE YOUR EMCEE, YOU'LL SEE MORE OF ME TODAY. THANKS. >> GOOD MORNING, EVERYONE. I ACTUALLY NEED SOME RESPONSE. GOOD MORNING, EVERYONE. THERE ARE A FEW PEOPLE IN THE ROOM. >> YES. >> OKAY. THANK YOU, HOLLY, FOR THE INTRODUCTION. THE MOST IMPORTANT THING TO SAY, I'VE BEEN TEACHING IN THIS COURSE SINCE THE FIRST DAY THAT WE EVER DID IT SO THAT'S 24 YEARS, I JUST LEARNED. SO THAT'S A LONG TIME. OKAY. I'M GOING TO TALK ABOUT A FRAMEWORK FOR THE ETHICAL CONDUCT OF CLINICAL RESEARCH TO SET THE STAGE FOR THE REST OF THE COURSE. I THINK THE REST OF THE COURSE IS GOING TO BE IN SOME RESPECTS REFERRING BACK TO SOME OF THE THINGS I'M GOING TO TALK ABOUT THIS MORNING. HERE'S MY DISCLAIMER, ALSO HAVE NO CONFLICTS OF INTEREST TO DECLARE. I THINK IF YOU THINK ABOUT THE ETHICS OF RESEARCH, THE ETHICS OF CLINICAL RESEARCH, I'M GOING TO DEFINE CLINICAL RESEARCH AS RESEARCH WITH HUMAN BEINGS. THERE ARE REALLY TWO QUESTIONS. ONE IS, SHOULD WE DO IT? SHOULD WE USE HUMAN BEINGS IN RESEARCH? THAT'S ONE REALLY IMPORTANT QUESTION. THE SECOND QUESTION, IF THE ANSWER TO THE FIRST IS YES, HOW SHOULD WE DO IT? HOW SHOULD WE GO ABOUT CONDUCTING THE RESEARCH IN AN ETHICAL WAY? SO, CONSIDERING THE QUESTION ABOUT SHOULD WE DO RESEARCH, ONE OF THE THINGS THAT WE KNOW IS THAT CLINICAL RESEARCH DOES AND HAS RESULTS IN COMPELLING SOCIETAL HEALTH BENEFITS. NEW THERAPY, DIAGNOSTIC AND PREVENTIVE STRATEGIES, IMPROVEMENT OF QUALITY OF LIFE, UNDERSTANDING OF HEALTH AND DISEASE. ONE REALLY RECENT OBVIOUS EXAMPLE, COVID VACCINES. COVID VACCINES WERE DEVELOPED BY RESEARCH, HAD A HUGE AMOUNT OF SOCIETAL BENEFITS BOTH IN THE UNITED STATES AND AROUND THE WORLD. I HAVE A GOOD FRIEND WHO JUST HAD A SUCCESSFUL LUNG TRANSPLANT. THAT IS ALL BECAUSE RESEARCH WAS DONE TO FIGURE OUT HOW TO DO IT, WHEN TO DO IT, HOW TO TAKE CARE OF PEOPLE AFTER THE TRANSPLANT HAS BEEN PERFORMED. THERE ARE GREAT EXAMPLES OF STATINS. I DON'T KNOW HOW MANY PEOPLE ARE ON STATINS. THAT'S A HUGE ADVANCE. TREATMENTS FOR CHILDHOOD LEUKEMIA, HUGE ADVANCE. USED TO BE 90% FATAL, NOW IT'S 10% FATAL. SO, LOTS OF EXAMPLES OF THINGS OVER THE COURSE OF TIME THAT HAVE LED TO EITHER THERAPEUTIC OR DIAGNOSTIC OR PREVENTIVE STRATEGIES THAT HAVE GREATLY BENEFITED HUMANKIND. IT'S ALSO IMPORTANT TO RECOGNIZE THAT RESEARCH PROVIDES AT A VERY LOCAL LEVEL THE EVIDENCE BASE FOR CLINICIANS. IF YOU GO TO YOUR DOCTOR BECAUSE YOU HAVE SOMETHING WRONG WITH YOU, YOU HOPE THAT THE APPROACH THAT THE DOCTOR WILL TAKE TO FIGURING OUT WHAT'S WRONG WITH YOU AND HOW TO TREAT YOU WILL BE BASED ON EVIDENCE. AND THAT EVIDENCE IS GATHERED THROUGH RESEARCH. SO RESEARCH HAS BENEFITS BOTH AT THE SOCIETAL LEVEL AND AT THE INDIVIDUAL LEVEL WHEN A PATIENT IS INTERACTING WITH A CLINICIAN. SO, THAT'S ALL GREAT, RIGHT? AS YOU CAN SEE, I THINK RESEARCH IS GOOD. THIS IS JUST A PAGE FROM THE NIH WEBSITE WHICH BASICALLY TELLS YOU THE IMPACT OF NIH RESEARCH. NIH IS ONLY ONE PLACE IN THE WORLD THAT DOES RESEARCH, BUT IT DOES DO A LOT OF RESEARCH AND SPENDS A LOT OF MONEY ON RESEARCH, BUT IT IMPACTS HEALTH, SOCIETY, KNOWLEDGE, AND THEN THERE ARE LOTS OF WONDERFUL STORIES. I THINK IT IS -- THERE'S PLENTY OF EVIDENCE THAT RESEARCH IS AN IMPORTANT THING. OH, THAT'S AN EXTRA SLIDE. THERE ARE ACTUALLY OTHER BENEFITS OF RESEARCH WHICH WE DON'T OFTEN THINK ABOUT. THIS IS ALSO FROM ONE OF THE NIH WEB PAGES. BUT BASICALLY SAYS NIH FUNDING CONTRIBUTES DIRECTLY TO A OF ECONOMIES ACROSS THE COUNTRY, IT HAS ECONOMIC BENEFITS, IT ALSO DRIVES ECONOMIC GROWTH. YOU CAN SEE IN THE SECOND CATEGORY EVERY DOLLAR INVESTED IN BASIC RESEARCH STIMULATES NINE DOLLARS OR EIGHT DOLLARS OF INDUSTRY R&D. THERE'S EXAMPLES OF ECONOMIC GROWTH BASED ON RESEARCH AND HEALTHIER CITIZENS LEAD TO HEALTHIER ECONOMY. SO, THERE ARE OTHER WAYS IN WHICH THE BENEFITS OF RESEARCH CAN BE MEASURED BESIDES JUST HOW MANY COVID VACCINES WERE GIVEN. SO, EVEN THOUGH I HOPE I'VE CONVINCED YOU THE ANSWER TO SHOULD WE DO RESEARCH IN HUMANS IS YES, IT'S NOT AN UNCONDITIONAL YES, BECAUSE WE HAVE TO USE HUMANS, AND I'M USING "USE" INTENTIONALLY, INCLUDE HUMANS IN THE RESEARCH TO KNOW HOW THINGS WORK ON HUMANS. AND SO THE PRIMARY GOAL OF DOING RESEARCH WITH HUMANS IS TO GENERATE USEFUL KNOWLEDGE ABOUT HUMAN HEALTH AND ILLNESS, NOT TO BENEFIT THE PEOPLE IN THE STUDY. THAT'S NOT THE GOAL. EVEN THOUGH OFTEN PARTICIPANTS IN STUDIES DO BENEFIT, THAT'S NOT THE REASON WE'RE DOING THE RESEARCH. AND SO, THE SORT OF ETHICAL CHALLENGE HERE IS THAT WE'RE ASKING A SMALL NUMBER OF PEOPLE TO ACCEPT RISK AND BURDEN AND INCONVENIENCE IN ORDER TO LEARN HOW TO BENEFIT OTHERS. WHICH THEN PUTS THOSE PARTICIPANTS, THOSE INDIVIDUALS, IN A SITUATION WHERE THEY ARE THE MEANS TO DEVELOPING USEFUL KNOWLEDGE AND THEREFORE THEY ARE AT RISK OF BEING EXPLOITED, BEING TAKEN ADVANTAGE OF, AS THE MEANS TO SOMETHING THAT MAY OR MAY NOT BE RELEVANT TO THEM. AND THAT'S WHERE WE END UP WITH THIS SORT OF GENERAL SOCIETAL PERCEPTION SOMETIMES THAT PEOPLE WHO ARE PARTICIPANTS IN RESEARCH ARE GUINEA PIGS, HUMAN GUINEA PIGS. THEY ARE BEING USED TO DO SOMETHING FOR SOMEBODY ELSE. THEY ARE BEING EXPERIMENTED ON SO THAT WE CAN LEARN SOMETHING FOR SOMETHING ELSE. THERE'S SOME TRUTH TO THIS, BUT, YOU KNOW, IT'S A MUCH MORE COMPLICATED SITUATION. SO, IF I'VE CONVINCED YOU SO FAR, I THINK THE ETHICS OF CLINICAL RESEARCH HAS TWO REALLY IMPORTANT GOALS, AND THEY ARE IN TENSION WITH EACH OTHER. ONE IS TO PROMOTE RESPONSIBLE AND USEFUL RESEARCH IN ORDER TO BENEFIT SOCIETY AND FUTURE PATIENTS. AND WHEN DOING SO, WE NEED TO MAKE SURE THAT WE MINIMIZE HARM AND EXPLOITATION BY PROTECTING AND RESPECTING THE PARTICIPANTS WHO ARE IN THE STUDY, THEIR WELFARE AND THEIR RIGHTS. THERE'S ANOTHER WAY THAT CLINICAL RESEARCH IS ETHICALLY COMPLICATED. THAT IS, BECAUSE SO MUCH CLINICAL RESEARCH TAKES PLACE IN CLINICAL ENVIRONMENTS, IN HOSPITALS, HEALTH CARE FACILITIES, AND THE RESEARCHERS ARE OFTEN DOCTORS, NURSES, PSYCHOLOGISTS, PEOPLE WHO LOOK LIKE HEALTH CARE PROVIDERS AND ARE HEALTH CARE PROVIDERS, AND YET THERE'S A REALLY IMPORTANT DIFFERENCE BETWEEN WHAT CLINICAL RESEARCH IS AND WHAT CLINICAL PRACTICE IS, AND THESE, AGAIN, SOMETIMES COME INTO TENSION IN THE CONDUCT OF CLINICAL RESEARCH. I'VE ALREADY MENTIONED THE DIFFERENT GOALS. YOU KNOW, RESEARCH'S GOAL IS TO DEVELOP KNOWLEDGE, THE GOAL OF CLINICAL PRACTICE IS TO TAKE CARE OF PATIENT OR PATIENTS IN FRONT OF YOU. THERE'S ALSO A REALLY IMPORTANT DISTINCTION IN METHODS. SO, IN RESEARCH WE OFTEN USE THINGS LIKE DOSE ESCALATION, RANDOMIZATION, BLINDING, PLACEBO CONTROLS, THINGS LIKE THAT, WHICH ARE IMPORTANT FOR RIGOROUS RESEARCH, RIGOROUS DEVELOPMENT OF A GENERATION OF KNOWLEDGE, BUT WOULD BE VERY UNUSUAL TO ENCOUNTER IN CLINICAL PRACTICE. SO, IMAGINE, FOR EXAMPLE, GOING TO YOUR DOCTOR, YOU HAVE, I DON'T KNOW, STREP THROAT AND THE DOCTOR SAYS, WELL, I'M GOING TO GIVE YOU ONE OF TWO DRUGS, BUT I'M NOT GOING TO KNOW WHICH ONE IT IS, NEITHER ARE YOU. AND THAT WOULD BE AN UNUSUAL THING IN A GENERAL PRACTICE ENVIRONMENT UNLESS THERE WAS A RESEARCH STUDY GOING ON. THERE'S ALSO A DIFFERENCE IN TERMS OF JUSTIFICATION FOR RISKS TO THE INDIVIDUALS IN THE STUDY. SO, THAT DOES NOT MEAN THAT PEOPLE WHO ARE IN CLINICAL PRACTICE ARE NOT SUBJECT TO SOME RISK. MOST INTERVENTIONS WE USE IN MEDICAL PRACTICE HAVE RISKS ASSOCIATED WITH THEM. BUT THOSE RISKS ARE JUSTIFIED BY THE BENEFITS OF USING THAT INTERVENTION FOR THAT PERSON. IN RESEARCH, WE SOMETIMES, ACTUALLY FAIRLY OFTEN, ASK PEOPLE TO DO EXTRA THINGS, BLOOD DRAW, MRI, BIOPSY, WHERE THE RISK IS NOT JUSTIFIED BY BENEFIT TO THE INDIVIDUALS BUT BY THE NEED FOR THE INFORMATION FOR GENERATING KNOWLEDGE. AND THERE ARE ALSO DIFFERENT LEVELS OF UNCERTAINTY. CERTAINLY NOT ALL MEDICAL PRACTICE IS CERTAIN. YOU KNOW, PEOPLE MAKE JUDGMENTS AND TRIAL AND ERROR IN TERMS OF TREATING PATIENTS. THAT'S REALLY GOOD. BUT PREFERABLY MOST OF THAT IS BASED ON EVIDENCE THAT DOES EXIST. EVIDENCE THAT'S BEEN GENERATED BY PRIOR RESEARCH OR BY LOTS OF USE, WHEREAS IN RESEARCH THE STARTING POINT IS UNCERTAINTY. YOU DON'T DO A STUDY UNLESS YOU'RE UNCERTAIN ABOUT THE QUESTION, THE ANSWER TO THE QUESTION. SO THERE'S A DIFFERENCE IN TERMS OF LEVELS OF UNCERTAINTY. THERE'S ALSO A DIFFERENCE IN TERMS OF OBLIGATIONS OF THE PEOPLE DOING THE RESEARCH. SO CLINICIANS IN CLINICAL CARE HAVE OBLIGATION TO CARE AND TREAT THEIR PATIENTS IN ACCORD WITH THE PATIENT'S BEST INTEREST. RESEARCHERS HAVE AN OBLIGATION TO COMPETENTLY CONDUCT RESEARCH WHILE THEY ARE RESPECTING THEIR PARTICIPANT'S RIGHTS AND WELFARE. THESE TOO OFTEN COME INTO CONFLICT BECAUSE SO MANY RESEARCHERS, CLINICAL RESEARCHERS, ARE ALSO CLINICIANS. AND SO THIS WAS ANOTHER WAY -- ANOTHER PLACE WHERE ETHICAL TENSION ARISES. SO, WHAT DO WE DO ABOUT ALL THAT? SO WE DO HAVE A WHOLE BUNCH OF ETHICAL REQUIREMENTS AND GUIDANCE. I SAY A WHOLE BUNCH BECAUSE SOME ARE LAWS AND REGULATIONS, SOME ARE CODES OF ETHICS, SOME OF THEM ARE, SORRY, LITERATURE AND GUIDANCE, THAT'S FOUND IN OTHER PLACES. THEY ALL SORT OF HAVE THE SAME GOAL. THE GOAL BEING TO PROMOTE THE RESPONSIBLE CONDUCT OF RESEARCH WHILE SEEKING PROGRESS IN UNDERSTANDING AND INTERVENING IN HUMAN HEALTH, WHILE MINIMIZING THE POSSIBILITY OF HARM AND EXPLOITATION FOR THE PARTICIPANTS, AND ENSURING THAT RIGHTS AND WELFARE WITH PROTECTED. THERE'S ALSO AN IMPORTANT GOAL IN HELPING TO MAINTAIN PUBLIC TRUST. HOW DOES RESEARCH ENTERPRISE WORK, HOW DO WE PROTECT PEOPLE IN THE PROCESS OF LEARNING, IS REALLY IMPORTANT FOR PUBLIC TRUST. SO, HOW DO WE KNOW HOW TO DO THIS AND HOW DO WE KNOW WHAT THE GUIDANCE ARE? THERE ARE REALLY THINK TWO SOURCES OF GUIDANCE THAT HELP US. ONE ARE HISTORICAL LESSONS, I'M GOING TO SAY ALMOST NOTHING ABOUT THOSE BECAUSE OUR NEXT SPEAKER, SUSAN LETTERER, IS GOING TO TALK ABOUT THE HISTORY, BUT WE'VE LEARNED A LOT FROM THE HISTORY OF MAKING MISTAKES REALLY AND DOING SOME THINGS RIGHT AND SOME THINGS WRONG. WE'VE LEARNED ABOUT HOW TO THINK ABOUT SCOPE AND LIMITATIONS OF CLINICAL RESEARCH FROM AN ETHICAL PERSPECTIVE. AND THEN THERE ARE ETHICAL REASONS. SO I'M GOING TO FOCUS MOST OF MY NEXT HALF HOUR ON SOME OF THE ETHICAL REASONS. BUT JUST TO GIVE YOU A PREVIEW OF HISTORY, AND DR. LETTERER WILL TALK ABOUT A LOT OF THIS, I THINK THE HISTORY OF THE ETHICS OF CLINICAL RESEARCH IS QUITE FASCINATING. SHE'S A WONDERFUL HISTORIAN AND PERSON WHO KNOWS A LOT ABOUT THIS AND CAN GIVE YOU REAL DETAILS ABOUT EPISODES IN HISTORY, BUT I LIKE TO THINK OF HAVING GONE THROUGH AT LEAST FIVE DIFFERENT STAGES, SORT OF STAGE WHEN THERE WERE NO RULES, SORT OF OPEN SEASON FOR PEOPLE WHO HAD THE LUXURY REALLY AND RESOURCES TO BE ABLE TO DO RESEARCH WITHOUT ANY RULES. THEN WE WENT THROUGH A UTILITARIAN PHASE, WHERE IT WAS VERY COMMON FOR STUDIES, LARGE STUDIES, TO USE PEOPLE WHO WERE CONSIDERED MARGINALIZED, ORPHANS, PRISONERS, SOLDIERS AND OTHERS, IN ORDER TO BENEFIT THE REST OF US, THE REST OF SOCIETY. THAT LED TO A PERIOD OF PRETTY INTENSE SCRUTINY BECAUSE PEOPLE STARTED TO RECOGNIZE SOME OF THE EXPERIMENTS THAT WERE BEING DONE ON PEOPLE IN PRISONS, FOR EXAMPLE, SAYING, WHOA, WHAT ARE WE DOING HERE? HOW DO WE THINK ABOUT RESPECTING THE PEOPLE THAT WE'RE ASKING TO INVITE INTO THESE STUDIES? SO THERE WAS A PERIOD OF INTENSE SCRUTINY, BOTH PUBLIC SCRUTINY AND PROFESSIONAL SCRUTINY, WHICH LED TO THE BEGINNING OF AN ERA OF RULES AND REGULATIONS. AND WE STILL OPERATE UNDER A LOT OF PRETTY CLEAR RULES AND REGULATIONS, AND I'M GOING TO MENTION SOME OF THOSE IN A MINUTE. I THINK IN MY LIFETIME, I'VE ALSO, IN MY PROFESSIONAL LIFETIME, I'VE ALSO SEEN A LITTLE BIT OF A PENDULUM SWING TO RE-RECOGNIZE THE IMPORTANT BENEFITS OF RESEARCH. SOME OF THIS STARTED WITH HIV. MY EXPERIENCE WITH HIV-INFECTED PEOPLE IN OF IN HIV-RELATED RESEARCH WHERE PEOPLE ARGUED, YOU KNOW, RESEARCH IS BENEFICIAL. WE NEED TO GET INTO STUDIES, WE HAVE NO OTHER OPTIONS, WE ALSO NEED TO LEARN HOW TO TREAT PEOPLE WITH HIV, OTHERWISE WE'LL NEVER BE ABLE TO SURVIVE. SIMILAR SWING WITH RESEARCH, THEY NEED TO BE PROTECTED IN RESEARCH BUT ALSO STUDIED OR WE DON'T KNOW HOW TO TREAT CHILDREN. THERE'S A LOT OF RECOGNITION OF THAT. IT'S NOT JUST PROTECTION; IT'S ALSO BENEFIT. YOU'LL HEAR MORE ABOUT ALL OF THIS. SO, THESE HISTORICAL ERAS HAVE LED TO A NUMBER OF CODES AND REGULATIONS AND GUIDELINES THAT I'M GOING TO MENTION BRIEFLY, AND I BELIEVE SUSAN WILL MENTION SOME OF THEM AS WELL. NUREMBERG CODE WAS A CODE THAT WAS WRITTEN AT THE NAZI DOCTORS' TRIALS AFTER WORLD WAR II, VERY INFLUENTIAL DOCUMENT WRITTEN IN 1949, NOT TAKEN SERIOUSLY AT LEAST IN THE UNITED STATES FOR MANY, MANY YEARS AFTERWARDS. DECLARATION OF HELSINKI WAS WRITTEN BY THE WORLD MEDICAL ASSOCIATION, ASSOCIATION OF ALL THE LIKE AMERICAN MEDICAL ASSOCIATIONS FROM EVERY COUNTRY AROUND THE WORLD, THEY WROTE THE DECLARATION OF HELSINKI IN 1964 TO BE A GUIDE FOR PHYSICIANS BECAUSE THIS IS MEDICAL ASSOCIATION, FOR PHYSICIANS DOING RESEARCH BOTH WITH THEIR PATIENTS AND NON-PATIENTS. AND IT'S BEEN REVISED MULTIPLE TIMES SINCE 1964. THE BELMONT REPORT IS I THINK ON YOUR SYLLABUS OR IN YOUR CANVAS, A SHORT BUT VERY INFLUENTIAL DOCUMENT THAT WAS WRITTEN BY THE NATIONAL COMMISSION FOR THE PROTECTION OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH IN THE UNITED STATES IN 1979. AND IT EXPLICATES THREE PRINCIPLES THAT GUIDE CLINICAL RESEARCH. THE CIOMS, INTERNATIONAL ORGANIZATION OF MEDICAL SCIENCES, I FORGET WHAT THE C IS. >> YEAH, SOMETHING LIKE THAT. >> W.H.O., WORLD HEALTH ORGANIZATION. THESE INTERNATIONAL GUIDELINES WHICH, AGAIN, WERE REVISED SEVERAL TIMES WERE WRITTEN WITH A SPECIFIC PURPOSE, TO TAKE GUIDANCE IN DECLARATION OF HELSINKI FROM A RICH PLACE CONDUCTED IN A POOR PLACE. THE ORIGINAL MOTIVATION. WHAT'S GREAT ABOUT THE CIOMS GUIDELINES IN EVERY ITERATION THEY NOT ONLY HAVE PRINCIPLES THEY SPELL OUT BUT THEY HAVE LONG EXPLANATIONS OF HOW THEY CAME AND HOP YOU SORT HOW YOU THINK ABOUT THEM USEFUL FOR UNDERSTANDING ETHICAL PRINCIPLES OF RESEARCH. ICH/GCP, INTERNATIONAL CONFERENCE ON HARMONIZATION, GOOD CLINICAL PRACTICE GUIDELINES WHICH WERE DEVELOPED ORIGINALLY IN THE '90s AS A WAY TO KIND OF HARMONIZE DIFFERENT REGULATIONS ACROSS DIFFERENT JURISDICTIONS. SO IT WAS FIRST THE U.S., JAPAN, AND AUSTRALIA I THINK. MAYBE WESTERN EUROPE, WHO DECIDED -- AGREE ON A SET OF GUIDELINES SO THAT THEY WOULDN'T HAVE TO REDO OR RE-REGULATE RESEARCH FINDINGS IN THEIR JURISDICTION. AND ICH-GCP IS RECOGNIZED WORLDWIDE AS A GUIDANCE FOR RESEARCH. THERE ARE SOME REGULATIONS. MANY OF YOU I SUSPECT HAVE HEARD OF THE COMMON RULE, A SET OF REGULATIONS THAT THE UNITED STATES GOVERNMENT HAS, FOR THE DEPARTMENT OF HEALTH AND HUMAN SERVICES, FOUND AT THE TITLE 45 OF THE CODE OF FEDERAL REGULATIONS PART 46. YOU WILL HEAR PEOPLE SAY OTHER 45CFR .46, IT MEANS THE COMMON RULE. IT'S CALLED THE COMMON RULE, THE SAME SET OF REGULATIONS BASICALLY HAVE BEEN ADOPTED BY 16 OTHER U.S. GOVERNMENT AGENCIES. ALL VERY SIMILAR. ONE ORGANIZATION THAT DOES NOT FALL UNDER THE COMMON RULE IS THE FDA. AND SO THE FOOD AND DRUG ADMINISTRATION IN THE UNITED STATES AS ITS OWN SET EVE REGULATIONS FOUND IN TITLE 21, OF FEDERAL REGULATION, 50 AND 56 ARE PARTS THAT ARE VERY SIMILAR TO WHAT'S IN 45CFR .46 BUT NOT IDENTICAL. THERE ARE OTHER FDA REGULATIONS VERY IMPORTANT FOR PEOPLE TO KNOW ABOUT WHEN THEY ARE DOING RESEARCH THAT THEY ARE GOING TO SUBMIT FINDINGS TO THE FDA. EVERYWHERE PEOPLE WORK, THERE ARE INSTITUTIONAL GUIDELINES. NIH NOT ONLY FOLLOWS THE COMMON RULE, ANYONE FUNDED BY THE NIH HAS TO KNOW ABOUT THOSE GUIDELINES AND FOLLOW THEM. DEPENDING ON WHETHER YOU'RE DOING RESEARCH THERE ARE OFTEN LAWS AND REGULATIONS FOR THAT JURISDICTION THAT YOU NEED TO KNOW ABOUT AND FOLLOW. SO LOTS OF GUIDANCE, LOTS OF REGULATIONS, LOTS OF RULES. WHICH I THINK LEADS PEOPLE TO KIND OF FEEL LIKE THIS WHEN THEY ARE TRYING TO DO RESEARCH. YOU KNOW KNOW, HOW DO I KNOW WHAT TO DO? HOW DO I FOLLOW ALL THESE RULES AND REGULATIONS AND GUIDELINES AND DO SOMETHING THAT'S COHERENT AND COHESIVE? IT'S FURTHER COMPLICATED BY MOST OF THE GUIDANCES I JUST WENT THROUGH WERE WRITTEN IN RESPONSE TO A HISTORICAL EVENT AND THEREFORE HAVE A PARTICULAR EMPHASIS BASED ON WHATEVER THE HISTORICAL EVENT WAS. AND IN DIFFERENT JURISDICTIONS, DIFFERENT GUIDELINES AND REGULATIONS APPLY. SO, FOR EXAMPLE, IN YOU'RE AN NIH-FUNDED INVESTIGATOR, WHO IS ALSO DOING -- DOING A STUDY ON A PRODUCT THAT YOU WANT TO ULTIMATELY GET APPROVED BY THE FDA, AND YOU'RE DOING IT IN A DIFFERENT COUNTRY, YOU PROBABLY HAVE TO KNOW -- NOT PROBABLY, YOU HAVE TO KNOW THE RULES THAT THE COMMON RULE LAYOUT, FDA REGULATIONS LAYOUT, ICH-GCP, MAYBE DECLARATION OF HELSINKI AND LAWS OF THE COUNTRY YOU'RE IN, A LOT OF RULES. SOMETIMES THE RULES AT LEAST APPEAR TO BE DIFFERENT OR DIVERGENT AND INTERPRETATION IS OFTEN DIVERGENT. SO, YEARS AGO WE IN THE DEPARTMENT HERE THOUGHT THERE WAS A NEED FOR A SYSTEMATIC COHERENT UNIVERSALLY APPLICABLE ETHICAL FRAMEWORK FOR THINKING ABOUT CLINICAL RESEARCH. THIS FRAMEWORK WHICH HAS 8 PRINCIPLES WHICH I'LL TALK ABOUT EACH OF REALLY WAS DERIVED FROM SORT OF SYNTHESIS OF MANY OF THOSE OTHER GUIDES, GUIDELINES, CODES, AND REGULATIONS. WE DIDN'T MAKE THIS ALL UP, RIGHT? WE SORT OF PUT IT TOGETHER FROM GUIDANCE THAT WAS ALREADY OUT THERE AND STUDYING IN DETAIL SOME OF THE CODES THAT WERE INEXISTENCE AND SOME OF THE HISTORY AS WELL. SO, THE 8 PRINCIPLES ARE COLLABORATIVE PARTNERSHIP, VALUABLE SCIENTIFIC QUESTION, VALID SCIENTIFIC METHODOLOGY, FAIR SUBJECT SELECT, FAVORABLE RISK/BENEFIT, INDEPENDENT REVIEW, INFORMED CONSENT, RESPECT FOR ENROLLED SUBJECTS. AS I MENTIONED EARLIER, IN THIS COURSE, THIS FRAMEWORK WILL BE REFERRED TO MANY TIMES. IT'S USEFUL. I OBVIOUSLY THINK IT'S USEFUL, BUT I THINK A LOT OF OTHER PEOPLE HAVE FOUND IT USEFUL TOO. WHAT I'M GOING TO DO NOW IS TALK ABOUT EACH OF THOSE, WHAT THEY MIGHT, HOW YOU MIGHT THINK ABOUT IT IN THE CONTEXT OF RESEARCH AND WHAT SOME CHALLENGES ARE. COLLABORATIVE PARTNERSHIP, THE IDEA IS THAT ETHICAL RESEARCH SHOULD BE A COLLABORATIVE PARTNERSHIP WITH THE RELEVANT PARTNERS, IN PLANNING, CONDUCTING, OVERSEEING, AND INTEGRATING RESEARCH RESULTS INTO THE HEALTH SYSTEM. THIS MAKES SENSE BECAUSE IF WE'RE TRYING TO GENERATE USEFUL KNOWLEDGE THAT SOMEBODY WILL USE, WE NEED TO UNDERSTAND THE CONTEXT IN WHICH IT WILL BE USED, RIGHT? AND COLLABORATE WITH THOSE PARTNERS SO THAT IT WILL MAKE SENSE FOR THEM, BE USEFUL FOR THEM, AND BE INTEGRATED INTO THE HEALTH SYSTEM. IT ALSO COLLABORATIVE -- COLLABORATIVE PARTNERSHIPS DEMONSTRATES RESPECT FOR CONTRIBUTIONS OF THE PARTNERS, VARIOUS PARTNERS. AND I ALREADY MENTIONED COLLABORATION WITH EXISTING SYSTEMS OF HEALTH CARE. THIS COULD MEAN COLLABORATIVE PARTNERSHIPS WITH POLICYMAKERS AND HEALTH SYSTEMS, COMMUNITY ADVISORY BOARDS OR COMMUNITIES, PATIENT ADVOCATES, COLLABORATING INVESTIGATORS, PRACTICING CLINICIANS, PARTICIPANTS, OR IN SOME CASES ALL OF THE ABOVE. IT DEPENDS ON THE RESEARCH. LOTS OF DIFFERENT WAYS IN WHICH PARTNERSHIP MAKES SENSE IN RESEARCH. AND SO THESE ARE JUST SOME EXAMPLES. YOU CAN SEE IN THE BOTTOM RIGHT-HAND CORNER A COMMUNITY ADVISORY GROUP, I BELIEVE IT'S IN UGANDA. THE ONE AT THE TOP IS AN NIH -- I FORGET THE NAME OF IT. THEY IDENTIFY RESEARCH PRIORITIES. THERE IS -- SORRY -- AN INSTITUTION IN THE UNITED STATES CALLED PCORI INVOLVING PATIENT AND FAMILIES IN THE PLANNING DESIGN AND CONDUCT OF RESEARCH SO THERE'S LOTS OF WAYS THIS IS MANIFESTED. THE SECOND PRINCIPLE IS VALUABLE SCIENTIFIC QUESTION. AND THIS BASICALLY IS THE QUESTION OF SO WHAT, WHY ARE WE DOING THIS. IT SHOULD ANSWER A QUESTION OR GENERATE UNDERSTANDING ABOUT HUMAN HEALTH OR ILLNESS, SOCIALLY, CLINICALLY OR SCIENTIFICALLY USEFUL. THAT'S A PRETTY BROAD STATEMENT, IT IS A CRITICAL ESSENTIAL STATEMENT IN TERMS OF UNDERSTANDING THE ETHICS OF RESEARCH BECAUSE WHY WOULD YOU EVER ASK A PERSON TO EVEN BE INCONVENIENCED FOR SOMETHING THAT ISN'T USEFUL. OR WHY WOULD YOU WASTE RESOURCES ON SOMETHING THAT WOULDN'T BE USEFUL IN ANY WAY? SO APPRECIATING USEFULNESS, SOCIAL VALUE OF A RESEARCH QUESTION IS CRITICAL. THERE ARE DETAILS THINKING ABOUT WHAT THIS MEANS, WHAT'S THE VALUE OF ANSWERING THE QUESTION? I THINK ONE OF THE BIG CHALLENGES IS HOW WILL THAT VALUE BE JUDGED AND TO WHOM WILL THE KNOWLEDGE BE VALUABLE, THE PARTICIPANTS, COMMUNITY, PEOPLE IN SOCIETY, DRUG COMPANY, SPONSORS, QUESTIONS HOW TO THINK ABOUT WHAT THE VALUE OF THIS RESEARCH IS. AND THERE'S STILL SOME ROOM FOR SORT OF SUSSING OUT WHAT THIS REQUIREMENT ENTAILS. WHO JUDGES IT, HOW IT'S JUDGED, WHAT HAS VALUE AND WHAT DOESN'T, HOW MUCH VALUE MATTERS, THOSE ARE ALL IMPORTANT QUESTIONS. THIS IS JUST ONE INTRODUCTORY PAGE FROM AN ISSUE OF BIOETHICS DEVOTED TO THIS QUESTION OF SOCIAL VALUE IN 2017, AND A LOT OF THE COMMENT, PEOPLE WHO WROTE ARTICLES FOR THIS ISSUE, MANY OF THEM SUPPORT THE IDEA OF SOCIAL VALUE AND ARGUE FOR HOW IMPORTANT IT IS AND THERE ARE SOME SKEPTICS WHO SAY, OH, IT'S NOT IMPORTANT OR ONLY IMPORTANT IN CERTAIN CASES, THINGS LIKE THAT FROM. MY PERSPECTIVE, IT IS THE FUNDAMENTAL FIRST STEP IN TERMS OF UNDERSTANDING ETHICAL RESEARCH. THE SECOND STEP, OR THE THIRD REALLY, ONCE YOU'VE GOT PARTNERS YOU'VE GOT YOUR VALUABLE QUESTION, THIRD IS SCIENTIFIC METHODOLOGY. YOU'VE GOT A GOOD QUESTION, YOU KNOW WHO YOU'RE WORKING WITH, COLLABORATING WITH, AND FOR %HY, WHAT FOR, EXCUSE ME, NOW THE QUESTION IS HOW DO YOU DESIGN IT? HOW DO YOU PUT IT TOGETHER SO YOU GET THE INFORMATION THAT YOU'RE LOOKING FOR? AND SO, IT NEEDS TO BE METHODOLOGICALLY RIGOROUS, IN THE DESIGN, METHODS, STATISTICAL POWER AND STATISTICAL METHODS, IN ORDER TO YIELD VALID RELIABLE GENERALIZABLE AND INTERPRETABLE DATA. SO IF YOU HAVE, YOU KNOW, A MESS OF DATA AND CAN'T FIGURE OUT WHAT IT IS EVEN TELLING YOU, YOU'VE WASTED EVERYBODY'S TIME AND DONE SOMETHING TECHNICALLY UNETHICAL. IT'S ALSO IMPORTANT AT THIS STAGE TO MAKE SURE THAT YOUR PROPOSED RESEARCH ANSWERING AN IMPORTANT QUESTION IS FEASIBLE. THERE ARE LOTS OF REASON THAT THAT MIGHT NOT BE THE CASE AND SO THINKING CAREFULLY ABOUT HOW IT'S FEASIBLE BECAUSE IF YOU PUT IT TOGETHER THEN YOU CAN'T DO IT, THAT'S ALSO A PROBLEM. A LOTS OF PEOPLE LOOK AT THAT VALID SCIENTIFIC METHODOLOGY REQUIREMENT, WE CALL THAT ETHICAL, IT'S SCIENCE, HAS NOTHING TO DO WITH ETHICS, I THINK MY VIEW IS, AND MANY PEOPLE SHARE THIS VIEW, THEY ARE INEXTRICABLE. YOU CANNOT DO A GOOD RESEARCH STUDY UNLESS IT'S SCIENTIFICALLY RIGOROUS, AND IF IT'S NOT, IT'S NOT ETHICAL. THERE'S A WAY THEY ARE INTEGRATED IN TERMS OF THINKING ABOUT THE DETAILS. AND YOU CAN THINK OF SOME OF THE SORT OF DETAILS OF SCIENTIFIC METHODOLOGY THAT ARE CHALLENGING IN TERMS OF THIS NOTION OF SCIENTIFIC VALIDITY, WHEN YOU'RE TRYING TO ANSWER A RESEARCH QUESTION THAT'S USEFUL AND ALSO TRYING TO PROTECT THE PARTICIPANTS, RIGHT? AND SOCIETY. SO, ONE INTERESTING -- ALL OF THESE HAVE SCIENTIFIC REASONS THAT YOU CHOOSE ONE OR ANOTHER BUT THEY ALSO HAVE LOTS OF VALUE-LADEN REASONS, ETHICAL REASONS. EXAMPLE OF CHOICE OF ENDPOINTS, IN THE VACCINE STUDIES THERE WAS WHAT ARE THE END POINTS, ANTIBODIES, INFECTION, DISEASE? DOES IT MATTER? HOW DOES IT MATTER? WHO DOES IT MATTER TO? WHAT ABOUT DESIGNS, RANDOMIZED DOUBLE BLINDED CONTROLS, WHEN DO YOU USE OR NOT USE, INFERIORITY OR SUPERIORITY STUDY, MEASURES OUTCOME, FOLLOWING PEOPLE, POWER, SAMPLE SIZE, THOUGHTS, -- METHODS. THERE ARE PEOPLE WHO RAIL AGAINST THE USE OF PLACEBO, THERE ARE JUSTIFIABLE USE ALSO OF PLACEBO, AND THERE'S A LOT OF JOKES AND CHALLENGES TO GETTING STATISTICS RIGHT, THERE'S WAYS YOU CAN FINAGLE STATICS TO MAKE YOUR OUTCOME BE WHAT YOU WANT IT TO BE. THE NEXT PRINCIPLE IS FAIR SUBJECT SELECTION. SO, YOU GOT YOUR PARTNERS, YOU'VE GOT USEFUL QUESTION, A VALID AND RIGOROUS DESIGN. NOW YOU HAVE TO DECIDE WHO YOU'RE GOING TO INVITE TO PARTICIPATE. AND THIS IS GUIDED BY THE SCIENTIFIC OBJECTIVES, YOU NEED TO KNOW WHO YOU NEED TO STUDY IN ORDER TO ANSWER THE SCIENTIFICALLY VALUABLE QUESTION. BUT IT'S NOT THE ONLY THING THAT GUIDES THIS. SO, SCIENTIFIC OBJECTIVES GUIDE IT, GUIDE THE INCLUSION CRITERIA, RECRUITMENT STRATEGIES AND SELECTION, AND NOT PRIVILEGE OR EASY AVAILABILITY OR VULNERABILITY, BUT THEN THERE'S THIS FURTHER REQUIREMENT TO SORT OF CONSIDER THE BENEFITS AND BURDENS OF THE PARTICIPATION IN THIS STUDY AND ARE WE FAIRLY DISTRIBUTING THEM. ONE OF MY COLLEAGUES SORT OF HAS WRITTEN ABOUT TURNING FAIR SUBJECT SELECTION ON ITS HEAD IN THE FOLLOWING WAY, THAT YOU SHOULD START BY ASSUMING EVERYBODY IS ELIGIBLE AND NOBODY SHOULD BE EXCLUDED UNLESS THERE'S JUSTIFICATION. AND SO THE QUESTION THEN IS, WHAT ARE THE -- WHAT WOULD BE THE JUSTIFICATIONS? IN MY -- MOST PEOPLE WOULD AGREE, TWO OF THEM ARE SCIENTIFIC OBJECTIVES, YOU CANNOT -- YOU DON'T NEED TO INCLUDE PEOPLE THAT CAN'T ANSWER THE SCIENTIFIC OBJECTIVE, AND SECOND IS RISK, ALTHOUGH EVEN SOME PEOPLE ARGUE ABOUT THIS, PEOPLE AT EXCEPTIONAL HIGH RISK MIGHT BE EXCLUDED. THE THIRD AND MORE CONTROVERSIAL ISSUE IS VULNERABILITY. AND VULNERABILITY IS ANOTHER CONTESTED CONCEPT IN BIOETHICS, OR IN THE WORLD, BECAUSE IT MEANS DIFFERENT THINGS. IT MEANS SOME VERY SPECIFIC THINGS IN RESEARCH, BUT SOME PEOPLE DO NOT BELIEVE THAT'S A GOOD JUSTIFICATION FOR EXCLUDING PEOPLE. IT'S ALSO INTERESTING TO THINK ABOUT THE PENDULUM SWING I MENTIONED A WHILE AGO, THAT, YOU KNOW, I THINK BOTH OF THESE THINGS ARE TRUE, AND YET IF WE LOOK HISTORICALLY THERE WAS A TIME WHEN RESEARCH REALLY WAS THOUGHT OF PRIMARILY AS A BURDEN AND SUBJECTS NEEDED TO BE PROTECTED. I THINK THERE'S BEEN MORE RECOGNITION OF RESEARCH AS A BENEFIT AND SUBJECTS NEED ACCESS. THEY NEED ACCESS TO STUDIES. AND SO SORT OF REMEMBERING THAT TENSION AS WELL IS AN IMPORTANT WAY TO THINK ABOUT FAIR SUBJECT SELECTION. I MENTIONED ALREADY VULNERABLE GROUPS. THERE ARE SOME REGULATIONS THAT ARE SPECIFIC TO GROUPS THAT ARE CONSIDERED VULNERABLE. THOSE ARE CHILDREN, PREGNANT WOMEN AND FETUSES, AND PRISONERS. THOSE ARE THE ONLY THREE IN THE UNITED STATES REGULATIONS THAT ARE COVERED BY ADDITIONAL REGULATIONS FOR VULNERABILITY. BUT YOU CAN LOOK AT LOTS OF DIFFERENT GUIDANCES AND LITERATURE ON VULNERABLE POPULATIONS IN RESEARCH AND THE LIST IS MUCH, MUCH LONGER. YOU MIGHT THINK ABOUT PEOPLE WHO CAN'T CONSENT FOR THEMSELVES FOR A VARIETY OF REASONS, PEOPLE WHO ARE SEVERELY ILL, AND THE LIST GOES ON AND ON. THERE'S ALSO SOME CHALLENGES IN TERMS OF FAIR SUBJECT SELECTION IN TERMS OF MAKING CHOICES. SO THIS IS ONE THAT CAME UP YEARS AGO IN A GENE THERAPY TRIAL, THE QUESTION OF WHETHER IT WAS PREFERABLE TO TEST EARLY, SO EARLY PHASE, POTENTIALLY RISKY THERAPY IN HEALTHY ADULTS BECAUSE THEY COULD CONSENT, BUT THE FACT THAT THEY WERE ADULTS MEANT THAT THEY HAD A MILDER FORM OF DISEASE THAT ALLOWED THEM TO LIVE TILL ADULTHOOD. OR TO TEST THIS EARLY POTENTIALLY RISKY THERAPY IN SEVERELY ILL INFANTS WHO WERE OTHERWISE LIKELY TO DIE AS INFANTS, COULDN'T CONSENT FOR THEMSELVES OBVIOUSLY, BUT THEY HAD MORE TO GAIN, SOME PEOPLE SAY LESS TO LOSE, BUT THEY COULDN'T CONSENT FOR THEMSELVES. SO THIS WAS A REAL LIVE STRUGGLE ABOUT WHICH WAY TO GO. ANYBODY IN THE ROOM WANT TO GUESS WHAT THEY CHOSE? YOU WILLING FADDLE? INFANTS? NO, ADULTS. WE CAN TALK ABOUT THAT MORE BECAUSE IT'S A REALLY INTERESTING CASE. I MENTIONED EARLIER THE BELMONT REPORT. I'M GOING TO INSERT THIS HERE BECAUSE I THINK THE BELMONT REPORT TALKS ABOUT THREE IMPORTANT PRINCIPLES UNDERLYING THE CONDUCT OF RESEARCH. RESPECT FOR PERSONS, BENEFICENCE, JUSTICE. JUSTICE AS A SORT OF PRINCIPLE THAT GUIDES SELECTION OF SUBJECTS FOR RESEARCH WASN'T RECOGNIZED BEFORE THE BELMONT REPORT WAS PUT INTO PLACE. SO THE WHOLE FAIR SUBJECT SELECTION WE'VE BEEN TALKING ABOUT IS BASED ON THE NOTION OF JUSTICE. AND DISTRIBUTIVE JUSTICE IN MANY RESPECTS. BUT THIS IS REALLY THE FIRST PLACE THAT IT WAS ENUNCIATED AS AN IMPORTANT PART OF RESEARCH. BELMONT ALSO I THINK VERY CLEARLY BECAUSE ABOUT BOUNDARIES BETWEEN PRACTICE AND RESEARCH I MENTIONED BEFORE. NOW THERE'S ASSESSMENT OF RISK/BENEFIT WITH THE FOCUS HERE BEING ON RISKS TO THE PARTICIPANTS IN THE STUDY. AND THE QUESTIONS TO BE ASKED ARE, ARE THE RISKS IN THE STUDY TO THE INDIVIDUALS IN THE STUDY NECESSARY AND HAVE THEY BEEN MINIMIZED TO THE EXTENT POSSIBLE? AND ARE THEY JUSTIFIED, EITHER BY BENEFIT TO THOSE INDIVIDUALS OR THE SOCIAL VALUE? THE IMPORTANCE OF THE KNOWLEDGE TO SOCIETY. AN INTERESTING KIND OF ASSESSMENT, RIGHT? RISKS TO THESE PEOPLE VERSUS VALUE TO SOMEBODY ELSE. THEN THERE'S A THIRD QUESTION THAT'S OFTEN PUT INTO THIS EQUATION FAVORABLE RISK/BENEFIT ARE THERE WAYS WE CAN ENHANCE BENEFIT FOR PARTICIPANTS IN THE STUDY? THESE ARE BASED ON PRINCIPLES OF NON-MALEFICENCE AND BENEFICENCE. I STARTED WITH THIS AT THE BEGINNING, WE DO ACCEPT THE FACT PEOPLE IN THE STUDY MAY NOT BENEFIT, THAT THAT'S NOT THE ROLE OR GOAL OF THE RESEARCH. INTEREST OF SOCIETY OR GENERATION OF KNOWLEDGE MIGHT JUSTIFY RISKS AS LONG AS WE PROTECT THE RIGHTS OF THE PEOPLE IN THE STUDIES. THERE ARE LOTS OF REALLY INTERESTING CHALLENGES IN TERMS OF IDENTIFYING RISKS AND BENEFITS. LIKE WHICH ONES COUNT. I'M RUNNING OUT OF TIME. DAVE WINDLER USED TO RAISE THE ISSUE IF SOMEBODY HAS TO DRIVE TO THE CLINIC FOR THE VISIT AND WALK ACROSS A DARK PARKING LOT TO GET INTO THE CLINIC AND, YOU KNOW, GO OVER CONSTRUCTION SITES, IS THAT A RISK WE SHOULD COUNT FOR RESEARCH? I WOULD SAY MOST OF THE TIME THAT IS NOT A RISK WE COUNT FOR RESEARCH BUT INTERESTING TO THINK ABOUT WHETHER OR NOT THAT WOULD MAKE SENSE. MINIMIZING RISKS IS A REALLY IMPORTANT PART OF THIS EQUATION, AND MINIMIZING IT BY MAKING SURE PEOPLE ARE TRAINED, KNOW WHAT THEY ARE DOING, YOU KNOW, DRAWING BLOOD ONCE INSTEAD OF FOUR TIMES IF THERE ARE FOUR REASONS FOR DRAWING BLOOD. LIMITING RISKS IS SOMETHING WE DO FOR SOME POPULATIONS. IT'S THE BASIS OF THE CHILDREN'S REGS. THERE'S HUGE DISCUSSIONS ABOUT THE DIFFERENCE BETWEEN DIRECT RISKS, SORRY, DIRECT BENEFITS FROM A STUDY AND INDIRECT BENEFITS THAT PEOPLE GET FROM PARTICIPATING, AND LOTS OF JUDGMENT REQUIRED FOR DETERMINING BOTH LEVEL OF RISK AND WHETHER OR NOT A PARTICULAR STUDY HAS A PROSPECT OF BENEFIT. INDEPENDENT REVIEW IS TO ENSURE THINGS ARE BEING DONE ETHICALLY AND BIASES AND CONFLICTS ARE CHECKED AND TO ASSURE THE PUBLIC WE'RE NOT USING PEOPLE INAPPROPRIATELY, IN THE UNITED STATES THIS IS DONE BY INSTITUTIONAL REVIEW BOARDS, IRBs, IN OTHER PLACES RESEARCH ETHICS COMMITTEES, BASICALLY THE SAME IDEA. THESE ARE THE CRITERIA FROM 45CFR . .46. THESE ARE THINGS I'VE ALREADY TALKED ABOUT, OTHER THAN THE LAST ONE. RISKS ARE MINIMIZED, JUSTIFIED, SUBJECTS WILL BE SELECTED AND TREATED FAIRLY. THE NEXT -- OH, TWO THINGS ABOUT OVERSIGHT, I THINK I'LL SKIP AND CHALLENGE IS INDEPENDENT REVIEW, LOTS OF VOLUME, LOTS OF VARIED INTERPRETATIONS, STUDIES DONE ON IRB JUDGMENT, LOTS OF INCONSISTENCY, AND IN THE LAST FEW YEARS WE HAVE MOVED AS A UNITED STATES UNDER THE REGULATIONS TO SINGLE IRB REVIEW AND RELIANCE, I THINK WE'RE STILL WORKING OUT KINKS OF THAT. SEVENTH OF EIGHT, INFORMED CONSENT, IMPORTANT IN THE FOLLOWING SENSE, MANY PEOPLE WHEN THEY THINK ABOUT WHAT'S ETHICAL RESEARCH, IT'S INFORMED CONSENT. BUT IT DOESN'T MAKE SENSE TO ASK SOMEBODY TO BE IN A STUDY UNLESS YOU'RE SURE THERE'S A STUDY THAT'S WORTH DOING, WELL DESIGNED, HAS THE RIGHT PEOPLE IN IT, AND THE RISKS ARE MINIMIZED, BENEFITS ENHANCED. THEN YOU APPROACH PEOPLE AND SAY WOULD YOU LIKE TO BE IN THIS, AND ON BASIS OF RESPECT FOR PERSONS INFORMED CONSENT GIVES OPPORTUNITY FOR THEM TO DECIDE. THERE'S GOING TO BE A WHOLE OTHER LECTURE ON INFORMED CONSENT SO I WON'T SAY MORE THAN SAYING IN THE PROCESS OF INFORMED CONSENT THERE ARE A LOT OF THINGS TO TAKE INTO ACCOUNT, A PERSON HAS TO BE ABLE TO GIVE CONSENT, THAT'S COMPETENCY, GET THE RIGHT INFORMATION, THEY HAVE TO UNDERSTAND IT, AND THEY HAVE TO MAKE A CHOICE. LOTS OF CHALLENGES TO INFORMED CONSENT. I THINK I'M GOING TO TALK ABOUT QUALITY WHEN I TALK ABOUT INFORMED CONSENT AND APPROACHES, AND I THINK SCOTT IS GOING TO TALK ABOUT CAPACITY SO WE WON'T BELABOR THIS HERE. THE EIGHTH AND I THINK REALLY IMPORTANT PRINCIPLE THAT DOESN'T GET AS MUCH ATTENTION IN MANY OF THE OTHER CODES AND REGULATIONS IS WHAT WE CALLED RESPECT FOR ENROLLED PARTICIPANTS, A CATCH-ALL, AGAIN COULD USE MORE ATTENTION. BASICALLY THE IDEA WAS IF YOU READ MANY OF THE OTHER REGULATIONS ABOUT RESEARCH, SORT OF ETHICAL RESPONSIBILITIES AND WHEN YOU START THE STUDY -- END WHEN YOU START YOUR STUDY. BUT THATTENT KA -- BUT THATTENT -- THAT CAN'T BE RIGHT. YOU'RE ENGAGING IN INTIMATE WAYS OVER LONG PERIOD OF TIME. A LOT OF THINGS FALL UNDER THIS, I'M SURE I DON'T HAVE THEM ALL ON THIS LIST BUT THESE ARE SOME OF THEM. I THINK THERE ARE ALSO SOME REALLY INTERESTING CHALLENGES IN TERMS OF HOW WE DO THIS. THERE'S BEEN LOTS OF REALIZATION THAT WE DO NOT DO WELL AT PROVIDING PEOPLE INFORMATION AND RESULTS AT THE END OF THE STUDY WHERE THEY HAVE PARTICIPATED AND GIVEN OF THEMSELVES AND THEY DON'T EVER FIND OUT WHAT HAPPENED. AND THERE'S ALSO BEEN A LOT OF ATTENTION IN RECENT YEARS TO WHAT SHOULD HAPPEN AT THE END OF A STUDY IN TERMS OF ACCESS TO THE INTERVENTIONS THAT HAVE BENEFITED PEOPLE IN THE STUDY. SO THOSE ARE THE EIGHT. THEY ARE SEQUENTIAL AND SYSTEMATIC. THEY ARE NECESSARY, MEANING IN EVERY STUDY THEY ALL NEED TO BE CONSIDERED. SOME OF THE PROCEDURAL REQUIREMENTS, SOMETIMES, CAN BE WAIVED WITH GOOD JUSTIFICATION. THEY ARE UNIVERSAL. THEY APPLY TO EVERY STUDY, EVERYWHERE, OVER TIME. AND YET HOW YOU IMPLEMENT THEM HAS TO BE IN CONTEXT. THEY DO REQUIRE BALANCING SPECIFICATION AND JUDGMENT AND IN ORDER TO HAVE THAT JUDGMENT PEOPLE NEED NT PEOPLE NEED TO TAKE COURSES LIKE THIS SO THEY CAN UNDERSTAND NUANCES IN THE TRADEOFF AND MAKE THOSE DECISIONS. THAT'S IT. QUESTIONS? COMMENTS? >> THANK YOU, DR. GRADY. >> YOU'RE WELCOME. SO CLAP, CLAP, CLAP, CLAP, EVERYONE. SO WE HAVE ABOUT TEN MINUTES FOR QUESTIONS. FOR THOSE OUT THERE, WE HAVE SOME STUDENT LEARNERS IN CLASS. THEY ARE ALL ABLE TO ASK QUESTIONS. SO IF THEY HAVE QUESTIONS THEY ARE GOING TO WALK OVER TO THE MIC. IF YOU HAVE QUESTIONS OUT THERE, YOU CAN GO TO THE SPOT IN THE DISCUSSION BOARD THAT SAYS SUBSTANTIVE QUESTIONS FOR SESSION 1, AND IF YOU ARE NOT IN CANVAS YOU CAN SEND A MESSAGE TO THE BIOETHICS-INQUIRIES E-MAIL. ERIN IS GOING TO COME AND -- AARON IS GOING TO COME AND ASK A QUESTION. >> I'M WONDERING ABOUT WITH THE EIGHT PRINCIPLES, IF WE SHOULD THINK OF THEM AS PRINCIPLES THAT WE USE TO EVALUATE A PROPOSED STUDY PROSPECTIVELY OR RETROSPECTIVELY, THAT MIGHT MAKE A DIFFERENCE WHETHER ALL EIGHT ARE NECESSARY, SPECIFICALLY I'M THINKING ABOUT WITH RETROSPECTIVE ASSESSMENT OF SOME STUDY THAT'S ALREADY COMPLETED MAYBE A LONG TIME AGO, WE MAY LOOK FAVORABLE AT A STUDY FROM A LONG TIME AGO EVEN IF IT'S NOT SCIENTIFICALLY VALID BECAUSE SCIENCE IS CHANGE, MIGHT NOT THINK IT'S AUTOMATICALLY AN UNETHICAL STUDY BECAUSE PEOPLE DIDN'T HAVE A CHANCE TO KNOW BETTER BUT PROSPECTIVELY WOULDN'T WANT TO WAIVE THAT REQUIREMENT BECAUSE THE SCIENCE MIGHT CHANGE, IT SEEMS LIKE MAYBE THIS HOLDS FOR OTHER PRINCIPLES TOO BUT WHAT SHOULD BE ON THE LIST MIGHT CHANGE DEPENDING ON WHAT THE LIST IS EXACTLY FOR. >> GREAT YES. I THINK IT'S USEFUL FOR BOTH, PROSPECTIVELY AND RETROSPECTIVELY BUT YOU RAISE TWO IMPORTANT ISSUES. ONE IS I THINK IN EVERY CASE SOME OF THE PRINCIPLES WE'RE CALLING THEM ARE GOING TO HAVE MORE EMPHASIS THAN OTHERS. THERE ARE TIMES WHEN, YOU KNOW, I DON'T KNOW, THE RISKS ARE SO SMALL THAT YOU DON'T HAVE TO SPEND A LOT OF TIME THINKING ABOUT HOW TO MINIMIZE RISKS, OR THE DESIGN, APPROPRIATE DESIGN, TO ANSWER THE QUESTION, IS SO OBVIOUS YOU'VE GOT TO FIGURE OUT HOW TO DO IT. THERE ARE WAYS, THERE ARE STUDIES IN WHICH THAT IS TRUE. AND THAT HAPPENS PROSPECTIVELY. I ALSO THINK THAT IN EVERY CASE IT REQUIRES SOME JUDGMENT AND SOME BALANCING SO PEOPLE HAVE TO REALLY THINK ABOUT IN THIS CASE WHAT DO WE MEAN BY FAIR SUBJECT SELECTION, OKAY? I THINK RETROSPECTIVELY THEY HAVEN'T BEEN USED AS MUCH RETROSPECTIVELY BUT I THINK THEY ARE QUITE VALUE. SIMILARLY WE HAVE TO USE JUDGMENT ABOUT WHAT MAKES SENSE GIVEN THE CONTEXT OF THIS STUDY. ONE OF THE THINGS PEOPLE HAVE DONE WHICH WE SHOULD DO WITH HUMILITY IS TRY TO JUDGE STUDIES DONE IN THE PAST, HOW DO YOU JUDGE SOMETHING DONE IN THE PAST WHEN THE RULES WERE DIFFERENT, EXPECTATIONS WERE DIFFERENT, CULTURE WAS DIFFERENT, WHATEVER. I THINK YOU CAN MAKE SOME JUDGMENTS BUT YOU HAVE TO BE HUMBLE ABOUT HOW TO DO IT. I THINK IT STILL PROVIDES A FRAMEWORK BY WHICH ONE COULD BEGIN TO MAKE THOSE KINDS OF JUDGMENTS. DOES THAT HELP? >> YEAH, THANK YOU. >> WHILE WE'RE WAITING ON QUESTIONS PERHAPS SOMEONE IN THE ROOM HAS A QUESTION. I'LL JUST SAY VERY BRIEFLY THAT ALMOST ALL, I THINK I CAN SAY ALMOST ALL OF THE DOCUMENTS AND REFERENCES THAT DR. GRADY MENTIONED ARE IN CANVAS AND AVAILABLE. THEY ARE ATTACHED TO MODULE ONE. THE ONE THAT TALKS YOU THROUGH EACH OF THE PRINCIPLES IS THERE. YOU MIGHT WANT TO PULL THAT OUT AND REFER TO IT OVER AND OVER AGAIN BECAUSE IT'S REALLY GOING TO BE THE FRAMEWORK FOR THE COURSE IN ADDITION TO ETHICAL ANALYSIS WE DO. KAJI? >> YES, THANK YOU. I WAS WONDERING IF YOU COULD A LITTLE BIT TALK ABOUT HOW YOU THINK THIS FRAMEWORK AFFECTS THE VERY WELL-KNOWN INEQUALITIES IN GLOBAL BIOMEDICAL RESEARCH, THE 90-10 GAP, SOCIAL VALUE OR UNIVERSAL VALUE OR PARTICULAR VALUE OF SPECIFIC RESEARCH PROJECTS, HOW DO YOU THINK THAT HAS AN IMPACT? >> GREAT QUESTION. I'M ASSUMING EVERYBODY HEARD IT. >> YEAH, I THINK SO. QUICKLY TO REPEAT, THE QUESTION WAS ABOUT HOW DO WE THINK ABOUT THIS IN THE GLOBAL CONTEXT WHERE THERE ARE LOTS OF DISPARITIES? >> YES. AND THE 90-10 GAP. I DO THINK IN SOME WAYS, THIS IS ALSO A SOURCE OF CRITICISM ACTUALLY, IN SOME WAYS PRINCIPLES ARE BROAD ENOUGH THEY CAN BE APPLIED IN DIFFERENT CONTEXTS. I THINK FOR THE SPECIFIC QUESTION YOU'RE ASKING, HOW DO WE SORT OF REEQUILIBRATE FAIRNESS IN RESEARCH IT DOESN'T SPEAK TO THAT UNLESS YOU THINK ABOUT VALUE AS CONTEXTUALIZED ISSUE. AND IT IS, IN MANY CASES. I MEAN, ALSO FAIR SUBJECT SELECTION CAN BE CONTEXTUALIZED, A LOT OF THINGS COULD BE CONTEXTUALIZED IN A SPECIFIC SPOT. LET ME GIVE AN EXAMPLE OF WHAT I'M THINKING ABOUT. THERE HAVE BEEN EXAMPLES IN THE PAST OF PEOPLE WHO HAVE SAID, LET'S TAKE OUR STUDY TO INDIA AND DO IT THERE BECAUSE THERE ARE A LOT OF UNTREATED PEOPLE. AND WE CAN DO IT FAST AND WE CAN DO IT CHEAPER AND WE'LL GET IT DONE. WITHOUT ANY INTENTION OF EVER COLLABORATING WITH PEOPLE AT A REAL SORT OF RESPECTFUL ETHICAL COLLABORATIVE PARTNERSHIP LEVEL. AND WITHOUT ANY INTENTION OF MAKING THE PRODUCT USEFUL FOR AND AVAILABLE TO THE PEOPLE IN INDIA. I DON'T MEAN TO PICK ON INDIA, JUST USING IT AS AN EXAMPLE. BUT THAT I THINK COULD BE CRITICIZED, APPROPRIATELY, BUT IT WOULD BE A QUESTION OF WHO YOUR PARTNERS ARE, COLLABORATIVE PARTNERSHIP, VALUE OF THE STUDY AND TO WHOM, WHETHER OR NOT THE SELECTION OF PARTICIPANTS IN SITES IS FAIR. I MEAN, THOSE ARE ALL BUILT INTO THIS FRAMEWORK IN A WAY THAT IS NOT AT THE LEVEL THAT I'VE BEEN TALKING ABOUT AND NOT EVEN AT THE LEVEL IN THIS ARTICLE BECAUSE THIS IS JUST A GENERAL INTRODUCTION OF WHAT THE PRINCIPLES MEAN BUT I THINK APPLYING IT ALLOWS YOU TO MAKE THOSE KINDS OF DISCERNMENTS. DOES THAT MAKE SENSE? >> KELSEY? >> A BIG QUESTION. MANY CODES WERE WRITTEN IN THE 20th CENTURY AND YOU MENTIONED HOW DECLARATION OF HELSINKI AND W.H.O. GUIDELINES HAVE BEEN UPDATED RECENTLY, WONDERING IF YOU COULD BRIEFLY TOUCH ON SOME OF THE FOCUSES OF UPDATES AS WE GETTING INTO THE 21ST CENTURY NOW, MORE RECENT FOCUSES. >> THEY HAVE BEEN UPDATED IN THE LAST 20 YEARS. AND SOME OF THE UPDATES BASICALLY ARE REPEATS OF WHAT WAS THERE BEFORE BUT MAYBE WITH MORE CLARITY. THERE HAVE BEEN SOME ADDITIONS TO SOME OF THE -- LIKE I THINK IT WAS IN THE 2000 VERSION OF HELSINKI, THEY ADDED TWO THINGS NOT IN PREVIOUS VERSIONS AND SET UP AN INTERNATIONAL FIRESTORM OF CONTROVERSY OVER WHETHER OR NOT THEY MADE SENSE, AND THE TWO WERE, IF I CAN REMEMBER, ONE WAS ABOUT POST-TRIAL STUFF, IT DIDN'T USE THOSE WORDS BUT IT WAS ABOUT THE PEOPLE SHOULD HAVE ACCESS TO INTERVENTIONS THAT WERE PROVEN BENEFICIAL. AND THAT CREATED A HUGE CONTROVERSY FOR THE FOLLOWING REASON. THERE WERE QUESTIONS ABOUT WHAT DOES BENEFICIAL MEAN, WHO GETS TO DECIDE, WHO IS RESPONSIBLE FOR MAKING THINGS AVAILABLE AFTERWARDS, AND THE REVISIONS, MORE RECENT REVISIONS OF HELSINKI SOFTENED LANGUAGE, STILL THERE, BUT IT BASICALLY SAYS STAKEHOLDERS HAVE TO COME TOGETHER AND WORK ON THIS TOGETHER. THE OTHER THING THAT HAPPENED IN 2000 WAS ABOUT THE USE OF PLACEBO, HUGE CONTROVERSIES AT THAT TIME IN HISTORY, I DON'T KNOW IF SUSAN WILL TALK ABOUT THESE OR NOT, ABOUT LARGE INTERNATIONAL TRIAL THAT USED PLACEBO FOR STUDYING PREGNANT WOMEN WITH HIV. AND SO HELSINKI CAME UP WITH A NEW PROVISION THAT REALLY LIMITED THE USE OF PLACEBO IN CLINICAL TRIALS, SET UP A LOT OF DISCUSSION AND MEETINGS ALL OVER THE WORLD ABOUT WHAT THAT MEANT, HOW TO INTERPRET IT, WHATEVER. IT HAS ALSO BEEN CHANGED IN MORE RECENT VERSIONS, TO SORT OF RECOGNIZE THAT THERE ARE TIMES WHEN PLACEBO IS ACTUALLY VERY IMPORTANT TO USE AND SO THERE HAVE BEEN THAT KIND OF CHANGE IN THE GUIDANCE. SOME PEOPLE CRITICIZE THAT AND SAY ETHICS SHOULDN'T CHANGE BUT, YOU KNOW, IT'S NOT -- I THINK IT'S NOT ETHICS CHANGING, IT'S UNDERSTANDING THE PARTICULAR TENET AND HOW IT APPLIES TO WHAT'S IMPORTANT IN RESEARCH, REALLY FIGURING OUT HOW TO DO IT AS ETHICALLY AS POSSIBLE. SO THOSE ARE SORT OF LIVING DOCUMENTS. AND ICH-GCP HAS UPDATED. >> AND THE COMMON RULE. >> IT'S APPROPRIATE TO HAVE UPDATES. IT'S HARD. BUT THEY ARE. >> WITH THE COMMON RULE WE'RE GOING TO SPEAK BRIEFLY ABOUT ONE THAT DR. GRADY MENTIONED ABOUT THE SINGLE IRB. NOTHING REALLY IN THOSE REVISIONS TO THE COMMON RULE ARE 21ST CENTURY RELATED, RIGHT? THEY ARE VERY MUCH REFINEMENTS OF THINGS WE'VE BEEN CHATTING AND ARGUING ABOUT FOR MANY YEARS. AND OF BUT THERE ARE LOTS OF THINGS COMING DOWN THE PIKE AS IT WERE. >> YEP. >> ARTIFICIAL INTELLIGENCE, USE OF DIGITAL TECHNOLOGIES, THAT THESE TYPES OF FRAMEWORKS WILL AT LEAST HELP US FRAME WHAT WE DON'T KNOW. >> AND THERE ARE OTHERS -- I MEAN, IT'S A GREAT EXAMPLE, USE OF DIGITAL TECHNOLOGY FOR CONSENT, FOR EXAMPLE. YOU KNOW, IN THE FRAMING OF THE COMMON RULE, NOBODY WOULD HAVE THOUGHT OF THAT. THERE'S NOTHING IN THERE SPECIFICALLY ABOUT IT. BUT THERE HAVE BEEN -- THERE HAS BEEN A GUIDANCE WRITTEN BY FDA AND NIH ON HOW TO USE DIGITAL TECHNOLOGY TO GET INFORMED CONSENT IN THE WAY THAT THE COMMON RULE REQUIRES. >> OKAY, THANK YOU. [APPLAUSE] AS I PROMISED, YOU'LL SEE ME MULTIPLE TIMES A DAY, AND IT'S ALSO THE CASE THAT WE'RE GOING TO HAVE SOME GUEST LECTURERS. TODAY WE'RE HAVING OUR FIRST LECTURE, DR. SUSAN LEDDERRER, AND OUR GUESTS ARE GOING TO JOIN US BY ZOOM. SO THERE YOU CAN SEE SUSAN ON THE SCREEN. SHE'S AT HOME IN WISCONSIN. SHE IS THE ROBERT TERRELL PROFESSOR OF HISTORY OF MEDICINE AND BIOETHICS, UNIVERSITY OF WISCONSIN. SHE'S A HISTORIAN OF MEDICINE AND BIOMEDICAL ETHICS, TAUGHT AT PENN STATE AND YALE BEFORE MOVING TO UNIVERSITY OF WASHINGTON AT MADISON. HER FULL BIO IS POSTED IN CANVAS, I'LL JUST MENTION IN 1994 SHE WAS APPOINTED BY PRESIDENT CLINTON TO THE ADVISORY COMMITTEE ON HUMAN RADIATION EXPERIMENTS WHICH COVERED A TON OF HISTORICAL TERRITORY AND SHE CONTRIBUTED TO THE COMMITTEE'S LENGTHY REPORT ON RADIATION RESEARCH SPONSORED BY THE FEDERAL GOVERNMENT BETWEEN 1944 AND 1974. SO WITH THAT, I'M GOING TO HAND IT OVER TO DR. LEDERER. >> GOOD MORNING. AND WELCOME, FROM MADISON, WISCONSIN, NOT UNIVERSITY OF WASHINGTON, HOLLY. >> I'M SO SORRY. SORRY! >> WE'RE SENSITIVE ABOUT THAT OTHER UW, LET ME SAY THAT. I'M HAPPY TO BE HERE EVEN IF I HOPED TO BE IN WASHINGTON BUT I AM NOT. SO, HERE IS MY DISCLOSURE SLIDE THAT I HAVE NO RELATIONSHIPS TO DISCLOSE AND THESE ARE MY OWN VIEWS. I'VE ALSO PUT UP MY E-MAIL ADDRESS, BECAUSE I'M HAPPY TO TAKE QUESTIONS BY MAIL OR IF ANY OF YOU IN THE AUDIENCE WOULD LIKE ADDITIONAL READINGS, I'M HAPPY TO PROVIDE INFORMATION ABOUT THAT. HISTORY OF RESEARCH ETHICS IS TITLE OF MY TALK BUT I WOULD NEED MANY MORE HOURS THAN ALLOTTED TO DO THAT JUSTICE. I'M GOING TO TAKE A SLICE OF HISTORY AND FOCUS ON WHY DO WE HAVE THE RULES FOR RESEARCH THAT WE HAVE. IN A SENSE, DR. GRADY HAS ALREADY CLUED YOU IN, MANY OF THE RULES AND GUIDANCES WRITTEN HAVE BEEN IN RESPONSE TO TRAGIC EVENTS, TRAGIC ABUSES OF HUMAN SUBJECTS, IN THE PAST. AND YOU'RE GOING TO HEAR MANY MORE IN THE NEXT 40 MINUTES OR SO. BUT JUST TO STEP BACK FOR A MINUTE, I WANT TO SUGGEST AS IN THE BOTTOM OF THIS SLIDE THAT THIS IS A PATTERN ONE COULD DISCERN OVER THE COURSE OF THE 20th CENTURY, AND I APOLOGIZE FOR TAKING US BACK TO THE 20th CENTURY RATHER THAN THE 21st. OVER THE COURSE OF THE 20th CENTURY A LOT OF U.S. HEALTH POLICY CAN BE UNDERSTOOD AS A RESPONSE TO SCANDALS AND TRAGEDIES, AND I'LL JUST BRIEFLY ALLUDE TO SOME OF THEM. SO, YOU MAY BE FAMILIAR WITH THE FACT THAT PATENT MEDICINE, OVER-THE-COUNTER DRUGS WERE A LOT LESS SAFE IN THE 19th CENTURY. COCAINE TOOTH DROPS OR WINE BLESSED BY THE POPE THAT HAD COCAINE. THE PUBLICATION IN 1905 OF UPTON SINCLAIR'S "THE JUNGLE," AND EXPOSƒ ABOUT THE MEAT PACKING INDUSTRY AND FOOD SUPPLY, LED AFTER DECADES OF CONSUMER ACTIVISM TO CONGRESS PASSING THE FOOD AND DRUG ACT IN 1906. NOW, WASN'T PERFECT LEGISLATION, IT DIDN'T GO NEARLY FAR ENOUGH, NOT UNTIL 1938 FOLLOWING THE ELIXIR OF SULALINOMIDE TRAGEDY THERE WAS REHAULING OF THE FOOD DRUG AND COSMETIC ACT. SULFA DRUGS WAS ONE OF THE GREAT INNOVATIONS OF THE 1930s, MASSENLIG COMPANY USED THE SOLVENT, USED IN ANTI-FREEZE, LED TO DEATH OF 107 PEOPLE INCLUDING CHILDREN. THERE WAS LACK OF OVERSIGHT WITH COSMETICS, WOMEN WOULD USE MASCARA AND GO BLIND OR REDUCING DRUGS BECAUSE DIET WAS IMPORTANT, THEY THEY WOULD KILL PEOPLE. EFFECTIVE FOR LOSING WEIGHT BUT KILLED, THAT LED TO A MAJOR REVISION, FOR THE FIRST TIME DRUGS AND COSMETICS HAD TO BE TESTED FOR TOXICITY BEFORE MARKETING. THERE HAD TO BE ADEQUATE DIRECTIONS ON PACKAGES, AND A NUMBER OF DRUGS WERE DESIGNATED BY PRESCRIPTION ONLY TO ENSURE THAT PEOPLE WERE USING THESE UNDERSTOOD A PHYSICIAN'S ADVICE. THERE CONTINUED TO BE MAJOR REVISIONS, PARTICULARLY IN THE LATE 1950s, EARLY 1960s, OVER A TRAGEDY INVOLVING A DRUG INTRODUCED IN EUROPE AND THEN IN THE UNITED STATES, THALIDOMIDE. MANY OF YOU ARE FAMILIAR. IT'S NOW BEING USED AGAIN I THINK SELECTIVELY. BUT THERE CAME REPORTS THAT THERE WERE CHILDREN BORN WITH UNUSUAL BIRTH DEFECTS, MADE CONNECTION WITH THE FACT THAT WOMEN IN EARLY PREGNANCY WERE USING THIS DRUG AND LED TO THE BIRTH OF THESE EXTRAORDINARY CHILDREN. AFTER A SERIES OF HEARINGS, AGAIN IN CONGRESS, THE HARRIS AMENDMENTS WERE MADE TO THE FOOD AND DRUG ADMINISTRATION RULES THAT DRUG MAKE HERS TO ESTABLISH EFFICACY BEFORE THEY WENT ON THE MARKET, AND THEN THEY HAD TO REPORT ANY ADVERSE EFFECTS OR SERIOUS SIDE EFFECTS ASSOCIATED WITH THOSE DRUGS. AND IT ALSO REQUIRED THAT CLINICAL STUDIES, THAT IS STUDIES INVOLVING HUMANS, HAD TO BE CONDUCTED BY CLINICAL EXPERT OR QUALIFIED EXPERTS AND THE FIRST KIND OF REGULATION IN THE FEDERAL GOVERNMENT THAT CONSENT -- WELL, CONSENT -- INFORMED CONSENT WAS REQUIRED OF STUDY SUBJECTS. ONE WE OFTEN DON'T THINK ABOUT WAS PROTECTION FOR ANIMAL SUBJECTS. I'M REFERRING HERE TO THE ANIMAL WELFARE ACT WHICH WAS PASSED IN 1966. THIS FOLLOWED SIX DECADES OF EFFORTS BY ANIMAL PROTECTIONISTS TO INTRODUCE REGULATIONS TO PREVENT ANIMAL USE IN LABORATORIES, BUT WHAT REALLY TIPPED CONGRESS INTO ACTION WAS A PHOTO ESSAY IN "LIFE" MAGAZINE, SOME OF YOU MAY BE OLD ENOUGH TO REMEMBER "LIFE" MAGAZINE, AN EXTRAORDINARILY POPULAR PERIODICAL. IT RAN A PHOTO ESSAY, YOU CAN SEE IT, YOUR DOG IS IN CRUEL DANGER, CONCENTRATION CAMPS FOR DOGS, STOLEN DOGS SOLD TO RESEARCH, AND LED CONGRESS TO ACT. AND WHAT WAS THE TIPPING POINT FOR THE PASSAGE OF LEGISLATION TO PROTECT HUMAN SUBJECTS OF BIOMEDICAL RESEARCH WAS NATIONAL RESEARCH ACT IN 1974, AND I'M GOING TO TALK ABOUT SOME OF THE MOST FAMOUS OR INFAMOUS CASES THAT, ESPECIALLY TUSKEGEE SYPHILIS STUDY THAT LED CONGRESS TO ENACT THIS LEGISLATION IN 1974. THIS ACT, WITH CHANGES, CONTINUES TO INFLUENCE THE CONDUCT OF CLINICAL RESEARCH IN THE UNITED STATES. BEFORE GETTING TO THAT, I WANT TO GO EVEN FURTHER BACK, JUST TO REMIND YOU THAT THE HISTORY OF HUMAN EXPERIMENTATION AS WELL AS HISTORY OF CONTROVERSY OVER HUMAN EXPERIMENTATION ACTUALLY IS MUCH OLDER THAN POST WORLD WAR II. I WON'T DWELL HERE BUT I ENCOURAGE YOU IF YOU HAVE ANY INTEREST TO PURSUE IT BUT I'LL GIVE TWO VERY BRIEF EXAMPLES. THIS WAS A LAW THAT WAS CONSIDERED BY THE U.S. SENATE IN 1900. A LAW THAT WOULD REQUIRE INVESTIGATORS TO DISCLOSE IN ADVANCE THE PURPOSE AND PROCEDURES OF ANY NON-THERAPEUTIC EXPERIMENT INVOLVING HUMAN BEINGS. WHICH IS, I STILL FIND IT REALLY INTERESTING THAT THE SENATE WAS CONSIDERING THIS IN 1900 BECAUSE WE DON'T CONSIDER 1900 TO BE THE HEY-DAY OF BIOMEDICAL RESEARCH. BUT THIS BILL WAS NOT PASSED, LET ME TELL YOU, BUT THE SENATE DID DISCUSS IT. IT CALLED FOR EXPLICIT BAN ON -- THEY DIDN'T USE THE WORLD, VULNERABLE, BUT CLASSES OF INDIVIDUALS WHO HAVE BEEN CONSIDERED VULNERABLE AND CONTINUED TO BE CONSIDERED VULNERABLE OVER THE COURSE OF THE 20th AND 21ST CENTURY, A BAN ON EXPERIMENTS ON PEOPLE DEEMED UNABLE TO CONSENT, THAT INCLUDED INFANTS, THAT INCLUDED CHILDREN UNDER THE AGE OF 21, AND PERHAPS NOT SURPRISINGLY PREGNANT WOMEN. BECAUSE IT WAS CONSIDERED THAT PREGNANT WOMEN BECAUSE OF CHANGES IN THEIR BODY WERE UNABLE TO EXERCISE DECISIONAL CAPACITY. NOW, I ALSO DON'T WANT TO SUGGEST THAT EVERY HUMAN EXPERIMENT THAT WAS CONDUCTED BEFORE WE HAD THE COMMON RULE OR REVISED COMMON RULE WAS NOT CONDUCTED WITHOUT CONCERN FOR THE HUMAN SUBJECTS, THE HUMAN BEINGS WHO WERE PARTICIPATING IN THE STUDY. AND SO THE SLIDE THAT I'M SHOWING YOU IS A PAINTING CELEBRATING U.S. ARMY'S YELLOW FEVER BOARD IN CUBA IN 1900. THOSE OF YOU MAY RECALL YELLOW FEVER WAS A PARTICULAR IMPEDIMENT TO LONG LIFE AND WELL-BEING IN TROPICAL AREAS, NOT ONLY IN CUBA BUT IN PANAMA WHERE THE PANAMA CANAL WOULD BE BUILT. THE BOARD THERE UNDERTOOK EXPERIMENTS TO ESTABLISH THE MOSQUITO VECTOR OF YELLOW FEVER, THAT IT WAS NOT TRANSMITTED IN OTHER WAYS. AND IN WHAT I THINK IS REALLY A REMARKABLE EVENT WALTER REED AND COLLEAGUES INTRODUCED WRITTEN PERMISSION FORMS FOR THOSE PEOPLE TO UNDERSTAND, THE PEOPLE THEY WERE TRYING TO RECRUIT INTO THE STUDY, TO UNDERSTAND THAT THEY WERE PARTICIPATING IN SOMETHING THAT HAD RISKS, THERE WERE BENEFITS INCLUDING CASH. THESE WOULD NOT PASS OUR IRBs TODAY BUT NONETHELESS I THINK IT'S A REMARKABLE PRESCIENSE ON HIS PART. THEY WERE TRYING TO RECRUIT PEOPLE OF SPANISH DESCENT NEW TO THE ISLAND, AND MADE THE FORMS AVAILABLE IN ENGLISH AND SPANISH, ONLY RECRUITED SPANISH MEN WHO WERE OVER THE SPANISH AGE OF CONSENT WHICH AT THAT TIME WAS 25. YOU COULDN'T READ THAT. BUT I MEAN HERE'S AN EXAMPLE OF SOME LANGUAGE. UNDERSIGNED UNDERSTANDS HE ENDANGERS HIS LIFE TO SOME EXTENT, BUT ENTIRE TO ESCAPE INFECTION ON THE ISLAND. HE WILL RECEIVE MEDICAL CARE FROM THE COMMISSION WHICH WOULD NOT BE AVAILABLE TO HIM IF HE INCURRED YELLOW FEVER IN OTHER CIRCUMSTANCE. SUBJECTS RECEIVED $100 IN GOLD, A CONSIDERABLE AMOUNT IN 1900, AND THEIR FAMILIES WOULD RECEIVE $200 IF DEATH OCCURRED OF ONE OF THE PARTICIPANTS. THERE WERE NO DEATH AMONG LAY PARTICIPANTS. ONE OF THE PHYSICIANS JESSE LOZERE DID DIE IN THE COURSE OF THE EXPERIMENTS. THE CUBAN-BORN DOCTOR RECALLED A WRITTEN CONSENT OBTAINED FROM EACH ONE SO THAT MORAL RESPONSIBILITY WAS TO A CERTAIN EXTENT LESSENED. WE ONLY SELECTED THE HEALTHIEST PEOPLE TO EXPERIMENT ON. SO, I WANT TO JUMP FROM 1900 TO WORLD WAR II, WHICH MANY PEOPLE WOULD SUGGEST IS WHEN THE MODERN ERA OF BIOMEDICAL RESEARCH BEGINS IN EARNEST. IT WAS THE FIRST AMERICAN WAR IN WHICH SCIENTIFIC DEVELOPMENT RECEIVED PRESIDENTIAL ATTENTION, AND A HUGE INFLUX OF RESEARCH DOLLARS. FDR ESTABLISHED OFFICE OF SCIENTIFIC RESEARCH AND DEVELOPMENT WITH A COMMITTEE ON MEDICAL RESEARCH. AND RESEARCH RELATED TO THE WAR WAS PRIORITIZED BY THIS BODY. SO THEY WERE INTERESTED IN EXPOSURE TO COLD WATER FOR PILOTS SHOT DOWN, EFFECTS OF HIGH ALTITUDE, DESALINIZATION STUDIES, BURNS AND WOUNDS, BLOOD SUBSTITUTES, PREVENTION OF DISEASES GERMANE TO THE WAR EFFORT, MALARIA, GONORRHEA, HEPATITIS. A STUDY IN THE GULF OF MEXICO INVOLVED SOMEONE IN A RAFT, VARIOUS FILTRATION DEVICES, AND INTENT WAS TO ALLOW SEAMEN WHOSE SHIP HAD GONE DOWN TO SURVIVE LONG ENOUGH TO BE RESCUED. HERE IS AN EXAMPLE OF MA MALARIA RESEARCH, GLASS VIALS CONTAINING INFECTED MOSQUITO, INFECTED WITH MOSQUITO, IN AN ATTEMPT TO PRODUCE MALARIA IN SUBJECTS TO STUDY NATURAL HISTORY, AND THE EFFICACY OF INTERVENTIONS IN THIS VERY IMPORTANT DISEASE, PARTICULARLY IN THE EUROPEAN THEATER AND IN THE PACIFIC THEATERS. NOW, OF COURSE THE UNITED STATES WAS NOT THE ONLY NATION INTERESTED IN MEDICAL RESEARCH THAT WOULD AID IN THE WAR EFFORT. THIS IS THE RESEARCH PRIORITIES OF NAZI MEDICAL RESEARCH. IT'S SIMILAR. HYPOTHERMIA, HIGH ALTITUDE, SALINIZATION, BLOOD SUBSTITUTES. VACCINES. MANY OF YOU ALREADY KNOW THIS IN ADVANCE THAT THE NAZIS USED DIFFERENT ENDPOINTS THAN AMERICANS DID AND THERE WAS A GREAT LOSS OF LIFE AND GREAT DEAL OF SUFFERING ASSOCIATED WITH NAZI RESEARCH THAT WAS NOT THE CASE IN THE UNITED STATES. AND IN PARTICULAR, WE KNOW MOST ABOUT THE USE OF CONCENTRATION CAMP INMATES AS SUBJECTS OF BIOMEDICAL RESEARCH DURING THE NAZI PERIOD. THE FIRST STUDIES UNDERTAKEN WERE AT THE DACHAU CAMP, INTERESTED IN EFFECTS OF HYPOTHERMIA. THIS IS A PHOTOGRAPH OF SUBMERSION OF AN INMATE, DEATH AS ENDPOINT, WHETHER LIFE VESTS WOULD PROMOTE LONGEVITY SO SOMEONE COULD BE RESCUED. ALSO, IN THE INTEREST OF THE GERMAN AIR FORCE, THEY STUDIED EFFECTS OF HIGH ALTITUDE ON THE BRAINS OF CONCENTRATION CAMP INMATES AND INTENT WAS TO KILL PEOPLE IN ORDER SO THEIR BRAINS COULD BE STUDIED FOR EFFECTS OF HIGH ALTITUDE AND LOW OXYGEN CONTENT. THEY ALSO CONDUCTED SEA WATER STUDIES, NOT ON VOLUNTEERS, BUT ON CONCENTRATION CAMP INMATES, AGAIN IN A MUCH LESS HUMANE WAY. THIS IS A PHOTOGRAPH OF A ROMA, A GYPSY OF THAT PERIOD, TO MAKE SEA WATER POTABLE. WE KNOW THIS FROM TESTIMONY AT A DACHAU CONCENTRATION CAMP TRIAL, BUT THESE WERE CONDUCTED IN 1944. 44 CAMP INMATES, GERMAN, CZECH AND POLISH ROMA RECRUITED FROM BUCHENWALD AND AUSCHWITZ, GROUPS ASSIGNED TO REGIMENS, ONE GOT NO WATER, TO SEE HOW LONG WE COULD LIVE WITHOUT WATER, ONE GOT FRESH WATER, ONE GOT ORDINARY SEA WATER, ONE CHEMICALLY TREATED SEA WATER, ANOTHER SEA WATER TO TOMATO EXTRACT TO MASK SALT TASTE. RUDY TAUBMAN NOTED WHEN THEY REFUSED THEY WERE PHYSICALLY HEALTH DOWN, A TUBE PLACED IN THE MOUTH, SEA WATER ADDED INTO THE SUBJECT. IT WENT INTO THE STOMACH. TEST SUBJECTS WERE FORCED TO UNDERGO PAINFUL LIVER PUNCTURES, SPINAL PUNCTURES, SO THEY COULD TEST THE EFFECTS OF HIGH SALT CONTENT IN PRISONERS. STUDIES OF BURNS AND WOUNDS THE NAZI DOCTORS CONDUCTED, THAT INVOLVED CREATION OF WHAT WAS CONSIDERED A STANDARD BURN OR WOUND, IN THE UNITED STATES THIS WAS DONE BUT ON ANIMALS. HERE THEY USED POLISH WOMEN AT THE RAVENS BRUECK CAMP, OPEN THE WOUND AND INVERT SLIVERS OF GLASS, ONCE THEY HAD A STANDARD BURN OR WOUND COULD TEST EFFICACY OF VARIOUS WOUND TREATMENT REGIMENS. SO YOU'VE ALREADY KNOWN THE WORD FOR THE DAY, NUREMBERG. YOU ALSO KNOW THAT AFTER WORLD TWO AN AMERICAN MILITARY TRIBUNAL PUT THE CASE ON TRIAL, UNITED STATES VERSUS KARL BRANDT, HE WAS THE MOST HIGH RANKING GERMAN PHYSICIAN AND HITLER'S PERSONAL PHYSICIAN. IT ACTUALLY WAS NOT A TRIAL OF THE GERMAN MEDICAL PROFESSION BUT INSTEAD OF 23 HIGH RANKING NAZI MEDICAL PERSONNEL, THERE YOU SEE SITTING AT THE DOCK. A CRITICAL ISSUE FOR THE TRIBUNAL FOR THE JUDGES WAS HOW DO YOU JUDGE THE EXPERIMENTS THAT WERE CONDUCTED BY THESE NAZI DOCTORS? AND ESPECIALLY BECAUSE THE DEFENSE ATTORNEYS WHO WERE REPRESENTING THE NAZI DOCTORS MADE COMPARISONS TO THE FACT, WELL, JUST AS THE NAZI WERE USING CONCENTRATION CAMP INMATES, IN THE UNITED STATES PRISON INMATES WERE BEING RECRUITED AND STUDIED IN DANGEROUS DISEASES LIKE ACQUIRING MALARIA, YOU KNOW, WHAT'S THE MORAL DIFFERENCE THERE, THE NAZI ATTORNEYS EXPLAINED. IN FACT, ONE OF THE ATTORNEYS ACTUALLY PRESENTED HIS EVIDENCE, THIS ISSUE OF "LIFE" MAGAZINE, FROM JUNE 4, 1945, THAT SHOWED EXPERIMENTS IN MALARIA AT PRISON IN ILLINOIS THAT SHOWED PEOPLE VOLUNTEERING AND BEING RECRUITED INTO STUDIES THAT REQUIRED TRYING TO DELIBERATELY INFECT THEM WITH MALARIA, AGAIN TO STUDY TREATMENT REGIMENS. NOW, IN ORDER TO JUDGE THE GUILT AND INNOCENCE OF NAZI DOCTORS, THE AMERICAN RESEARCHER ANDREW IVY WAS SENT BY AMERICAN MEDICAL ASSOCIATION IN 1946 TO SERVE AS MEDICAL CONSULTANT TO THE JUDGES. HE HAD PARTICIPATED AS A RESEARCHER AT THE OFFICE OF NAVAL RESEARCH, HIMSELF, IN SEA WATER STUDIES, HIGH ALTITUDE STUDIES, SO FORTH. AND HE WAS ONE OF THE KEY CONTRIBUTORS IN ADVISING THE JUSTICES TO CREATE A DOCUMENT THAT HAS COME TO BE KNOWN AS THE NUREMBERG CODE BUT WHICH THEY REFERRED TO AS PRINCIPLES OF PERMISSIBLE MEDICAL EXPERIMENTS. I KNOW THAT THIS IS IN YOUR READING. AND THE FIRST PRINCIPLE IS THE PRINCIPLE THAT'S MOST OFTEN CITED, IT'S ACTUALLY MUCH LENGTHIER THAN THIS. ESSENTIALLY IT LAYS OUT THE IMPORTANCE THAT THE VOLUNTARY CONSENT OF HUMAN SUBJECT IS ABSOLUTELY ESSENTIAL. I WON'T GO THROUGH ALL OF THESE BUT THERE WERE NINE ADDITIONAL PRINCIPLES BUT THERE HAD TO BE PRIOR ANIMAL EXPERIMENTS, YOU DON'T JUST BEGIN ON HUMAN BEINGS. THE INTENT WAS TO AVOID FROM THE OUTSET ALL UNNECESSARY SUFFERING OR INJURY. THERE WAS NO REASON IN ADVANCE TO THINK DEATH WOULD RESULT, SO THE KINDS OF STUDIES CONDUCTED BY THE NAZI IN WHICH THEY WANTED TO SEE HOW LONG SOMEONE COULD LIVE WITHOUT, YOU KNOW, DRINKING ANY WATER, FOR EXAMPLE, WOULD HAVE BEEN -- WOULD NOT BE PERMITTED. THAT THE RISK SHOULD NOT EXCEED THE BENEFIT, AND THAT INSTEAD OF HAVING UNQUALIFIED PEOPLE CONDUCT SUCH EXPERIMENTS, THAT THE EXPERIMENTS BE CONDUCTED ONLY BY PEOPLE WITH ADEQUATE AND EXPERT SCIENTIFIC QUALIFICATIONS. I'D LIKE TO REMIND PEOPLE THAT THERE WAS AN OUTCOME OF THE DOCTORS' TRIAL. SEVEN OF THE NAZI DOCTORS THERE WERE ACQUITTED BECAUSE OF INADEQUATE EVIDENCE. SEVEN RECEIVED DEATH SENTENCES. AND NINE RECEIVED PRISON SENTENCES THAT RANGED FROM TEN YEARS TO LIFE IN INPRISON. . KARL BRANTT HIMSELF OFFERED HIS BODY FOR EXPERIMENTATION BEFORE EXECUTION TO THE U.S. ARMY WHICH REJECTED THE OFFER, HE WAS EXECUTED IN IN THE LANDSBERG PRISON IN 1948. DR. GRADY ALLUDED TO THE FACT THE NUREMBERG CODE WAS FOR MANY RESEARCHERS A CODE THAT YOU WOULD NEED IF YOU WERE A NAZI DOCTOR BECAUSE YOU DIDN'T KNOW WHAT WAS RIGHT AND WRONG. AND THERE'S BEEN MUCH DISCUSSION IN THE LITERATURE ABOUT WHETHER OR NOT THE NUREMBERG CODE INFLUENCED THE AMERICAN CONDUCT OF MEDICAL EXPERIMENTATION IN THE DECADES AFTER 1947. ONE OF THE QUESTIONS WAS WHETHER AMERICAN DOCTORS EVEN KNEW THAT THERE WAS A NUREMBERG CODE. WELL, I THINK IT'S SAFE TO SAY MANY OF THEM DID KNOW BECAUSE IT WAS PUBLISHED IN THE MOST POPULAR SCIENTIFIC JOURNAL IN THE UNITED STATES, THAT IS "SCIENCE," IN 1953, AND IT WAS ACTUALLY PART OF A SYMPOSIUM THAT WAS CONDUCTED UNDER AUSPICES OF NIH ABOUT THE LIMITS AND DILEMMAS, THE CHALLENGES IF YOU WILL, POSED BY EXPERIMENTATION ON HUMAN BEINGS IF EXPERIMENTATION ON HUMAN BEINGS IS AND CONTINUES TO BE IMPORTANT TO LEARNING MORE ABOUT MEDICAL ADVANCES AND MORE ABOUT BIOMEDICAL KNOWLEDGE. WE ALSO KNOW THAT THE NUREMBERG CODE WAS ADOPTED FOR THE ARMED FORCES BY THE SECRETARY OF DEFENSE, CHARLES WILSON, IN 1953. HOWEVER, IN THE CASE OF ARMED FORCE FORCES IT WAS CLASSIFIED AS TOP SECRET, IMPLEMENTATION FAILURE ENSURING FURTHER KNOWLEDGE OF THESE PRINCIPLES AND THEIR IMPORT FOR HUMAN EXPERIMENTATION WAS NOT DISTRIBUTED TO THE NECESSARY INDIVIDUALS. I DO HAVE EVIDENCE, YOU KNOW, FROM ARCHIVES IN THIS PERIOD WHERE VERY ESTEEMED AMERICAN PHYSICIANS WOULD WRITE TO THE ARMY ASKING ABOUT, YOU KNOW, THIS DIRECTIVE THAT WAS ADOPTED BY THE SECRETARY OF DEFENSE AND THEY WERE TOLD IT WAS TOP SECRET AND THEY COULD NOT HAVE ACCESS TO IT. SO, I THINK THAT'S SORT OF AN IRONIC DEVELOPMENT. NOW, WOULD AMERICAN INVESTIGATORS HAVE MET THE NUREMBERG CODE? THIS IS A NO-BRAINER. THE ANSWER IS NO, THEY WOULD NOT NEED IT BECAUSE VOLUNTARY CONSENT, VERY FIRST PRINCIPLE, WAS NOT NECESSARILY SALIENT TO THE WORK AMERICAN INVESTIGATORS WERE CONDUCTED, THERE ARE MANY OTHER EXAMPLES OF FAILURE TO MEET SOME OF THE PRINCIPLES IN THE NUREMBERG CODE. THERE WAS DISCUSSION ABOUT THE NUREMBERG CODE AS A SOURCE OF GUIDANCE, EXPANSION OF PHARMACEUTICALS, PERIOD OF ENORMOUS EXPANSION OF VACCINES, PARTICULARLY FOR CHILDREN. AND IF YOU ACTUALLY FOLLOWED THE CODE TO THE LETTER, SUCH EXPERIMENTS, TESTING OF LIKE A NEW MEASLES VACCINE AND SO FORTH, WOULD NOT PERMIT EXPERIMENTS IN CHILDREN, THOSE IN INSTITUTIONS, DYING PATIENTS AND THE MENTALLY ILL. INSTITUTIONS, SAY, ORPHANAGES, PRISONS, SO FORTH. WAS THERE POPULAR CONCERN ABOUT MEDICAL RESEARCH IN THE 1950s? I WOULD SAY IF THERE IS, IT'S CERTAINLY NOT VISIBLE. MEDICAL RESEARCH WAS CELEBRATED BY PEOPLE WHO VOLUNTEERED, THERE WAS ACTUALLY A RESEARCH HERO AWARD BY A RESEARCH DEFENSE SOCIETY, IN THEIR DISCUSSIONS IN MEDICAL JOURNALS, THE TRADITION OF SELF-EXPERIMENTATION WAS CELEBRATED. THE IDEA THE -- NOT AN IDEA WE WOULD DO TODAY BUT THE INVESTIGATOR WOULD SUBMIT HIMSELF ORER HERSELF WAS EVIDENCE OF THEIR CONCERN FOR THE SAFETY AND WELFARE OF OTHERS OR THEY WOULD SUBMIT THEIR CHILDREN, FOR EXAMPLE, TO PARTICIPATION IN THE TRIAL OF A NEW VACCINE. THERE WAS AN ELEMENT OF UTILITARIANISM, DURING WORLD WAR II THERE WERE ENORMOUS ADVANCE WAS WONDER DRUG PENICILLIN AND WITH THE SPREAD, DISSEMINATION, OF THINGS LIKE BLOOD TRANSFUSION WHICH BECAME VERY IMPORTANT TO CIVILIAN PRACTICE. MANY PEOPLE BELIEVED THERE WERE GREAT ADVANCES IN MEDICINE TO COME FROM A CONTINUATION OF THE RESEARCH THAT HAD BEGUN IN WORLD WAR II. TODAY WHEN VOLUNTEERS DIE IN RESEARCH THERE'S ATTENTION AND CONCERN ABOUT THIS. I FOUND THIS ARTICLE IN THE "NEW YORK TIMES" IN 1952 WHICH DESCRIBED HOW AN 18-YEAR-OLD STUDENT AT SEATTLE UNIVERSITY WAS KILLED OR DIED AS A RESULT OF HIS PARTICIPATION IN A BLOOD PRESERVATION STUDY. AGAIN, THERE WAS CONCERN ABOUT THE SAFETY OF VOLUNTEERS BUT WHEN HIS FATHER WAS ASKED WHETHER HE WAS GOING TO SUE THE INSTITUTION OR FUNDING AGENCY, HE TOLD THE REPORTERS, NO, HIS SON HAD VOLUNTEERED, HIS LOSS WAS CERTAINLY UNEXPECTED AND TRAGIC BUT HE WOULD HAVE WANTED THE RESEARCH TO CONTINUE. AND I THINK THAT'S A VERY DIFFERENT ATMOSPHERE. ANOTHER ILLUSTRATION SORT OF THE WILLINGNESS AND EXPECTATIONS ABOUT FURTHER HUMAN EXPERIMENTATION CAME FROM THE NATIONAL FOUNDATION FOR INFANTILE PARALYSIS. I'LL REMIND YOU, UNLIKE MOST OTHER EPIDEMIC DISEASES WHICH DECLINED OVER THE COURSE OF THE 20th CENTURY, POLIO WAS ACTUALLY A DISEASE OF THE 20th CENTURY. FIRST BIG EPIDEMIC OCCURS IN 1916, THE WORST EPIDEMIC OCCURRED IN 1952. AND THERE WAS LOTS OF MONEY RAISED BY FDR'S NATIONAL FOUNDATION FOR INFANTILE PARALYSIS, FORERUNNER OF THE MARCH OF DIMES, AND LOTS OF ATTENTION TO A WAY TO PREVENT THIS TERRIBLE KILLER AND CRIPPLER OF AMERICAN CHILDREN. SO IN 1954, IN THE LARGEST FIELD TRIAL I BELIEVE EVER CONDUCTED IN THE NAME OF RESEARCH, JONAS SALK HAD A VACCINE HE HAD BEEN WORKING ON AND 1.2 AMERICAN CHILDREN FIRST AND SECOND GRADERS WERE RECRUITED AS POLIO PIONEERS TO TEST THE SAFETY AND EFFICACY OF THIS NEW VACCINE. HERE YOU CAN SEE THE CHILDREN LINED UP. FOR PARTICIPATION, PARENTS ACTUALLY SIGNED NOT A CONSENT FORM BUT INSTEAD A PARENTAL REQUEST FOR PARTICIPATION OF CHILD IN THE VACCINATION FIELD TRIAL. YOU CAN SEE IT'S VERY SHORT, DIFFERENT THAN TODAY'S SORT OF PERMISSION FORMS, EVEN THE PERMISSION FORM USED BY WALTER REED IN 1900 BUT DOES SAY WHAT'S GOING TO HAPPEN, WHAT ARE POTENTIAL DOWN SIDES OF PARTICIPATION. AND THE PARENTS CAN THEN SIGN OFF. FORTUNATELY, OF COURSE, IT WAS A SUCCESSFUL FIELD TRIAL. IT WAS ONE OF THE MOST QUICKLY -- WELL, BEFORE COVID, ONE OF THE MOST QUICKLY IMPLEMENTED VACCINES IN AMERICAN PRACTICE. AGAIN, WAS A TERRIFIC ILLUSTRATION OF THE INVESTMENT IN MEDICAL RESEARCH THAT WOULD LEAD TO THINGS THAT WOULD IMPROVE PEOPLE'S LIVES FOR THE BETTER. MEANWHILE BACK TO THE PEOPLE, PHYSICIANS AND RESEARCHERS WHO ARE INTERESTED IN CONDUCTING FURTHER HUMAN EXPERIMENTATION. THERE WAS A LOT OF DISCUSSION, A LOT OF EFFORT, IN TRYING TO PULL TOGETHER, YOU KNOW, A DOCUMENT, A SET OF PRINCIPLES OR GUIDANCE THAT WOULD DO SEVERAL THINGS. ONE, THEY WANTED TO PROTECT HUMAN WELFARE OF THE PARTICIPANTS WHO WOULD TAKE PLACE. AT THE SAME TIME, THEY WANTED MEDICAL RESEARCH TO ADVANCE AND DID NOT WANT IMPEDIMENTS OR OBSTACLES TO SUCH ADVANCE. AND WE'VE SEEN THE DISCUSSIONS THE WORLD MEDICAL ASSOCIATION WHICH DR. GRADY ALLUDED TO EARLIER THAT WERE UNDERTAKEN OVER A PERIOD OF TEN YEARS, IT TOOK THEM TEN YEARS BECAUSE OF CONSIDERABLE DISAGREEMENTS AMONG AMERICANS, GERMAN, BRITISH, WELL, NOT GERMANS, BRITISH, FRENCH, SO FORTH, HOW BEST TO ACCOMPLISH THESE THINGS AT THE SAME TIME. NONETHELESS, IN 1964, THE WORLD MEDICAL ASSOCIATION UNANIMOUSLY ADOPTED THE DECLARATION OF HELSINKI AND YOU'LL NOTE ONE OF THE CHANGES THEY DEBATED WAS INSTEAD OF REQUIREMENTS, RECOMMENDATIONS GUIDING DOCTORS IN CLINICAL RESEARCH. JUST A LITTLE BIT ABOUT SORT OF THE FOUNDATIONAL DOCUMENT FOR INTERNATIONAL COMMUNITY OF RESEARCHERS, IT DISTINGUISHED CLINICAL THERAPEUTIC RESEARCH FROM NON-THERAPEUTIC BIOMEDICAL RESEARCH, SO, FOR EXAMPLE, THE KINDS -- TESTING OF VACCINE THAT A CHILD MIGHT BENEFIT FROM WAS DIFFERENT THAN TRYING TO GIVE SOMEBODY MALARIA. CLINICAL THERAPEUTIC RESEARCH WAS JUSTIFIED IF IT WAS INTENDED TO IMPROVE THE WELL-BEING OF THE PATIENT. NON-THERAPEUTIC RESEARCH WAS JUSTIFIED AS LONG AS THE INTERESTS OF SOCIETY DID NOT TRUMP THE CONCERN FOR THE WELL-BEING OF THE PATIENT. SO YOU HAD TO HAVE GOOD REASON THAT THIS WAS SAFE ENOUGH AND WOULD NOT LEAD TO THE DEATH OF THE PATIENT OR DEATH OF THE RESEARCH SUBJECT IN THE RESEARCH. AND PERHAPS MOST IMPORTANTLY, FOR THOSE WHO THOUGHT THE NUREMBERG CODE WAS TOO RESTRICTIVE, IT PERMITTED PROXY CONSENT. SO THAT PARENTS, FOR EXAMPLE, OR DIRECTORS OF ORPHANAGES COULD ALLOW PARTICIPATION OF CHILDREN IN FIELD TRIALS. OR, YOU KNOW, THE FAMILY MEMBERS OF THOSE IN MENTAL INSTITUTIONS, OR THE LOVED ONES OR FRIENDS OF PEOPLE WHO WERE DYING. NOW, WE'VE ALREADY HEARD THAT IT WAS -- THAT DOCUMENT'S BEEN AMENDED, I DIDN'T GO BACK TO CHECK IF THERE'S BEEN AMENDMENTS SINCE 2013, BUT THERE HAVE BEEN CONSIDERABLE ATTEMPT -- I THINK IT WOULD BE A MISTAKE TO THINK THE ETHICAL PRINCIPLES HAVE NOT REMAINED THE SAME. AND TAKE, FOR EXAMPLE, YOU KNOW, THE PRINCIPLE OF RESPECT FOR PERSONS. I THINK ONE OF THE THINGS THAT CERTAINLY HAS CHANGED OVER TIME IS WHO IS A PERSON AND WHO IS A PERSON WHO IS CONSIDERED WORTHY OF MORAL CONSIDERRABILITY, THAT HAS CHANGED. ALSO, HOW WE RESPECT PERSONS AND THEIR AUTONOMY AND THEIR WELFARE HAS CHANGED OVER TIME. SO, I'M GOING TO RETURN NOW TO THE UNITED STATES AND RESPONSES TO SCANDAL AND TRAGEDY IN TERMS OF HUMAN EXPERIMENTATION. WELL, I THINK CERTAINLY THERE WAS A CHANGE FROM THE 1950s TO 1960s, THOSE OF YOU MAY RECALL THAT 1960s WAS A PERIOD OF MASSIVE SOCIAL CHANGE. THERE WAS NO LONGER THE FAITH AND TRUST IN MEDICAL RESEARCHERS. THERE WAS AS WELL FROM INSIDE THE COMMUNITY OF MEDICAL RESEARCHERS SORT OF A LITTLE BIT OF, YOU KNOW, SELF-DISCLOSURE ABOUT WHAT WAS GOING ON IN THAT COMMUNITY, WHAT YOU SEE REFERRED TO AS HARRY BEECHER'S BOMBSHELL, THE PUBLIC DISCUSSION OF ABUSES OF HUMAN SUBJECTS, ESPECIALLY TUSKEGEE SYPHILIS STUDY. FIRST HENRY BEECHER, HE WAS PROFESSOR OF ANESTHESIA RESEARCH AT HARVARD MEDICAL SCHOOL, AN EXTRAORDINARY IMPORTANT FIGURE IN BIOETHICS. AFTER HIS BOMBSHELL IN TERMS OF RESEARCH ETHICS, HE WOULD GO ON AT THE REQUEST OF THE HARVARD DEAN OF THE MEDICAL SCHOOL TO CONVENE THE AD HOC COMMITTEE ON BRAIN DEATH WHICH WOULD HAVE FAR-REACHING IMPLICATIONS FOR DETERMINATIONS OF DEATH PARTICULARLY IN REGARD TO ORGAN TRANSPLANTATION IN THE DECADES TO COME. BUT THE BOMBSHELL ARTICLE WAS PUBLISHED ABOUT RESEARCH PUBLISHED IN THE NEW ENGLAND JOURNAL, ON JUNE 16, THE INNOCUOUS TITLE ETHICS IN CLINICAL RESEARCH, BUT IF IT BEECHER IDENTIFIED WHAT HE CALLED 22 EXAMPLES OF QUESTIONABLE RESEARCH PRACTICES. HE DID NOT NAME NAMES. BUT HE EMPHASIZED THAT THESE WERE NOT FROM, YOU KNOW, IN SOMEBODY'S GARAGE OR, YOU KNOW, FROM POORLY FUNDED OR ALTERNATIVE INSTITUTIONS, BUT FROM MAINSTREAM RESEARCHERS AND INSTITUTIONS THAT WERE FUNDED BY, YOU KNOW, NIH, BY THE U.S. PUBLIC HEALTH SERVICE, BY THE DEPARTMENT OF DEFENSE. SO THAT THIS -- OR THE AMERICAN HEART ASSOCIATION. THAT THESE WERE MAINSTREAM. MOREOVER, THEY WERE PUBLISHED IN MAINSTREAM MEDICAL JOURNALS. FIVE FROM THE NEW ENGLAND JOURNAL OF MEDICINE, FIVE FROM JOURNAL OF CHRONIC DISEASE, EXCUSE ME, FROM CLINICAL INVESTIGATION, TWO FROM CIRCULATION, TWO FROM JAMA. MUCH DEBATE ABOUT WHY BEECHER WOULD DO THAT, HE READ THE BIBLE EVERY DAY AS WE LEARNED, HE WAS AN ANETHEOLOGIST, HE TESTED EFFECTS ON COLLEGE STUDENTS OF MIND CONTROL DRUG AND CONTINUED TO BE A RESEARCHER IN DECADES AFTER AND FELT THE ANSWER WAS NOT SO MUCH A SET OF PRINCIPLES LIKE THE NUREMBERG CODE BUT FAILURE TO INCULCATE INTO YOUNG RESEARCHERS THEIR RESPONSIBILITY TO THE WELFARE OF THEIR PATIENTS AND PARTICIPANTS IN RESEARCH. USEFUL TO CONSIDER THE PEOPLE BEECHER WAS CONCERNED ABOUT, WHAT GROUPS? THEY IN SOME WAYS THEY REPRESENT WHAT WE MIGHT THINK OF CLASSICALLY VULNERABLE SUBJECTS, CHILDREN IDENTIFIED AS, QUOTE, MENTALLY DEFECTIVE, DELINQUENTS, AND, QUOTE, MENTALLY RETARDED CHILDREN, THE VERY ELDERLY, SENILE OR DEMENTED PATIENTS, SOLDIERS IN THE ARMED FORCES, CHARITY PATIENTS, TERMINALLY ILL, ALCOHOLICS, CHILDREN AND NEWBORNS, AND PATIENTS AT THE NIH CLINICAL CENTER. AND SOME OF THESE MAY BE FAMILIAR TO YOU, THERE'S A LOT OF LITERATURE, EXAMPLE 16 WAS WELL KNOWN WELL PUBLICIZED CASE CONDUCTED AT THE WILLOW BROOKE STATE SCHOOL, A MASSIVE INSTITUTION THAT WAS USED TO HOUSE CHILDREN IDENTIFIED AS, QUOTE, MENTALLY DEFECTIVE, MENTALLY RETARDED. IT WAS AN INSTITUTION WHERE RATES OF INFECTIOUS HEPATITIS WERE HIGH, THEY WANTED TO STUDY THE BEST WAY, NATURAL HISTORY OF THE DISEASE IN THE INSTITUTION, WHAT WAS THE BEST WAY TO TREAT CHILDREN. AND SO THERE WAS A STUDY THAT WAS CONDUCTED BY PHYSICIANS AT NYU IN WHICH NEWLY RECRUITED PATIENTS WHOSE PARENTS GAVE CONSENT WERE GIVEN EITHER INTRAMUSCULAR INJECTIONS OF HEPATITIS VIRUS OR MILKSHAKES THAT CONTAINED HEPATITIS. A PEDIATRICIAN IN INFECTIOUS DISEASE RESEARCHER BEGAN STUDIES TO ACQUIRE, WHAT WAS THE NATURAL CASE, OR NATURAL HISTORY OF THE DISEASE IN CHILDREN, AND WHAT THEY COULD OFFER PARENTS WAS IF THEY DEVELOPED HEPATITIS IN THE INSTITUTION, AT LARGE, THEY WOULDN'T GET THE SAME QUALITY OF MEDICAL CARE THAT IF THEY DEVELOPED HEPATITIS AS A RESULT OF THEIR PARTICIPATION IN THE STUDY BECAUSE THEY WOULD BE IN THE SPECIAL WING WHERE THEY HAD WELL QUALIFIED NURSES AND DOCTORS LOOKING AFTER THEM. KRUGMAN DEFENDED HIS STUDIES, CONTINUES TO BE SOMEWHAT CONTROVERSIAL, ISSUES PERSIST TODAY ABOUT INFORMED CONSENT BECAUSE HE USED GROUP INFORMED SENT RATHER THAN INDIVIDUAL, COERCION, IT WAS THE ONLY WAY TO GET YOUR CHILD IN AN INSTITUTION, AND STUDY DESIGN, WITHHOLDING GAMMAGLOBULIN TO TEST QUALITY OF THE TREATMENT REGIMEN. ANOTHER NOTORIOUS EXAMPLE STUDIES CONDUCTED AT THE JEWISH CHRONIC DISEASE HOSPITAL, FUNDED BY THE U.S. PUBLIC HEALTH SERVICE, AMERICAN CANCER SOCIETY. AND THERE WAS INTEREST IN THE PASSAGE OF LIVE CANCER CELLS IN THE BODY SO THEY INJECTED LIVE CANCER CELLS INTO ELDERLY PATIENTS WITHOUT CONSENT. THIS HAD BEEN CONDUCTED PREVIOUSLY IN PRISONS IN OHIO, FOR EXAMPLE, WHERE THE INMATES WERE TOLD THAT THEY WERE PARTICIPATING IN SUCH A STUDY WITH LIVE CANCER CELLS BUT IN THE CASE OF THESE ELDERLY AND THEY ARE IDENTIFIED IN THE TEXT AS DEMENTED OR SENILE DID NOT WISH TO STIR UP UNNEXT ANXIETY IN PATIENTS WITH PHOBIA AND IGNORANCE ABOUT CANCER. CHESTER SOUTHAM WAS IN CHARGE, HE DID NOT PERFORM INJECTIONS, MADE UNFORTUNATE FROM HIS POINT OF VIEW COMMENT TO A WRITER FOR SCIENCE MAGAZINE IN 1964, WHEN ASKED WOULD HE PARTICIPATE HIMSELF IN THE STUDIES. AND SOUTHAM SAID I WOULD HAVE IF IT WOULD HAVE SERVED A USEFUL PURPOSE. I DO NOT -- HE WOULD SAY GENERALS SHOULDN'T -- THE OLD QUESTION, WHETHER GENERALS SHOULD MARCH BEHIND OR IN FRONT OF HIS TROOPS. HE SAID I DON'T REGARD MYSELF AS INDISPENSABLE BUT DID NOT REGARD EXPERIMENTS DANGEROUS. LET'S FACE IS. THERE ARE FEW SKILLED CANCER RESEARCHERS, IT SEEMED STUPID TO TAKE EVEN THE LITTLE RISK. HE ACTUALLY HAD HIS LICENSE SUSPENDED I THINK FOR SIX MONTHS FOR HIS OVERSIGHT OF THIS PARTICULAR EXPERIMENT. SO, THESE WERE SOME NOTORIOUS EXAMPLES BUT IT WAS MORE THAN ANY OTHER SINGLE STUDY THE REVELATION OF THE TUSKEGEE SYPHILIS STUDY IN JULY OF 1972 THAT PUSHED CONGRESSIONAL ACTION. THE STUDY WAS NOT PART OF HENRY BEECHER'S, BUT IT WENT OUT ON THE WIRE SERVICE AND BECAME THE SUBJECT OF NATIONAL DISCUSSION. NOW, IF I WERE THERE IN PERSON I WOULD HAVE ASKED HOW MANY OF YOU WERE FAMILIAR WITH THE STUDY AND I ASSUME THAT MANY OF YOU ALREADY ARE. BUT IT HAS SERVED AS SORT OF A BENCHMARK, GOING FORWARD, WHETHER SOMETHING IS LIKENED TO THE TUSKEGEE SYPHILIS STUDY OR REFERRED TO AS AMERICA'S HOLOCAUST OR CONCENTRATION CAMP STUDIES, WORTH REMINDING OURSELVES OF WHAT ACTUALLY HAPPENED IN TUSKEGEE. THIS IS ONE OF THE EDITORIAL CARTOONS, A NO-TREATMENT STUDY OF 600 AFRICAN AMERICAN MEN IN RURAL ALABAMA, EFFECTS OF UNTREATED SYPHILIS. IT BEGAN IN 1932, ENDED IN 1972. THE STUDY WAS UNDERTAKEN AT TUSKEGEE BECAUSE THEY HAD AN EXTRAORDINARILY HIGH INCIDENCE OF SYPHILIS IN THE AFRICAN AMERICAN POPULATION AS DEMONSTRATED BY AN EARLIER STUDY. IT WAS SOMETHING OF A PUBLIC HEALTH EMERGENCY. AND BECAUSE THE TUSKEGEE INSTITUTE AND V.A. HOSPITAL FOR AFRICAN AMERICANS WAS LOCATED IN TUSKEGEE. IT WAS ENCOURAGED BY THE PUBLIC HEALTH SERVICE SURGEON GENERAL THOMAS PERRIN COMMITTED TO E NDING THE SCOURGE OF SYPHILIS. HE CAME ON IN 1936, HELDED PUBLIC HEALTH SERVICE UNTIL 1948. YOU'LL HEAR ABOUT HIM AS I GO ON. AGAIN, THE MACON COUNTY STUDY DISCLOSED THERE WAS A VERY HIGH INCIDENCE OF THE DISEASE. INITIALLY IT WAS INTENDED TO BE A SIX-MONTH OR ONE-YEAR OBSERVATIONAL STUDY AND TO OFFER TREATMENT TO ALL THOSE MEN RECRUITED IN THE STUDY. HOWEVER THE FUNDS DID NOT BECOME AVAILABLE. AND INSTEAD, AT THE BEHEST OF DR. RAYMOND MONDOLARE, HEAD OF THE VENEREAL DISEASE, WENT TO A STUDY IN NATURE, FROM TREATMENT. HE WAS ONE OF THE OFFICERS WHO WENT DOWN TO TUSKEGEE, CONDUCTED INITIAL SURVEYS, THEN HAD OPPORTUNITY TO SAY WE SHOULD FOLLOW THESE MEN TO AUTOPSY AND WE'LL REALLY UNDERSTAND CLINICAL EFFECTS OF UNTREATED SYPHILIS. AMONG THESE WAS LUMBAR PUNCTURE TO OBTAIN SPINAL FLUID FOR DIAGNOSIS, WHICH AT THE TIME WAS CONSIDERED A VERY PAINFUL PROCEDURE. AND ACTUALLY, VONDOLEHR WANTED GOING FORWARD FROM 1932 ADDITIONAL LUMBAR PUNCTURES. HAD THEY INSISTED THEY WOULD NOT HAVE HAD PARTICIPANTS BECAUSE THE MEN REFUSED TO PARTICIPATE IN FURTHER LUMBAR PUNCTURES. NOW, THE TUSKEGEE STUDY LASTED FOR FOUR DECADES. AND OVER TIME BECAME MUCH LESS AN UNTREATMENT STUDY AS A STUDY IN WHICH THE RESEARCHERS TRIED TO PROTECT THE INTEGRITY OF THE POPULATION BY KEEPING THEM FROM EFFECTIVE TREATMENTS. SO, FOR EXAMPLE, IN WORLD WAR II, THE PUBLIC HEALTH SERVICE ASKED THE DRAFT BOARD TO EXEMPT THE MEN IN THE STUDY FROM THE DRAFT, IF THEY HAD BEEN DRAFTED THEY WOULD HAVE UNDERGONE TESTING FOR SYPHILIS AND WOULD HAVE RECEIVED FREE TREATMENT BUT THE ARGUMENT WAS THEY WERE NECESSARY TO THIS WAR ON THE DISEASE. ONE OF THE THINGS THAT MADE THE STUDY POSSIBLE WAS THE EXTRAORDINARY SKILL OF NURSE EUNICE RIVERS, TRAINED AT THE TUSKEGEE NURSING SCHOOL, REPRESENTED A MEANS OF BRIDGING THE GAP BETWEEN WHITE PUBLIC HEALTH SERVICE INVESTIGATORS AND THE ALL AFRICAN AMERICAN MEN WHO PARTICIPATED IN THE STUDY. IT FELT TO NURSE RIVERS NOT TO OBTAIN CONSENT BUT PERMISSION TO OBTAIN AUTOPSY, IT FELL HADDER TO. A BURIAL STIPEND OF $50 BECAME AVAILABLE. IN AN ARTICLE PUBLISH THE IN 1943 SHE REPORTED THERE WAS ONLY ONE REFUSAL IN 140 REQUESTS. OVER TIME, THERE WERE 13 PUBLISHED STUDIES FROM THE TUSKEGEE STUDY. MEN WERE IDENTIFIED AS VOLUNTEERED WITH SOCIAL INCENTIVES. IN 1954. IN 1958 THE SURGEON GENERAL SIGNED CERTIFICATES IN GRATEFUL RECOLLECT RECOGNITION, A DOLLAR GIVEN FOR EACH YEAR THEY WERE IN THE STUDY. IN 1969, CDC CONVENED BLUE RIBBON PANEL TO DETERMINE WHETHER TO CONTINUE. THE ONLY PHYSICIAN NOT FAMILIAR WITH THE STUDY BEFORE HE SIGNED ON TO THIS PANEL ARGUED THE EXPERIMENT SHOULD END AND MEN RECEIVE TREATMENT BUT THE STUDY CONTINUED UNTIL 1972. >> SUSAN, I'M GOING TO JUMP IN HERE FOR A MINUTE TO SAY WE HAVE ABOUT FIVE MORE MINUTES. >> THANK YOU SO MUCH. >> THANK YOU. >> SURE. SO AS I SAID, STUDY REVEALED IN 1972, PUBLIC HEARINGS WHICH THE MEN TESTIFIED, LEGISLATION WAS PASSED IN 1974. 1974 ACT CREATED A NATIONAL COMMISSION TO STUDY MORAL ISSUES, AND WAS HELPED FACILITATE NEW FEDERAL REGULATIONS FOR IRBs ABOUT WHICH YOU'LL HEAR MORE LATER AND WRITTEN INFORMED CONSENT. I'M GOING TO SKIP THIS, IT CONTINUED TO RECEIVE ATTENTION IN POPULAR CULTURE. AND THERE WERE PERSISTENT STORIES ABOUT THE DELIBERATE INFECTION OF THE MEN IN TUSKEGEE WITH SYPHILIS ALTHOUGH THIS WAS NOT TRUE. MEN WERE ONLY RECRUITED IN THE STUDY IF THEY HAD LESIONS OF AT LEAST FIVE YEARS STANDING. SO THEY COULD DATE THAT THEY WERE -- ASSUMPTION WAS IN LATENCY FROM THE DISEASE. THIS BECAME A FEATURE IN SORT OF THE RECOGNITION THAT AFRICAN AMERICANS DURING THE AIDS EPIDEMIC MIGHT BE SUSPICIOUS ABOUT A GOVERNMENT VACCINE BECAUSE OF THE TUSKEGEE SYPHILIS STUDY. DR. GRADY AND DR. TAYLOR REFERRED TO THE HUMAN RADIATION EXPERIMENTS WHICH I PARTICIPATED IN, NOT IN THE EXPERIMENTS BUT THE PANEL THAT REVIEWED THEM. I WAS SURPRISED TO LEARN THAT THERE WAS A PRESIDENTIAL APOLOGY FOR AMERICANS WHOSE LIVES HAD BEEN DARKENED BY THE SHADOW OF THE ATOM BUT THERE WAS NO PUBLIC APOLOGY OR ANY FORMAL RECOGNITION OF THE WRONG DONE TO THE PARTICIPANTS IN THE TUSKEGEE STUDY. AND SO AGAIN UNDER PRESIDENT CLINTON IN 1997 THERE WAS AN OFFICIAL APOLOGY. THESE ARE MEN NOW ELDERLY COMING TO THE WHITE HOUSE FOR THE APOLOGY. AND THERE WAS A CREATION OF A BIOETHICS INSTITUTE AT TUSKEGEE UNIVERSITY TO PAY PARTICULAR PETITION TO RECRUITMENT AND PARTICIPATION OF MARGINAL, SOCIALLY MARGINAL OR VULNERABLE POPULATIONS IN RESEARCH. BUT THE POINT THAT I WANT TO MAKE HUER IS -- HERE IS THE REVELATION OF SCANDAL AND TRAGEDY CONTINUED. 2010 CAME THE REVELATION PUBLIC HEALTH SERVICE HAD GONE TO GUATEMALA AND DELIBERATELY INFECTED MEN AND WOMEN WITH SYPHILIS, GONORRHEA, AND IN 2010 THERE WAS A FORMAL APOLOGY BY PRESIDENT OBAMA AND SECRETARY OF STATE HILLARY CLINTON FOR THE STUDIES THAT WERE CONDUCTED THERE. I'M GOING TO SKIP THIS. ORIGINALLY THEY WERE GOING TO FOCUS ON PRISONERS BUT TIME WAS RUNNING OUT SO THEY EXPANDED THEIR POPULATION POOL TO INCLUDE INMATES OF MENTAL I INSTITUTIONS, WITH THESE DISEASES WHO WERE CLEARLY UNABLE TO CONSENT TO PARTICIPATION. I'M GOING TO SKIP THAT. SKIP THAT. I'LL JUST POINT YOU TO DR. GRADY WAS A CONTRIBUTOR AND MEMBER OF THE PRESIDENTIAL COMMISSION FOR STUDY OF BIOETHICAL ISSUES WHO ISSUED THE REPORT ETHICALLY IMPOSSIBLE, STD RESEARCH IN GUATEMALA FROM 1946 TO 1948. THIS IS I BELIEVE STILL FREELY AVAILABLE, AND EXTRAORDINARILY INFORMATIVE ABOUT CONDITIONS OF RESEARCH, ABOUT THE QUALITY OF THE PROTECTIONS THAT WE HAVE TODAY, WHEN RESEARCH IN INTERNATIONAL FOCUS IS CONDUCTED. SO I WANT TO END HERE WITH A REMINDER THAT FIRST OF ALL WE DON'T KNOW ALL THE UNETHICAL OR PROBLEMATIC STUDIES THAT WERE CONDUCTED IN THE PAST. THERE ARE MANY MORE I'M SURE THAT ARE OUT THERE THAT HAVE YET TO SEE THE LIGHT OF DAY. AND SO I THINK THAT SORT OF KNOWING THE PAST IS USEFUL FOR KNOWING HOW THESE BECOME IMPORTANT BENCHMARKS FOR HOW WE EVALUATE CONTEMPORARY SITUATIONS. BUT I ALSO WANT TO ALLUDE TO THE FACT WE HAVE AN ONGOING CHALLENGE BECAUSE THESE TWO VERY OR EXTRAORDINARILY IMPORTANT GOALS CAN BE SEEN AS INTENTIONAL. WE DON'T -- WE DON'T WANT TO EXPOSE PEOPLE TO UNNECESSARY RISK AND SUFFER IN ANY WAY AS A RESULT OF PARTICIPATION. AT THE SAME TIME WE WANT TO ADVANCE MEDICAL KNOWLEDGE. AND WE CONTINUE TO SEEK THE BEST WAYS TO DO THAT. IF I HAD MORE TIME I MIGHT DISCUSS REVISIONS TO COMMON RULE BUT YOU'LL HEAR MORE IN THE WEEKS TO COME. SO WITH THAT I WILL END. [APPLAUSE] >> THANK YOU SO MUCH, DR. LEDERE FROM UNIVERSITY OF WISCONSIN. I WILL DREAD HAVING MISREPRESENTING YOU FOR WEEKS NOW. >> NO, NO, NO, NO. I HAD TO MENTION IT. >> NO, I APPRECIATE YOU MENTIONING IT. AND I FOR ONE COULD LISTEN FOR MANY MORE HOURS TO HEAR ABOUT THE HISTORY. I'M WONDERING IF THERE'S MAYBE ONE QUESTION HERE IN THE ROOM. GREAT, ETHAN WILL ASK A QUESTION. YOU WERE NICE ENOUGH TO SHARE YOUR E-MAIL. STUDENT CAN ALSO E-MAIL ME OR PUT MESSAGES ON THE DISCUSSION BOARD, AND WE WILL MAKE SURE YOU GET THOSE TO RESPOND TO. >> THANK YOU. I'M SORRY FOR GOING OVER TIME. >> IT'S OKAY. IT'S JUST MY LECTURE NEXT, I COULD HAVE JUST LISTENED. WE DO HAVE TO GET SOME INFORMATION DELIVERED. ETHAN, TAKE IT AWAY. >> YOU MENTIONED HOW THE PERCEPTION IN THE U.S. WAS THAT THE NUREMBERG CODE WASN'T REALLY NECESSARY FOR OUR DOCTORS BECAUSE WE'RE NOT NAZIS. I WONDER IF THE PUBLICATION OF JERUSALEM HAD ANY IMPACT, AS WAS POINTED OUT, NAZI EVIL WAS REALLY QUITE NORMAL AND BORING. >> THAT'S A REALLY INTERESTING QUESTION. I HAVE NOT SEEN IT IN THE PAPERS AND CORRESPONDENCE OF THE PHYSICIANS I'VE STUDIED. I WILL SAY, YOU KNOW, I AM ONE OF THOSE PEOPLE WHO WOULD ARGUE THAT IN FACT NUREMBERG MAY HAVE HAD MORE INFLUENCE THAN IT HAS BEEN GRANTED BECAUSE WHEN RESEARCHERS GOT NERVOUS, THEY WOULD REFER TO THINGS AND SAY, WELL, IT HAS A WHIFF OF BUCHENWALD, IT'S REMINISCE OF DACHAU OR BUCHENWALD WHICH SUGGESTS THEY WERE FAMILIAR BUT I'VE NOT SEEN ANY DISCUSSION OF JERUSALEM IN REFERENCE TO THEIR DELIBERATIONS. I'LL BE ON THE LOOKOUT. >> I'M GOING TO POST A LINK TO THE GUATEMALA STUDY ON THE SITE SO FOLKS WILL HAVE ACCESS TO THAT. AND SO, YEAH. GREAT. THANK YOU SO MUCH. HAVE A NICE REST OF YOUR DAY. >> THANK YOU, YOU TOO. >> SO, AS WE WILL EVERY DAY, EVERY DAY THAT WE MEET, WE'LL TAKE A 15-MINUTE BREAK, SLIGHTLY SHORTER TODAY, ABOUT 13 MINUTES, AND THEN I'LL BE BACK HERE AT 10:50 AND WE'LL SPEND A BIT OF TIME ON INSTITUTIONAL REVIEW BOARDS. SO IF EVERYONE CAN REJOIN US AT 10:50 THAT WOULD BE GREAT. I WILL SAY ONCE AGAIN, DR. LEDERER WAS NICE ENOUGH TO REFERENCE OUR WORD OF THE DAY, THE WORD OF THE DAY IS NUREMBERG. IT IS A MULTIPLE CHOICE QUESTION. SO IF I SOUND LIKE I'M MUMBLING, IT WILL BE PRETTY CLEAR WHEN YOU OPEN THE QUIZ THAT THERE IS AN ANSWER THERE THAT IS NUREMBERG. THANKS. I WANT TO MAKE ONE REQUEST. MANY OF YOU SENT IN QUESTIONS AFTER DR. GRADY SESSION BUT I DIDN'T GET THEM UNTIL DR. LEDDERER STARTED. FEEL FREE TO POST QUESTIONS IN THE DISCUSSION BOARD, WHEN YOU THINK ABOUT IT, RIGHT? THAT WAY WE'LL BE ABLE TO ANSWER MORE OF YOUR QUESTIONS LIVE IN REAL TIME, SO DON'T WAIT UNTIL THE LECTURE IS OVER. GET THOSE QUESTIONS IN AS SOON AS YOU FEEL LIKE IT. INSTITUTIONAL REVIEW BOARDS WERE MENTIONED A COUPLE TIMES ALREADY THIS MORNING. I'LL SPEND TIME TALKING MORE ABOUT THEM BECAUSE THEY ARE IMPORTANT IN THE OVERSIGHT AND REVIEW OF HUMAN SUBJECT RESEARCH. HERE IS MY DISCLAIMER AGAIN. YOU'LL SEE IT MANY MORE TIMES. I WANT US TO THINK ABOUT THE FACT THERE ARE BASICALLY WHAT WE REFER TO AS TWO PILLARS IN THE PROTECTION OF HUMAN SUBJECT RESEARCH. THE INSTITUTIONAL REVIEW BOARD BASICALLY STANDS BETWEEN THE RESEARCHERS AND THE POTENTIAL SUBJECTS. BOARD IS RESPONSIBLE FOR MAKING SURE RESEARCH IS ETHICAL, MEETS GUIDELINES, NEXT IS INFORMED CONSENT WHICH WE'LL HAVE A LECTURE ON LATER IN THE TERM. THAT'S WHERE THE HUMAN SUBJECT THEN HAS THE ABILITY TO HEAR ABOUT AND MAKE A DECISION ABOUT ENROLLMENT. SO, TWO KEY PROTECTIONS. THESE ARE THE KEY POINTS IF YOU DON'T GET ANYTHING OUT OF THE SESSION, THESE ARE THE KEY POINTS. IRBs ARE RESPONSIBLE FOR REVIEW AND OVERSIGHT OF HUMAN SUBJECT RESEARCH, GUIDED BY 46 CFR 46 AND 21 CFR 56, THEY ARE LOCAL, SO EVERY ACADEMIC MEDICAL CENTER IN THE UNITED STATES HAS AT LEAST ONE IF NOT MULTIPLE IRBs REVIEWING RESEARCH. HERE AT THE CLINICAL CENTER, FOR EXAMPLE, WE HAVE AN INTRAMURAL IRB, THE IRB MEETS AT LEAST FOUR TIMES A WEEK, AND HAS THOUSANDS OF PROTOCOLS IT IS RESPONSIBLE FOR AT ANY GIVEN TIME, LOCAL IN THE SENSE THAT WE, I'M A MEMBER OF THAT IRB, REVIEW RESEARCH CONDUCTED OR PROPOSED BY INTRAMURAL INVESTIGATORS, INTRAMURAL ARE THOSE INVESTIGATORS WHO ARE HERE IN THE CLINICAL CENTER. THEY DO THEIR WORK HERE IN THE CLINICAL CENTER VERSUS EXTRAMURAL INVESTIGATORS IN MEDICAL CENTERS FUNDED BY THE NATIONAL INSTITUTES OF HEALTH. THEY ALSO HAVE LOCAL IRBs TO REVIEW. IF WE WENT BACK TO 1950 WHEN FIRST THINKING ABOUT HAVING THESE INSTITUTIONAL REVIEW BOARDS THE FIRST POLICY WAS, HEY, WHY DON'T ALL OF YOU SEND YOUR RESEARCH TO BETHESDA AT THE NIH AND WE'LL REVIEW AND GET BACK TO YOU. IMAGINE IF WE STILL THAT SOMETHING LIKE THAT WHERE EVERYTHING REVIEWED HERE. REALIZED QUICKLY IT WOULD BE BETTER TO HAVE A LOCAL REVIEW AND FOR ALL OF YOU WHO ARE THINKING ABOUT PLANNING TO HAVE ALREADY DONE HUMAN SUBJECT RESEARCH, WHEN IN DOUBT, ASK YOUR INSTITUTIONAL REVIEW BOARD OR ITS EQUIVALENT. I KNOW THE REST OF THE WORLD REFERS TO THESE BODIES AS RESEARCH ETHICS COMMITTEES. WE'RE A BIT OF THE OUTLIER. BUT IRBs ARE THERE FOR YOU. THEY ARE THERE TO HELP YOU THINK ABOUT YOUR RESEARCH, SO WHEN YOU'RE CONCERNED ABOUT SOMETHING ASK THEM. THOSE ARE THE KEY POINTS. LET'S STEP BACK A BIT. DR. GRADY INTRODUCED THIS ETHICAL REQUIREMENT OF INDEPENDENT REVIEW. THIS HAS TWO POINTS. ONE WAS TO MINIMIZE THE POTENTIAL CONFLICTS OF INTEREST AMONG THE RESEARCHER AND HIS COMMITMENT, HER COMMITMENT TO HER IDEAS, AND TO ASSURE SOME PUBLIC SOCIAL ACCOUNTABILITY, SO THE AVERAGE PERSON -- I DON'T KNOW FOR A FACT THAT THE AVERAGE PERSON KNOWS WHAT AN INSTITUTIONAL REVIEW BOARD IS, BUT IF YOU EVER COME TO JOIN A RESEARCH PROJECT HERE AT THE NIH OR ELSEWHERE, YOU WILL FIND OUT THAT THERE IS AN INSTITUTIONAL REVIEW BOARD WHO HAS REVIEWED THE RESEARCH IN ADVANCE. SO, IT'S REALLY TO LET FOLKS KNOW THAT IT'S NOT JUST THE RESEARCHERS WHO ARE OVERSEEING IT, THERE'S ACTUALLY A BODY OF INTERESTED PEOPLE MAKING SURE THAT IT'S ETHICALLY SOUND BEFORE IT CAN BE CONDUCTED. THIS IS A QUOTE FROM AN ARTICLE I LIKE, AGAIN IF WE PUT OURSELVES IN THAT TIME CAPSULE TO THE POINT IN TIME WHERE THERE WAS NO IRB, I THINK THIS IS A REALLY APT ASSESSMENT. UNQUESTIONABLY THEIR VERY EXISTENS HAS TEMPERED THE INEVITABLE PRO PENS ACTIVE RESEARCHERS TO PURSUE INVESTIGATIONS WITHOUT DISPASSIONATELY WEIGHING RISKS RISKS FER ASKING OTHERS TO ASSUME OR FULLY INFORMING SUBJECTS OF THEM. IT'S A BIT OF A DETERRENCE IN THE SENSE THAT JUST THE FACT THE IRB EXISTS PUTS RESEARCHERS IN A SLIGHTLY DIFFERENT RELATIONSHIP WITH THE HUMAN SUBJECT, AND THAT ALONE SEPARATE FROM THE FACT THERE IS AN ACTUAL REVIEW PROCESS IS REALLY IMPORTANT TO HOW WE THINK ABOUT CONDUCT OF HUMAN SUBJECT RESEARCH. THIS IS SUPPOSED TO DEPICT CONFLICT OF INTEREST. HOLY COW, THIS MIGHT BE A CURE. IT'S THE IRB'S JOB TO SAY THIS LOOKS LIKE SCIENTIFIC WORK, LET'S MAKE SURE THE PLAN IS SOUND AND PROTECTS SUBJECTS, MEANT TO TEMPER ENTHUSIASM OF THE INVESTIGATOR WHO IS ALWAYS SUPER EXCITED ABOUT THEIR WORK. I'M GOING TO TALK ABOUT FOUR THINGS COVERING QUITE A BIT OF TERRITORY IN THE NEXT 20 MINUTES OR SO. THE IRB WILL POP UP MULTIPLE TIMES AS WE MARCH THROUGH TOPICS BECAUSE THEY ARE IMPORTANT AND HAVE AN OUTSIZED INFLUENCE ON CONDUCT OF HUMAN SUBJECT RESEARCH GENERALLY. SO, AS I SAID, THEIR ROLE IS TO REVIEW AND OVERSEE THE CONDUCT OF HUMAN SUBJECT RESEARCH. THE IRB USUALLY REFERS TO THE MEMBERS OF THE IRB COMMITTEE. IN 2022, MOST INSTITUTIONS LIKE OUR OWN HAVE WHAT'S REFERRED TO AS A HUMAN RESEARCH PROTECTION PROGRAM. THE IRB COMMITTEE IS JUST ONE COMPONENT OF THAT. SO, THERE ARE LOTS OF PROFESSIONALS HERE AT THE CLINICAL CENTER, WHO ARE LOOKING AT RESEARCH, MANAGING THE RESEARCH, ELECTRONIC SYSTEM, SO THE IRB REVIEW IS MUCH MORE THAN THE MINIMUM OF FIVE PEOPLE THAT YOU NEED, SITTING AROUND A TEAM, DELIBERATING. IT'S REALLY AN OFFICE THAT IS OVERSEEING THE CONDUCT OF HUMAN SUBJECT RESEARCH. BUT ACCORDING TO THAT LOVABLE 45 CFR 46 THE IRB HAS TO HAVE AT LEAST FIVE MEMBERS, AND IT'S LOCAL AND AUTONOMOUS. DR. GRADY MENTIONED BECAUSE THEY ARE LOCAL AND AUTONOMOUS WE HAVE DOCUMENTED EMPIRICALLY THERE'S A LOT OF VARIABILITY IN REVIEW. IT'S A BELL CURVE. IF YOU LOOK, MANY PEOPLE HAVE, LOOK AT THE REVIEW OF A PARTICULAR PROTOCOL THAT PRIOR TO THE SINGLE IRB WHICH WE'LL TALK ABOUT BRIEFLY WENT TO 20 DIFFERENT IRBs, ONE MIGHT CALL IT EXEMPT, MAJORITY CALL IT EXPEDITED, ONE SENDS IT TO FULL COMMITTEE. SO THERE'S LIKE MOST PEOPLE ARE DOING SOMETHING VERY SIMILAR, BUT THERE ARE SOME OUTLIERS. WE WORRY ABOUT THE OUTLIERS WHEN EITHER THEY ARE PUTTING INDIVIDUALS AT UNNECESSARY RISK OR THEY ARE NOT APPROVING OTHERWISE SCIENTIFICALLY AND ETHICALLY SOUND RESEARCH. AND GENERALLY WE DON'T HAVE MUCH TROUBLE WITH THOSE, PRINCIPAL INVESTIGATORS KNOW IRBs EXIST. I MENTIONED INDIVIDUAL CONFLICT OF INTEREST. YOU MAY HAVE THOUGHT, HEY, HOLLY, YOU SAID THEY ARE LOCAL. IF ATTACHED TO THE INSTITUTION SINCE THERE AN INSTITUTIONAL CONFLICT OF INTEREST? YES, THERE IS. ESPECIALLY BECAUSE THE MAJORITY OF INDIVIDUALS THAT ARE THE MEMBERS OF THE LOCAL IRB ARE LOCAL INVESTIGATORS. SO, I HAVE A VESTED INTEREST AS BOTH AN INVESTIGATOR AND IRB MEMBER PERHAPS TO BE SOFT ON MY COLLEAGUES, RIGHT? BECAUSE I KNOW I'M GOING TO HAVE TO COME THROUGH THE SAME PROCESS. I'M NOT SAYING THAT THAT'S TRUE OR CONSCIOUS, BUT THERE IS A POTENTIAL CONFLICT. OUTSIDE OF THE NIH, THE FOLLOWING IS TRUE. LET'S SAY YOU'VE RECEIVEDs A COUPLE MILLION DOLLARS TO DO AN AMAZING STUDY OF CANCER, YOU'VE DEVELOPED A NOVEL TREATMENT FOR CANCER. LET'S SAY THAT THE NCI WILL GIVE YOU THIS MONEY. THE MONEY IS NOT RELEASED TO YOUR INSTITUTION UNTIL THE IRB HAS REVIEWED AND APPROVED IT. THE INSTITUTION HAS A VESTED INTEREST. THERE'S A PHENOMENON CALLED COMMERCIAL IRBs, PRIVATE ENTITIES FEE FOR SERVICE INSTITUTIONAL REVIEW BOARDS. EVERYONE SAYS THEY ARE CONFLICTED. THEY ARE IN IT FOR THE MONEY. I MAKE THESE POINTS JUST BECAUSE IT'S NOT LIKE THE LOCAL IRB SYSTEM THAT WE HAVE ATTACHED TO ACADEMIC MEDICAL INSTITUTIONS IS SOMEHOW FREE FROM POTENTIAL BIAS AND CONFLICTS OF INTEREST. ANOTHER IMPORTANT THING, IT'S A GROUP AND CAN BE AFFECTED BY ALL SORTS OF GROUP DYNAMICS. OBSERVER DRIFT, MEANING THEY MIGHT HAVE STARTED HERE IN HOW THEY EVALUATED A PARTICULAR TYPE OF STUDY AND MOVED TO MAKE IT LESS -- THINK ABOUT IT AS LESS OR MORE RISKY, MEANING THEY CAN BE VARIABLE. IN MY EXPERIENCE OF SITTING ON MANY, MANY IRBs OVER THE YEARS, IS THAT THE CHAIR HAS A REALLY IMPORTANT ROLE. AND A VERY OPINIONATED CHAIR MAY START TO CREATE A PLACE OF GROUP THINK, WHERE INSTEAD OF THINKING HOW BEST SHOULD I REVIEW THIS RESEARCH I'M THINKING, WELL, WHAT'S THE CHAIR GOING TO SAY, IF I THINK LIKE THE CHAIR, HOW SHOULD I REVIEW IT? AND THEN YOU ALL END UP NOT BRINGING YOUR OWN INDIVIDUAL PERSPECTIVE BUT WHAT YOU THINK THE CHAIR, THAT IS THE GROUP, THINKS IS BEST. SO I REALLY LIKE STUDYING IRBs, THAT MIGHT BE SOME SORT OF, YOU KNOW, CONDITION UNDERLYING, BUT I THINK IT'S REALLY INTERESTING TO THINK ABOUT ALL THESE ISSUES AND ALL THE THINGS THAT CAN GO WRONG AND RIGHT. THE GOAL BEING TO MAKE SURE RESEARCH IS SAFE AND HUMAN SUBJECTS ARE PROTECTED. THE OTHER REASON THEY ARE IMPORTANT, I JUST ALLUDED TO, YOU NEED IRB APPROVAL TO GET YOUR FEDERAL FUND TO DO YOUR RESEARCH. SO, IT'S REALLY IMPORTANT TO HAVE AN IRB. IF YOU DON'T HAVE YOUR OWN HOME IRB, THESE DAYS YOU COULD PURCHASE AN IRB REVIEW FROM A COMMERCIAL ENTITY, BUT THAT WOULD MEAN YOU WOULD HAVE TO SPEND MONEY TO GET MONEY. EVERYONE WHO CONDUCTS HUMAN RESEARCH WITH FEDERAL FUND HAS TO HAVE AN IRB AND PERHAPS AS IMPORTANT, THE FDA WHEN DRUG COMPANIES ARE SUBMITTING THEIR APPLICATIONS FOR MARKETING, HAVE TO SHOW THAT ALL THE RESEARCH WAS REVIEWED BY AN IRB. SO THERE'S VERY LITTLE ROOM BETWEEN -- IN THE UNITED STATES ANYWAY, THERE'S VERY LITTLE ROOM FOR RESEARCH THAT IS NOT REVIEWED BY AN IRB TO HAPPEN BECAUSE IT'S EITHER HAPPENING BECAUSE YOU'RE AN ACADEMIC MEDICAL CENTER OR HOSPITAL OR HEALTH SYSTEM, OR YOU'RE WITH THE PHARMA COMPANY PLANNING TO SUBMIT RESEARCH FOR MARKETING. THERE COULD BE SOME ROGUE INDIVIDUALS DOING HUMAN SUBJECT RESEARCH, BUT I'M NOT SURE WE WOULD KNOW, INTERESTING THERE WAS A GUY MANY YEARS AGO, I CAN'T REMEMBER WHAT HE WANTED TO DO, HE WANTED TO LOOK AT LIKE -- I WANT TO SAY SOMETHING LIKE TRANSPLANTING ARMS ON HEALTHY SUBJECTS, SOMETHING CRAZY. I REMEMBER IT WAS SOMETHING CRAZY. EVERYONE SAID, WELL, HE WILL NEVER BE ABLE TO DO THAT BECAUSE HE WILL NEED TO BE REVIEWED BY AN IRB. BUT THIS WAS A SORT OF ROGUE GUY WHO WAS NOT AFFILIATED WITH AN ACADEMIC MEDICAL CENTER, NOT PLANNING TO SUBMIT ANYTHING TO THE FDA. BUT, AGAIN, THAT'S THE ABSOLUTELY THE EXCEPTION TO THE RULE. SO, THE WAY THIS HAPPENS, MEANING THE WAY THAT WE GET TO A POINT WHERE THERE IS LOCAL IRB HAPPENING, IS THAT ALL OF THOSE LOCAL IRBs ASSURE THE FEDERAL GOVERNMENT THAT IS THE OFFICE OF HUMAN RESEARCH PROTECTIONS, IN OUR DEPARTMENT OF HEALTH AND HUMAN SERVICES, THAT'S THE AGENCY THAT'S ABOVE THE NIH, AND THE FDA, AND A BUNCH OF OTHERS AGENCIES, ALL OF THOSE INSTITUTIONS BASICALLY SIGN A FORM THAT SAYS, I PROMISE TO REVIEW ALL OF THE RESEARCH IN MY INSTITUTION, WHETHER IT IS FEDERALLY FUNDED OR NOT, ACCORDING TO 45 CFR 46. BASICALLY THAT MEANS THAT IF I'M AT AN ACADEMIC MEDICAL CENTER, I HAVE A RESEARCH STUDY, IT'S FUNDED BY A NON-PROFIT OR IT'S FUNDED BY MY DISCRETIONARY ACCOUNT, FUNDING DOESN'T MATTER. ALL RESEARCH AT MY INSTITUTION IS REVIEWED BECAUSE THEY HAVE SIGNED AN ASSURANCE WITH THE FEDERAL GOVERNMENT. DR. GRADY MENTIONED REVIEW CRITERIA WHICH MAP NICELY ON THE PRINCIPLES WE DISCUSSED. INTERESTINGLY, THERE ISN'T MUCH MORE THAN THESE WORDS IN THE 45 CFR 46. THIS IS IN PART WHY A LOT OF INSTITUTIONS HAVE LOCAL GUIDANCE, LOCAL POLICY, BECAUSE THE REGULATIONS ARE PRETTY THIN, RIGHT? SELECTIONS OF SUBJECT SHOULD BE EQUITABLE. OKAY. WELL, THE INSTITUTION THEN SORT OF BUILDS THAT OUT AS IT RELATES TO RESEARCH THAT THEY ARE CONDUCTING. THESE ARE THE ADDITIONAL RESPONSIBILITIES. SAFETY MONITORING IS OBVIOUSLY IMPORTANT WHEN THERE'S A DRUG STUDY UNDERWAY. AND WE'LL TALK MORE ABOUT THIS OVER TIME BUT SPECIAL PROTECTIONS FOR VULNERABLE SUBJECTS, SIMA SHAW WILL JOIN US NEXT WEEK, INCLUSION OF CHILDREN IN RESEARCH, ONE OF THE COUPLE VULNERABLE SUBJECTS LISTED IN THE 45 CFR SO IT'S CHILDREN, PREGNANT WOMEN, PRISONERS, AND MAYBE A FOURTH? ANYONE? BUT WE'LL TALK ABOUT KIDS, ADDITIONAL CRITERIA, NIH GUIDELINES, SOME STATES, VERY VIEW, HAVE STATE-SPECIFIC LAWS RELATED TO IRB. MARYLAND, FOR EXAMPLE, HAS A LAW THAT SAID IRBs MUST MAKE THEIR MINUTES PUBLIC. SO TECHNICALLY, YOU COULD GO TO THE UNIVERSITY OF MARYLAND OR JOHNS HOPKINS, TO THE IRB, AND SAY I WOULD LIKE TO SEE THE MINUTES OF ALL YOUR MEETINGS. YOU WOULDN'T HAVE TO FILE A FOIA, FREEDOM OF INFORMATION ACT REQUEST, TECHNICALLY THEY SHOULD JUST HAND IT OVER TO YOU. SO, IRBs ARE RESPONSIBLE FOR THE REVIEW AND OVERSIGHT OF RESEARCH. THIS IS THE DEFINITION OF RESEARCH IN THE FEDERAL REGULATIONS. AND IT'S PRETTY UNSATISFYING, BUT THIS IS A STARTING POINT. SYSTEMATIC INVESTIGATION INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, DESIGNED TO CONTRIBUTE TO GENERALIZABLE KNOWLEDGE, THE LAST LINE IS IMPORTANT, THAT THE GOAL HERE IS THAT YOU ARE NOT USING THESE HUMAN SUBJECTS ONLY AS MEANS. YOU HAVE SOME GOAL OF CONTRIBUTING TO GENERALIZABLE KNOWLEDGE. IN SOME CASES, THAT'S A REALLY LONG PATH FROM A PHASE 1 STUDY TO A MARKETED DRUG. BUT THE INTENTION IS TO DEVELOP GENERALIZABLE KNOWLEDGE. IT'S CONTENTIOUS IN THE SENSE AS SOMEONE WHO DOES QUALITATIVE RESEARCH, MY GOAL IS OFTEN NOT GENERALIZABLE BUT TRANSFERABLE KNOWLEDGE, SO IT'S LIMITED BUT GENERALLY COVERS ALMOST EVERYTHING. THERE ARE A COUPLE CATEGORIES OF RESEARCH THAT ARE RELEVANT, SO THE IRB CAN BASICALLY SAY THAT'S NOT HUMAN SUBJECT RESEARCH, I DON'T NEED TO REVIEW IT. THEN THERE IS A SET OF RESEARCH THAT IS EXEMPT FROM IRB REVIEW. GENERALLY THAT IS RESEARCH WHERE THERE'S NO MORE THAN MINIMAL RISK, AND MEETS ONE OF EIGHT OTHER CRITERIA THAT ARE RIGHT IN THE CFR, FOR EXAMPLE, DATA COLLECTION WITHOUT IDENTIFIERS. IF I DID AN ANONYMOUS SURVEY PERHAPS OF YOUR KNOWLEDGE BEFORE THE CLASS, THAT MEANS THAT MY RESEARCH IS EXEMPT. THE OTHER TWO CATEGORIES ARE EXPEDITED OR FULL COMMITTEE REVIEW. EXPEDITED RESEARCH CAN BE NO MORE THAN MINIMAL RISK, BUT DOES ENGAGE -- DOES EXPOSE SUBJECTS TO A CERTAIN AMOUNT OF RISK. AND IMPORTANTLY, IT CAN BE REVIEWED BY JUST THE CHAIRPERSON OR EXPERIENCED REVIEWER. IT'S CALLED EXPEDITED BECAUSE IT'S SUPPOSED TO BE FASTER. IT'S NOT ALWAYS FASTER. BUT IT IS TECHNICALLY NOT AS HEAVY A LIFT AS THE REVIEW BY THE FULL COMMITTEE, MEANING THAT THERE'S FIVE-PLUS PEOPLE GET TOGETHER, HAVE READ THE PROTOCOL IN ADVANCE, DELIBERATE ABOUT IT AND MAKE A DECISION ABOUT WHETHER IT CAN BE MOVED FORWARD. THE IDEA BEING THAT IT'S EITHER REJECTED, ALMOST NEVER HAPPENS, APPROVED WITH CONDITIONS, OR APPROVED. THE MIDDLE CATEGORY IS 99 TIMES OUT OF 100 WHAT THE INVESTIGATOR HEARS. WE WILL APPROVE YOUR PROJECT, IF YOU DO THE FOLLOWING. BUT IN MY EXPERIENCE OF MAYBE NOT TENS OF THOUSANDS OF IRB REVIEWS BUT THOUSANDS, ONCE IN MY EXPERIENCE WAS A PROJECT REJECTED. THAT WAS WITH SOME CONCERN BY THE IRB THAT THIS INVESTIGATOR WOULD BE REALLY MAD AT US, BUT THAT'S NOT A REASON NOT TO REJECT IT. I WANT TO QUICKLY JUST TELL YOU A LITTLE ABOUT THIS SINGLE IRB REVIEW THAT WE'VE ALLUDED TO. SO, HERE'S HOW THIS USUALLY HAPPENS. AN INITIAL REVIEW HAPPENS, RIGHT? I SUBMIT A RESEARCH PLAN, CONSENT DOCUMENT, ADVERTISEMENTS. THE LATTER TWO BASICALLY ANYTHING THAT IS GOING TO BE SEEN BY A POTENTIAL SUBJECT. AND I SUBMIT THOSE TO THE IRB OR TO THE HUMAN RESEARCH PROTECTION PROGRAM. AND THERE'S AN ADMINISTRATIVE REVIEW THAT HAPPENS, THEN THE HUMAN SUBJECTS REVIEW BY THE IRB, THEN A DECISION. AND THE DECISIONS AS I MENTIONED ARE, YOU KNOW, ANYWHERE FROM APPROVE TO DISAPPROVE, BUT THAT'S ONE GROUP LOOKING AT ONE PROPOSAL COMING TO ONE DECISION. THERE ARE OTHER REVIEW PROCESSES THAT I WON'T SPEND OF TIME ON BUT SOME PROTOCOLS HAVE TO COME BACK EVERY YEAR FOR REVIEW. IF YOU AMEND YOUR PROJECT, YOU NEED TO SUBMIT -- I'M GOING TO CHANGE IT IN THE SUBSTANTIVE WAY AND IF THERE ARE ADVERSE EVENTS THAT HAS TO BE REPORTED. A NUMBER OF YEARS AGO BACK IN 2016 THE NIH FINALIZED A POLICY THAT SAID IF YOU'RE DOING MULTI-RIGHT RESEARCH YOU, INVESTIGATORS, MUST USE A SINGLE IRB REVIEW FOR THAT REVIEW. THE COMMON RULE WAS SUBSEQUENTLY REVISED TO BASICALLY SAY THE SAME EXACT THING. A COUPLE OF YEARS LATER. I GUESS JUST TWO YEARS LATER. SO, HERE'S HOW IT USED TO WORK, RIGHT? IT USED TO BE THAT IF I WAS CONDUCTING A STUDY IN COLLABORATION WITH NINE OTHER SITES, LET'S GO BACK TO MY ONCOLOGY STUDY EXAMPLE, THE IRB FROM EVERY INSTITUTION WHERE THE PROJECT WAS GOING TO BE CONDUCTED WOULD BE REVIEWING THE PROTOCOL. I HAVE FIVE HERE AS THE DENOMINATOR RATHER THAN TEN BUT BASICALLY THAT WOULD MEAN THAT THERE'S USUALLY A COORDINATING CENTER BECAUSE WHEN YOU HAVE TEN SITES COLLABORATING IT'S IMPORTANT TO HAVE SOMEONE IN CHARGE. BUT THERE WOULD BE FIVE IRB REVIEWS AT THE FIVE INSTITUTIONS WHERE THIS STUDY WOULD BE CONDUCTED. AND LOTS OF PEOPLE SAID HOLY COW, WHY ARE WE REVIEWING THIS FIVE TIMES? BY THE WAY, IT TAKES A LONG TIME. IT COULD TAKE A MONTH TO YEAR FOR IRB REVIEWS TO BE COMPLETED. SO, THE IDEA WAS THEN TO SAY, HEY, WHAT IF WE DO THIS, WHAT IF WE PUT THE COORDINATING CENTER IN CHARGE OF IDENTIFYING A SINGLE IRB OF RECORD WHO REVIEWS THE PROTOCOL AND THEN BASICALLY SENDS THE MESSAGE OUT TO THOSE OTHER COLLABORATORS THAT IT'S BEEN REVIEWED AND APPROVED? NOW, IN THEORY, THAT SHOULD ADDRESS SOME OF THE ADMINISTRATIVE BURDEN OF CONDUCTING FIVE REVIEWS, INSTEAD OF JUST ONE. OR IN MY EXAMPLE, SIX REVIEWS VERSUS ONE. NOW, THE CHALLENGE IS THAT IRB REVIEW IS NOT THE ONLY THING THAT HAPPENS IN THE REVIEW OF A RESEARCH PROTOCOL. SO, ALL OF THOSE LOCAL HRPPs, WHILE NOT DOING THE IRB REVIEW, THE ETHICS REVIEW, THEY ARE DOING THE PHARMACY AND THERAPEUTICS REVIEW, BIOSAFETY REVIEW, REVIEW OF THE INVESTIGATOR, CONFLICTS OF INTEREST. SO WHILE THIS ONE ACTIVITY HAS BEEN MOVED TO BE CENTRALIZED, IT DOESN'T NECESSARILY MEAN THAT IT HAS RELIEVED THAT MUCH ON BEHALF OF THE LOCAL HRPPs, AND BEFORE THE SINGLE IRB CAN BECOME THE SINGLE IRB OF RECORD RELIANCE AGREEMENT HAS TO BE NEGOTIATED. THAT TAKES TIME. NOW, ONCE THOSE RELIANCE AGREEMENTS ARE NEGOTIATED, IF THEY COLLABORATE AGAIN, MAYBE WE CAN JUST SAY WE DID THIS ONCE BEFORE, LET'S DO IT AGAIN. SO, AS DR. GRADY MENTIONED, THIS IS AN ACTIVE TRANSITION. THERE ARE MULTIPLE EVALUATIONS UNDERWAY. THE OUTCOMES ARE UNCLEAR. I'LL MENTION THAT THE -- IN ADDITION TO THE IDEA OF TURNING SIX REVIEWS INTO ONE REVIEW, THE OTHER THING THAT I THINK THEY DIDN'T THINK ABOUT MUCH WAS THE FOLLOWING, THAT IF I'M AN ACADEMIC INVESTIGATOR AT THE UNIVERSITY OF WISCONSIN, LET'S SAY, AND I JUST TOLD YOU THAT I'M INVOLVED WITH THIS ONE ONCOLOGY STUDY COLLABORATING WITH THESE FOUR OTHER SITES, I COULD BE DOING THIS FOUR OR FIVE TIMES OVER. RIGHT? I'M SELDOM DOING JUST ONE TRIAL. SO, I'VE HAD TO NEGOTIATE RELIANCE AGREEMENTS WITH UP TO FIVE DIFFERENT SINGLE IRB REVIEWS, AND IT USED TO BE THAT ALL I HAD TO DO WAS COMMUNICATE WITH MY OWN IRB. NOW I HAVE TO COMMUNICATE WITH MY OWN IRB AND THE SINGLE IRB AND I HAVE TO KEEP TRACK OF WHICH SINGLE IRB IS IN CHARGE OF THIS STUDY. YOU MAY HERE IN MY TONE I'M NOT A HUGE FAN OF THIS POLICY IN PART BECAUSE THE CLAIM WAS THIS WILL FIX THE PROBLEM, BUT WE DIDN'T HAVE ANY EMPIRICAL EVIDENCE THAT THIS WAS THE RIGHT SOLUTION. IT WAS REALLY A JUDGMENT CALL. PEOPLE SAYING MULTIPLE REVIEWS ARE TOO MUCH. THE RESPONSE, HEY, LET'S THINK ABOUT HAVING JUST ONE. FOR THOSE IN THE ROOM, YOU HEARD IN MY WORKS IN PROGRESS EARLIER THIS WEEK THAT I'M REALLY INTERESTED IN THE LOCAL IMPLEMENTATION OF FEDERAL POLICY. I THINK THIS IS SUPER INTERESTING BECAUSE, YOU KNOW, THERE'S JUST GOING TO BE A LOT. AGAIN, THE GOAL HERE IS TO BALANCE PROTECTING THE HUMAN SUBJECT ALONG WITH NOT GETTING IN THE WAY OF REALLY THOUGHTFUL VALUABLE IMPORTANT RESEARCH, AND THAT IS THAT THE TENSION WE'LL BE NEGOTIATING FOR THE REST OF THE TERM. ALWAYS HOW FAR CAN WE GO IN EITHER DIRECTION AND SORT THAT, REGULATE, WHAT POLICY SHOULD WE'VE IN PLACE. WE HAVE TEN MINUTES FOR QUESTIONS. I WOULD LOVE QUESTIONS FROM ANYONE IN THE ROOM. I'M ALSO GOING TO LOOK AT MY COMPUTER, BECAUSE SOME OF YOU MAY HAVE PUT QUESTIONS IN THERE AND I'LL BRING IT BACK. DO ANY OF YOU HAVE ANY QUESTIONS? THANK YOU BECAUSE APPARENTLY I HAVE TO OPEN MY COMPUTER BECAUSE IT'S ON BATTERY POWER. >> FIRST, JUST A COMMENT BECAUSE OF MY EXPERIENCE COMING FROM ESTONIA, BEING INVOLVED IN EUROPEAN PROJECTS. YOU KNOW, IN EUROPE WHEN YOU'RE DOING A COLLABORATION WITH DIFFERENT COUNTRIES IT'S VERY MUCH THE SAME PICTURE OF LIKE WHERE SHOULD WE GO FOR THE ETHICS COMMITTEE, RESEARCH ETHICS COMMITTEE, DO WE HAVE TO GO TO 15 COUNTRIES AND DO IT 15 TIMES, THIS IS A VERY -- A SUBJECT CLOSE TO MY HEART. I WANTED TO ASK ABOUT -- SO THE IRB AS RESEARCH ETHICS COMMITTEE ELSEWHERE ARE GOING TO LOOK AT ETHICS AND SCIENCE PART. I WAS WONDERING HOW OFTEN IN YOUR EXPERIENCE HAVE YOU HAD DISCUSSIONS ABOUT THE SCIENCE PART BECAUSE AS YOU KNOW, METHODOLOGIES IN MANY CASES ARE A VERY CONTESTED MATTER, LIKE IS THAT METHODOLOGY APPROPRIATE OR NOT, SO HOW OFTEN DO YOU SEE THAT THE IRBs ARE ACTUALLY GOING TO GO IN THERE AND SAY, WELL, THAT'S NOT AN APPROPRIATE METHODOLOGY FOR THAT KIND OF STUDY? >> GREAT QUESTION. SO, HERE ARE MY THOUGHTS. THERE IS CONTROVERSY AS YOU MENTIONED ABOUT SORT OF I'LL CALL IT PUSHBACK FROM INVESTIGATORS WHO SAY I'M THE SCIENTIST, THIS HAD SCIENTIFIC REVIEW, PERHAPS AS PART OF A FUNDING DECISION, PLEASE DON'T MESS AROUND WITH MY RESEARCH QUESTION AND THE WAY I'VE DESIGNED THIS STUDY BECAUSE I REALLY KNOW BEST. AND FRANKLY, SOME OF THAT IS TRUE, RIGHT? THEY ARE THE EXPERT. THEY ARE BRINGING THEIR BEST JUDGMENT, THEIR RESEARCH QUESTION TO THE GROUP. SO, UNDERSTANDABLY THERE'S SOME PUSHBACK AROUND THE SCIENCE. TWO THINGS. ONE, AS DR. GRADY SAID, YOU'VE GOT TO HAVE GOOD SCIENCE, YOU CAN'T HAVE GOOD ETHICS WITHOUT GOOD SCIENCE. MY EXPERIENCE IN THE WAY IN WHICH IRBs MAKE WHAT I'LL CALL SCIENTIFIC CALLS IS SOMETHING LIKE THE FOLLOWING. WE UNDERSTAND THAT YOU NEED TO INCORPORATE ALL OF THESE PROCEDURES OR YOU WOULD LIKE TO INCLUDE ALL OF THESE PROCEDURES IN ORDER TO ANSWER YOUR RESEARCH QUESTION.. SOME OF THESE ARE QUITE RISKY. HAVE YOU CONSIDERED WHETHER YOU NEED ALL OF THESE OR ARE THERE LESS RISKY WAYS FOR YOU TO GET THIS INFORMATION? THAT'S KIND OF GETTING INTO THE WEEDS OF THE RESEARCH DESIGN BUT THE GOAL THERE IS TO MINIMIZE THE RISK TO THE HUMAN SUBJECTS. I CERTAINLY HAVE BEEN IN IRB MEETINGS WHERE IRB MEMBERS HAVE SAID THINGS LIKE WHY DON'T THEY JUST DO A COHORT STUDY, WHY DO THEY NEED TO DO THIS RANDOMIZED CONTROLLED TRIAL, RIGHT? SELDOM DOES THAT MEAN WE REDESIGN THE STUDY FOR THE PERSON. THE OTHER THING THAT I THINK IS IMPORTANT TO THINK ABOUT AS RELATES TO THIS QUESTION IS, SOME RESEARCH DOES NOT HAVE A SCIENTIFIC REVIEW BEFORE IT GOES TO THE IRB. SO, THE MAJORITY OF RESEARCH THAT HAPPENS OUT IN AN ACADEMIC MEDICAL CENTER IS FUNDED BY THE NIH, AND THERE'S A PEER REVIEW PROCESS BY WHICH FUNDING DECISIONS ARE MADE. SO, THE ASSUMPTION IS A PRETTY RIGOROUS SCIENTIFIC REVIEW HAS OCCURRED. IN MY EXPERIENCE, IRBs ARE MUCH MORE LIKELY TO DEFER TO THE INVESTIGATOR IN TERMS OF STUDY DESIGN WHEN A SCIENTIFIC REVIEW HAS BEEN CONDUCTED. IF A REVIEW HASN'T BEEN CONDUCTED, I THINK THAT THERE'S BOTH A REASON TO LOOK CAREFULLY AT THE DESIGN AND A REASON TO BE THOUGHTFUL ABOUT HOW YOU CONVEY YOUR INTEREST OR WHAT YOU WOULD LIKE THE INVESTIGATOR TO DO. SO, A REALLY EASY EXAMPLE MIGHT BE SOMETHING LIKE WE UNDERSTAND THE STATISTICAL ANALYSIS THAT YOU'RE GOING TO DO AS YOU'VE DESCRIBED IT HERE BUT YOU HAVEN'T JUSTIFIED THAT THE SAMPLE SIZE THAT YOU'VE PROPOSED IS ADEQUATE TO ANSWER YOUR RESEARCH QUESTION. PLEASE, YOU KNOW, PLEASE SHARE MORE ABOUT HOW YOU DECIDED THIS IS THE RIGHT SAMPLE SIZE. AND, AGAIN, THAT'S NOT SORT OF MICROMANAGING THE RESEARCH BUT SAYING, LOOK, GENERALLY WE THINK THIS IS OKAY BUT IF YOU'VE UNDERPOWERED YOUR RESEARCH WE WANT TO MAKE SURE YOU HAVEN'T UNDERPOWERED YOUR RESEARCH BECAUSE IF IT'S UNDERPOWERED YOU'RE NOT GOING TO GET TO YOUR ANSWER. OR, IF YOU'VE OVERPOWERED YOUR RESEARCH AND YOU MIGHT BE EXPOSING MANY MORE PEOPLE THAN YOU NEED TO RISK. SO IT'S AT THAT LEVEL WHERE I THINK SOME SCIENCE COMES IN. AND I'LL ADD THERE'S ALSO BEEN CALLS FROM DIFFERENT CORNERS THAT SOMETHING LIKE EVERY IRB SHOULD HAVE A BIOSTATISTICIAN, SHOULD HAVE A RESEARCH ETHICIST, RIGHT? THERE AREN'T ENOUGH OF EITHER OF THOSE TO GO AROUND, BUT ONE THING I DIDN'T MENTION WHEN I TALKED ABOUT IRBs IS THAT THEY ALWAYS HAVE THE OPTION OF BRINGING OUTSIDE EXPERTISE INTO THE COMMITTEE MEETING. SO, IF WE'RE REVIEWING A PROTOCOL AND THE BIOSTATISTICS ARE QUITE COMPLICATED, PERFECTLY LEGITIMATE TO SAY I THINK WE SHOULD HAVE A BIOSTATISTICIAN TAKE A LOOK AT THIS TO MAKE SURE THEY UNDERSTAND WHAT THE INVESTIGATOR IS DOING SO THEY CAN LET US KNOW THAT THIS IS SOUND. SO, I SEE THERE'S A COUPLE QUESTIONS HERE. FROM AMIR, SORRY IF I MISPRONOUNCE YOUR NAME, WITH REGARD TO COMMERCIAL IRBs ISN'T CONFLICT OF INTEREST MORE PRONOUNCED THERE? YOU'RE PAYING MONEY AND GOOD REVIEWS WILL DEFINITELY ATTRACT MORE CLIENTS. WITH LOOSE NATIONAL REGULATIONS AS IN THE CASE OF LOW- AND MIDDLE-INCOME COUNTRIES WOULD YOU WANT TO ENCOURAGE COMMERCIAL ENTITIES DOING ETHICAL REVIEWS? I COMPLETELY AGREE THAT THERE ARE CONFLICTS OF INTEREST INHERENT IN COMMERCIAL IRB REVIEWS. YOU'RE PAYING FOR A PRODUCT. AND YOU EXPECT A GOOD REVIEW. NOW, INTERESTINGLY, TWO SENATORS, CURRENT SENATORS, ELIZABETH WARREN, I THINK CHUCK SCHUMER, WERE ALSO CONCERNED ABOUT THIS. AND ACTUALLY ASKED THE GOVERNMENT ACCOUNTING OFFICE TO LOOK SPECIFICALLY AT THIS CONCERN. THEY ARE GOING TO HAVE A REPORT THAT COMES OUT. WELL, IT'S ACTUALLY BEEN EXPECTED FOR A WHILE. BUT WE WILL ACTUALLY HAVE SOME EMPIRICAL EVIDENCE TO LOOK AT THIS. I'M HAPPY TO SHARE THAT. I GUESS THE POINT I WAS TRYING TO MAKE EARLIER IS THAT LOCAL IRBs ARE NOT CONFLICT FREE. THAT INDIVIDUALS HAVE CONFLICTS, INSTITUTIONS HAVE CONFLICTS. MAYBE IF WE LINE THEM UP THEY WOULD BE LESS THAN THE COMMERCIAL ENTITIES. BUT I THINK IT'S REALLY IMPORTANT TO THINK CAREFULLY ABOUT HOW WE ARE USING OR WHAT RESEARCH WE DECIDE TO SEND TO THESE COMMERCIAL IRBs. LOOKS LIKE WE HAVE TIME FOR ANOTHER -- OH, WE HAVE ANOTHER QUESTION. ANOTHER FROM AMIR. THANKS, AMIR, FOR POPULATING THIS. DESPITE OBVIOUS ADVANTAGES WITH REGARDS TO SINGLE IRB DO YOU THINK IT'S POSSIBLE IN LOW AND MIDDLE INCOME SETTINGS WITH EXISTING SHORTCOMINGS? SO, THIS IS A REALLY GREAT POINT, NOT ONE THAT I HAVE A LOT OF EXPERTISE ABOUT, MEANING THAT MY EXPERTISE, I REALLY FOCUS ON THE DOMESTIC SETTING, RESEARCH ETHICS IN THE DOMESTIC SETTING. I DON'T KNOW A TON ABOUT IRBs IN LOW- AND MIDDLE-INCOME COUNTRIES. I KNOW A LITTLE. IF I WAS IN CHARGE, YOU ASKED ME, HEY, HOLLY, HOW WOULD YOU FACILITATE CAPACITY OF IRBs IN LOW AND MIDDLE INCOME SETTINGS, I DO KNOW THAT THERE ARE FEW RESOURCES, FEW TRAINING, FEW FOLKS ON THE GROUND WHO ARE AVAILABLE TO BE INSTITUTIONAL REVIEW BOARD MEMBERS OR RESEARCH ETHICS COMMITTEE MEMBERS. I WAS IN UGANDA A NUMBER OF YEARS AGO, WHERE WE MET WITH CHAIRS OF ALL THE IRBs IN UGANDA AT THAT TIME, THERE WERE EIGHT OR NINE OF THEM. AND THEY COULDN'T AFFORD TO MASS PRODUCE, THIS WAS BACK WHEN THEY WERE STILL USING PAPER, THEY COULDN'T AFFORD TO MAKE MULTIPLE COPIES OF A RESEARCH PROTOCOL. SO, IT WAS PASSED FROM IRB MEMBER TO IRB MEMBER, I GUESS TO SAY RESOURCES ARE REALLY THIN. WHAT I WOULD SAY IS IN SETTINGS LIKE THAT, IT REALLY MAY BE USEFUL TO HAVE WHAT I'LL CALL REGIONAL RATHER THAN LOCAL IRBs, MAYBE A NATIONAL IRB, THOUGH I THINK THERE SHOULD BE SOME DIVISION BETWEEN, YOU KNOW, THE NATIONAL MEDICAL ASSOCIATION THAT IS PROBABLY FUNDING THE RESEARCH AND THE REVIEW AND OVERSIGHT. SO SOMETHING REGIONAL, WHERE YOU CAN BETTER CAPTURE ISN'T A GOOD WORD BUT CAPTURE EXPERTISE YOU HAVE AVAILABLE AND FOCUS FUNDING ON THAT REGIONAL IRB, SO THAT IT HAS THE RESOURCES, HUMAN AND FINANCIAL, TO DO THOSE REVIEWS. AND THAT REGIONAL IRB MIGHT REALLY BE A GOOD EXAMPLE OF THE VALUE OF A SINGLE IRB OF RECORD. THEY COULD BE EITHER WHETHER IT'S INDIVIDUAL TRIALS OR MULTIPLE TRIALS. I SEE WE HAVE REACHED OUR 11:30 TIME. ONCE AGAIN, THE WORD OF THE DAY IS NUREMBERG. THANK YOU ALL FOR YOUR ATTENTION. I'M LOOKING FORWARD TO SEEING YOU NEXT WEEK. WE WILL HAVE -- THE DAY WILL BE ON STUDY DESIGN, LECTURE ON RESEARCH WITH CHILDREN. PLEASE JOIN US THEN. THANK YOU.