>> GOOD MORNING, EVERYONE. WELCOME TO THE THIRD SESSION OF THE COURSE ON THE ETHICAL AND REGULATORY ASPECTS OF CLINICAL RESEARCH. THIS MORNING WE HAVE THREE PRESENTERS TO DISCUSS ISSUES OF SUBJECT SELECTION, RECRUITMENT, COERCION AND UNDUE INFLUENCE AND THEN AFTER THE BREAK THEETHICS OF RESEARCH WITH CHILDREN. SO I HAVE TWO ANNOUNCEMENTS. ONE IS PLEASE SIGN IN AND COMPLETE YOUR EVALUATIONS AT THE END OF THE SESSION. SECOND, THERE'S A NEW LINE ON THE SLIDE, IF ANYONE CAN TELL ME WHAT IT IS YOU GET A PRIZE. BASICALLY THE NNA -- ANCC ASKED US TO SAY THEY DO NOT ENDORSE OR APPROVE ANY COMMERCIAL PRODUCTS. THEY ARE THE ORGANIZATION THAT WILL SUPPLY THE CONTINUING EDUCATION UNITS. SO WITH THOSE TWO ANNOUNCEMENTS IN PLACE, OUR FIRST SPEAKER IS GOING TO TALK ABOUT FAIR SUBJECT SELECTION, AN IMPORTANT PART OF THE FRAMEWORK WE STARTED WITH AT THE BEGINNING. TO DO THAT WITH YOU THIS MORNING IS DR. DAVID WEDNESDAY HER, WHO IS -- WENDLER, MEMBER OF THE DEPARTMENT OF BIOETHICS AT THE CLINICAL CENTER, HE USED TO HEAD A GROUP CALLED VULNERABLE POPULATIONS. AND HE'S AN AVID NATIONALS FAN. YOU WILL NOTE THAT WHEN HE GETS UP TO TELL YOU ABOUT FAIR SUBJECT SELECTION. DAVE. >> THANK YOU. SO I WANTED TO START WITH THE MOST IMPORTANT ANNOUNCEMENT OF THE DAY, THIS IS THE FIRST ONE FOR PEOPLE WHO DON'T KNOW, MAYBE PEOPLE VIEWING REMOTELY, GET A GOOD SHOT OF THIS. IT'S THE FIRST BASEBALL PLAY-OFF GAME IN 79 YEARS IN D.C. SO I HOPE EVERYBODY KNOWS ABOUT THAT, IT'S VERY EXCITING. THE SECOND ONE, CHRISTINE IS RIGHT, I'M TALKING ABOUT THE NATIONAL IT IS WHOLE 45 MINUTES BUT I'LL TRY TO CONTROL MYSELF. SECOND THING, THIS COURSE HAS BEEN GOING ON FOR YEARS NOW AND CHRISTINE AND PEOPLE WHO HELP HER DO A FABULOUS JOB WITH IT. PEOPLE WHO HELP FOR THE MOST PART OUR BECKY CHIN, TONYA VAUGHN AND MERT STALLINGS ALL WHOM YOU SHOULD COMMEND WHEN YOU SEE THEM BUT YOU SHOULD PARTICULARLY THIS TIME FOCUS ON MERTA WHO GOT MARRIED OVER THE WEEKEND. SO WHEN SHE'S BACK MAKE SURE YOU CONGRATULATE HER. SHE'S GOING TO BE HE CAN STATIC WHEN YOU DO AND SHE FIND OUT I TOLD HER TO TELL YOU THAT. SO I'LL TALK ABOUT FAIR SUBJECT SELECTION TODAY. I WAS THINKING QUIZ QUESTIONS AND THEN MATH TESTS BUT I'M NOT GOING TO GIVE THEM AWAY. TERMS OF DISCLAIMER. I SAY WHAT I WANT AND CHRISTINE WILL CONFIRM IT'S NEVER OFFICIAL POSITION AND OFTEN MY OWN COLLEAGUES DON'T AGREE WITH WHAT I HAVE TO SAY NO CONFLICTS OF INTEREST. SO THREE ASPECTS OF SUBJECT SELECTION. THIS IS WAY I BREAK DOWN DIFFERENT ASPECTS OF SUBJECT SELECTION. FIRST, THERE'S SELECTION PER SE WHICH I THINK ABOUT AND I HI MOST IRB MEMBERS THINK ABOUT IN TERMS OF DETERMINING WHO IS ELIGIBLE FOR A STUDY. SO REVIEW A PROTOCOL, YOU SET THE INCLUSION EXCLUSION CRITERIA FOR THAT PROTOCOL AND THAT DECIDES WHO CAN AND WHO CAN'T GET INTO YOUR STUDY. SO THAT'S WHAT I'M GOING TO THINK SPECIFICALLY HAS SUBJECT SELECTION. THEN THAT'S RECRUITMENT, FIGURE OUT WHO IS ELIGIBLE AND YOU HAVE VARIOUS METHODS FOR TRYING TO GET PEOPLE WHO ARE IN THAT POOL INTO YOUR STUDY, NOT ONLY TO ENROLL THEM BUT TO RETAIN THEM OVER TIME. SO RETENTION IS A THIRD ASPECT OF SUBJECT SELECTION. I'M GOING TO TALK ABILITY SUBJECT SELECTION, THE FIRST SUBSET OF ALL OF THIS BUT THE OTHER TWO ARE EXTREMELY IMPORTANT AND GET SHORT SHIFT IN BIOETHICS AND TO A CERTAIN EXTENT REPEAT THAT. BUT WE NEED TO THINK MORE ABOUT THAT. PARTICULARLY WHAT WE'RE LEARNING IS MORE CHALLENGES OF GETTING GOOD STUDIES DONE, GETTING IMPORTANT DATA IS AROUND GETTING PEOPLE INTO STUDIES AND KEEPING THEM IN STUDIES. THAT TURNS OUT TO BE HARD AND POSES AND RAISES INTERESTING ETHICAL CHALLENGES.H IN ORDER TO FIGURE OUT HOW TO DO THESE THINGS YOU HAVE TO FIGURE OUT WHAT THE GOALS. THIS IS WHAT I THINK ABOUT THE GOALS FOR SUBJECT SELECTION RECRUITMENT AND RETENTION. YOU WANT TO DISTRIBUTE THE BENEFITS AN BURDENS OF THE STUDY FAIRLY, ENSURE YOU HAVE A VALUABLE STUDY, ENHANCE TO EXTENT YOU CAN THE VALIDITY OF THE STUDY. MINIMIZE THE RISKS TO SUBJECTS, ENHANCE THE BENEFITS. YOU WANT TO INCREASE IN ANY REASONABLE WAY THAT YOU CAN THE BENEFITS TO THE SUBJECTS. THEN YOU WANT TO PROTECT VULNERABLE POPULATIONS. SO I'LL TALK ABOUT EACH IN TURN. FIRST THING TO NOTICE IS THOSE SIX GOALS AREN'T CONSISTENT IN PARTICULAR CASES. SO A STANDARD EXAMPLE IS ONE TO MINIMIZE THE RISK TO SUBJECTS, THE OBVIOUS WAY TO MINIMIZE RISK TO SUBJECTS IS TO ELIMINATE PROCEDURES IN THE PROTOCOL. TAKE AWAY THE BLOOD DRAWS, THE RADIO LOGICAL SCANS, THE DRUG ADMINISTRATION, FROM THE PROTOCOL, THEN CLEARLY YOU'LL MINIMIZE OR REDUCE TO A SIGNIFICANT EXTENT THE RISKS OF THE STUDY. BUT YOU'RE GOING TO DO SOMETHING ELSE TOO, AT LEAST DECREASE AND MAYBE ELIMINATE SCIENTIFIC SOCIAL VALUE OF THE STUDY. SO THERE ARE CONFLICTS IN VARIOUS CASES. WHEN YOU KEEP A PROCEDURE, WHEN YOU ELIMINATE PROCEDURE, MINIMIZING RISK MORE IMPORTANT, WHEN IS ENHANCING BENEFITS OR INCREASING SOCIAL VALUE IMPORTANT. UNFORTUNATELY WE DON'T HAVE ANY CLEAR ALGORITHM HOW TO MAKE TRADE OFFS AND PRACTICE. THAT'S WHY THE WAY WE DO REVIEW AND APPROVAL OF CLINICAL RESEARCH IS DEDICATED SMART PEOPLE WHO DON'T HAVE PERSONAL CONFLICTS OF INTEREST TO DETERMINE IN PARTICULAR CASES HOW TO BALANCE COMPETING GOALS. SO THAT'S THE GOAL OF THE IRB, THE FUNDERS, REVIEWERS, PEOPLE ON THE SCIENTIFIC COMMITTEE, REVIEWING STUDIES. SO YOU DECIDE WHO GETS IN AND CAN'T GET INTO THE STUDY AND YOU DO THAT TYPICALLY BY THE INCLUSION EXCLUSION CRITERIA THAT'S SET BY INVESTIGATORS AND REVIEWED AND APPROVEDED BY THE IRB. ONE INTERESTING CHANGE THAT'S GONEN IN CLINICAL RESEARCHETHICS OVER THE LAST 30 YEARS OR SO, IF YOU LOOK IN THE '50s, AND '60s, THE EMPHASIS WAS EXCLUSIVELY ON RESEARCH PARTICIPATION AS RISKY ENDEAVOR, POTENTIALLY HARMFUL AND THINKING OF PROTECTIONS REQUIREMENTS FOR CLINICAL RESEARCH AS MEANS FOR PROTECTING SUBJECTS FROM THE RISK OF PARTICIPATING IN RESEARCH. THAT'S STILL TRUE TO A CERTAIN EXTENT BUT THERE WAS A BIG CHANGE IN THE '70s, '80s AND EARLY '90s, A LOT PROPELLED BY ADVOCACY AROUND TRIALS FOR HIV AND LATER TRIALS FOR BREAST CANCER WHERE PEOPLE WERE ARGUING NOT SIMPLY NOT ALWAYS ENROLLING IN A TRIAL DANGEROUS, SOMETIMES IT'S POTENTIALLY BENEFICIAL TO PEOPLE, SOMETIMES, FOR INSTANCE EARLY DAYS OF THE HIV CRISIS IT MIGHT BE THE ONLY OPPORTUNITY SOMEBODY HAD TO GET A POSSIBLE TREATMENT FOR THEIR VERY BAD DISEASE. SO AT LEAST IN SOME CASES IT'S A POTENTIAL BENEFIT. NOW THERE'S ALSO A WORRY NOT JUST ABOUT PROTECTING PEOPLE FROM RISKS BUT ALSO MAKING SURE THAT YOU'RE NOT INAPPROPRIATELY EXCLUDING PEOPLE FROM THE POTENTIAL BENEFITS OF BEING IN A STUDY. SO BASICALLY THE WAY I THINK ABOUT THAT IS START WITH A SIMPLE IDEA THAT EVERYBODY IN THE UNIVERSE IS ELIGIBLE FOR YOUR STUDY. YOU HAVE A STUDY AND JUST START WITH THE ASSUMPTION THAT ANYBODY WHO WANTS TO BE IN MY STUDY CAN BE IN MY STUDY. THEN YOU EXCLUDE INDIVIDUALS OR SUB SETS OF THAT UNIVERSE OF INDIVIDUALS ONLY WHEN YOU HAVE A GOOD REASON TO EXCLUDE THEM. SO THE OBVIOUS QUESTION IS WHAT COUNTS AS A GOOD REASON AND THERE ARE AT LEAST TWO DIFFERENT KINDS OF GOOD REASONS. THE FIRST ONE IS OBVIOUSLY A SCIENTIFIC ONE. THE PRINCIPLE ROLE IS COLLECTING GENERALIZABLE DATA, INFORMATION THAT'S HOPEFULLY SOCIALLY VALUABLE AT SOME POINT IN THE FUTURE. ONE THING WE NEED TO DO IS MAKE SURE THAT A STUDY IS VALUABLE AND MAKE SURE IT'S VALID. ONE MAJOR CONSIDERATION IN DECIDING INCLUSION EXCLUSION CRITERIA IS TO PROMOTE THESE TWO IMPORTANT GOALS. ONE THING YOU DO IS OBVIOUS EXAMPLE, IF YOU'RE DOING A TREATMENT TRIAL FOR BREAST CANCER ENROLL PEOPLE WHO HAVE BREAST CANCER, YOU DON'T ENROLL PEOPLE WHO DON'T HAVE BREAST CANCER. SLIGHTLY MORE SUBTLE EXAMPLES ARE CASES WHERE SOMEBODY HAS THE DISEASE IN QUESTION, BUT THEY'RE NOT -- YOU'RE NOT ABLE TO EVALUATE THEM FOR VARIOUS REASONS. SO ONE STANDARD EXAMPLE IS AT LEAST FOR SOME DRUGS IN STAGE 1 STUDIES PEOPLE HAVE BRAIN TUMORS ARE INCREASED RISK OF SEIZURES, IF YOU HAVE A SEIZURE YOU MIGHT NOT BE BE ABLE TO DETERMINE WHETHER THE SEIZURE IS A RESULT OF THE UNDERLYING CONDITION OR THE DRUG YOU GAVE THEM IN ORDER TO MAKE THIS CLEAR, AN IMPORTANT PART OF PHASE 1 AND 2 STUDIES. YOU MIGHT EXCLUDE THEM TO MAKE SURE YOU ENSURE THE SCIENTIFIC VALIDITY OF THE STUDY. I GAVE A TALK LAST WEEK TO A GROUP THAT STUDIES RARE DISEASES. THIS IS PARTICULARLY AN ISSUE IN RARE DISEASE RESEARCH WHICH IS SOMETIMES YOU HAVE A RELATIVELY SMALL POOL OF INDIVIDUALS WHOM YOU CAN ATRACK SUBJECTS FOR YOUR STUDY. SOMEBODY ELSE HAS A STUDY, THEY WANT TO ATTRACT PEOPLE TRILLION THE SAME RELATIVELY SMALL POOL AND YOU GET COMPETITION FOR SUBJECTS. THERE ARE A LOT OF INTERESTING QUESTIONS ABOUT HOW YOU HANDLE, HOW YOU NEGOTIATE THOSE CONFLICT S. WE HAD A CONSULT ONCE WHERE AN INVESTIGATOR ASKED IS IT OKAY FOR ME TO SAY IN ORDER TO GET IN MY STUDY YOU'RE NOT ALLOWED TO CONSIDER GOING INTO ANY OTHER STUDIES. IS THAT AN ACCEPTABLE THING TO DO OR IS THAT INAPPROPRIATELY LIMITING THE OPTIONS THAT PEOPLE HAVE? ONE OF THE ETHICAL QUESTIONS THAT COMES UP. SO I'M GOING TO TRY TO HIGHLIGHT SOME AS WE GO ALONG. THEN YOU GUYS CAN GIVE ME ANSWERS AT THE END. WHOEVER GETS THEM RIGHT WE'LL PRETEND I GIVE YOU A (INAUDIBLE). OTHER WAYS TO ENHANCE VALIDITY, IF YOU HAVE TO COME TO THE CLINIC, YOU HAVE TO STAY IN THE CLINIC TWO DAYS, I'M ON THE IRB FOR THE NATIONAL INSTITUTE OF DRUG ABUSE AND WE'LL HAVE STUDIES PEOPLE HAVE TO STAY ON THE UNIT FOR A WEEK, TWO WEEKS, SOMETIMES THREE WEEKS AT A TIME. SO OBVIOUSLY TO ENROLL IN THAT STUDY YOU NEED TO BE SOMEBODY IN A POSITION TO STAY ON THE UNIT FOR THAT LONG. THAT IS STRAIGHT FORWARD. ALSO MINIMIZING RISK. ENHANCE VALIDITY, MINIMIZE RISK, SO WHAT YOU WANT TO DO IS TAKE THAT POOL YOU NOW HAVE, YOU STARTED WITH THE UNIVERSE, YOU EXCLUDED PEOPLE WHO WON'T GET YOU VALUABLE INFORMATION, YOU EXCLUDE PEOPLE WHO WILL UNDERMINE THE SCIENTIFIC VALIDITY OF THE STUDY. YOU LOOK AT WHO YOU HAVE GOT LEFT AND ASK WHETHER OR NOT THERE ARE INDIVIDUALS OR GROUPS OR INDIVIDUALS WHO FACE PARTICULARLY INCREASEDED RISKS COMPARED TO THE OTHER INDIVIDUALS IN YOUR POOL. SO ONE OF THE STANDARD EXAMPLES OF THIS IS YOU MIGHT EXCLUDE PEOPLE WHO ARE AT INCREASED RISK BECAUSE FOR INSTANCE THEY MIGHT NOT BE ABLE TO METABOLIZE OR EXCRETE THE DRUG YOU'RE TEST, IT BUILDS UP IN THEIR SYSTEM AND HAVE A GREATER CHANCE OF BEING HARMED. SO SOMEBODY WITH POOR KIDNEY FUNCTION IF YOU HAVE A DRUG THAT'S CLEARED RENALLY, MIGHT BE A GOOD REASON TO EXCLUDE THEM FROM THE STUDY. SO I TAKE IT EVERYBODY THINKS THAT'S STRAIGHT FORWARD SO I WANT YOU TO KEEP THAT EXAMPLE IN MIND BECAUSE I'LL COME BACK TO IT AND COMPLICATE IT IN A WAY AND SEE IF IT LEADS TO CONCLUSION SOME DON'T LIKE AND RAISE THE QUESTION WHETHER WE CONSIDER THAT. AT LEAST AT THIS POINT THAT'S STANDARD. THAT'S STANDARD THAT INVESTIGATORS AND IRBs DO ALL THE TIME, SEEMS UNPROBLEMATIC. ENHANCE THE BENEFITS TO HAVE STUDY. ONE THING OUR IRB OFTEN DOES IS WE DON'T JUST SAY WHO FACES HIGHER AND LOWER RISKS, BUT WE ALSO ASK THE QUESTION WHOA IS MORE LIKELY TO BENEFIT THE STUDY. REALIZE PERSONAL OR MEDICAL BENEFIT AS A RESULT OF BEING IN THE STUDY. SO ONE EXAMPLE WAS I SAT ON THE INFECTIOUS DISEASE IRB, FIRST DEVELOPING PROTEASE INHIBITORS WHICH PEOPLE NOW TURNED OUT INCREDIBLY AND IMPORTANT EFFECTIVE DRUG FOR HIV INFECTION. AT THE TIME THEY WERE JUST GETTING STARTED. INVESTIGATORS WERE OPTIMISTIC. THOUGH INVESTIGATORS TEND TO BE P OPTIMISTIC IN MOST CASES, AND SO AS THE IRB WE WONDERED THERE'S TWO WAYS WE CAN DO THIS. WE CAN SAY EARLY STUDIES WE DONE KNOW HOW THIS WILL GO, SO WE WE SHOULD TAKE PEOPLE WHO ARE REASONABLE STABLE, REASONABLY HEALTHY AND TEST THE DRUG AND FIRST FAIRLY WELL OFF, THEY PROBABLY FACE LOWER RISK THAN PEOPLE WHO HAVE MORE ADVANCED DISEASE OR SAY NO WE'RE MORE WORRIED ABOUT ENHANCING BENEFITS IN THIS CASE AND PRECISELY FOCUS ON PEOPLE WHO HAVE MORE ADVANCED DISEASE BECAUSE THEY'RE THE ONE WHOSE HAVE EITHER A GREATER CHANCE OF BENEFITING OR A CHANCE OF BENEFITING IN A MORE SIGNIFICANT WAY BECAUSE OF THE FACT THAT THEY'RE SICK OR HAVE A MORE ADVANCED DISEASE. SO PROTECTING THE VULNERABLE. TAKING PEOPLE WHO ARE VULNERABLE AND EXCLUDING THEM OR IF YOU CAN TRYING TO FIND PROTECTIONS TO PROTECT THEM OR FIN NECESSARY OR EOLIPILE VULNERABILITY. SO THESE ARE QUOTE ABOUT THE WIDESPREAD RECOGNITION OF THIS BELMONT REPORT. YOU MAYBE HEARD THE COUNCIL FOR INTERNATIONAL ORGANIZATION MEDICAL SCIENCES, IT'S A GROUP OUT OF GENEVA THAT HAS WRITTEN UP GUIDELINES FOR RESEARCH MOSTLY IN DEVELOPING COUNTRIES. WHO IS VULNERABLE? THERE'S LOTS OF DEFINITIONS OF VULNERABLE SUBJECT. I THINK OF THEM AS VULNERABLE. INDIVIDUALS WHO ARE LESS ABLE TO PROTECT THEIR OWN INTERESTS RELATIVE TO OTHER POTENTIAL CANDIDATES FOR YOUR STUDY. SO NOW YOU HAVE THIS UNIVERSE, YOU FACE HIGH RISK YOU CUT OUT PEOPLE WHO CAN'T ANSWER YOUR QUESTION. NOW YOU SAY ARE PEOPLE SIGNIFICANTLY ABLE TO PROTECT OWN INTEREST COMPARED THE TO OTHER STILL ELIGIBLE PEOPLE FOR THE STUDY. THAT CAN BE IN A LOT OF CASES A GOOD REASON TO EXCLUDE THEM. ONE IS THEY JUST CAN'T OR LESS ABLE TO PROTECT THEIR OWN INTERESTS, MORE SPECIFICALLY IT'S USEFUL IN A LOT OF CASES WE CAN THINK OF VULNERABLE SUBJECTS AS INDIVIDUALS WHO CAN'T GIVE INFORMED CONSENT. YOUNG CHILDREN, PEOPLE WITH SEVERE ALZHEIMER'S DISEASE, PEOPLE IN A CAR ACCIDENT OR UNCONSCIOUS. I THINK THE MOST VULNERABLE SUBJECTS INITIALLY TEND TO BE PEOPLE WHO CAN'T GIVE INFORMED CONSENT. THE FIRST THING TO TRY TO DO IS SEE, THIS IS TRUE OF ALL ETHICAL DILEMMAS, THE FIRST ATTEMPT AT THEM IS TO SEE IF YOU CAN ELIMINATE THEM OR GET AROUND THE DILEMMA IN SOME WAY BEFORE ADDRESSING HEAD ON. AN OBVIOUS CASE IS IN THE U.S. TYPICALLY PEOPLE WHO CAN'T SPEAK ENGLISH ARE VULNERABLE, LESS ABLE TO UNDERSTAND, LESS ABLE TO KNOW WHAT RISK THEY FACE. LESS ABLE TO PROTECT THEMSELVES BUT YOU DONE NECESSARILY HAVE TO EXCLUDE THEM. AN ALTERNATIVE IS TO GET THEM A TRANSLATOR, A TRANSLATED CONSENT FORM, A NURSE WHO SPEAKS THEIR LANGUAGE, HAVE SOMEBODY AROUND WHO SPEAKS THEIR LANGUAGE AND COMMUNICATE TO THEM. THIS IS ONE OF THE WAYS THE CLINICAL CENTER HAS GOTTEN GOOD ABOUT TRYING TO HELP PEOPLE GIVE INFORMED CONSENT AND STAY INTO TRIALS SO WE HAVE TRANSLATED DOCUMENTS, TRANSLATED DIRECTED FORM INTO SPANISH. THERE ARE WAYS TO HELP PEOPLE IN THIS REGARD. SO HOW ABOUT SUBJECTS WHO CAN'T CONSENT? SHOULD WE INCLUDE THEM OR EXCLUDE THEM FROM THE STUDY? I WAS THINKING ABOUT THIS QUESTION. I EXPECT EVERYBODY TO HAVE AN ANSWER FOR IT IN A MINUTE. HERE IS THE STANDARD STICK AGAIN, YOU EXCLUDE THEM UNLESS THERE'S SOME COMPELLING REASON TO ENROLL THEM IN THE STUDY. AGAIN, OBVIOUSLY IF GIVEN THEIR INCAPACITY THEY CAN'T ENROLL IN THE STUDY, IF THEY CAN'T ANSWER THE SCIENTIFIC QUESTION, CAN'T COLLECT GENERALIZABLE INFORMATION FROM THEM THAT'S OBVIOUSLY A REASON TO EXCLUDE THEM AND MY QUESTION IS WHETHER OR NOT THAT'S THE ONLY REASON. HERE IS ANOTHER QUESTION. PROTECTING THE VULNERABLE MINIMIZING RISKS. WHAT ABOUT A CASE IN WHICH IT IS A QUESTION OF MINIMIZING RISK. SO TAKE THIS CASE. YOU HAVE A PHASE 1 STUDY CONDUCTED WITH LOW RISK AND COGNITIVELY IMPAIRED ADULTS OR HIGH RISK IN COGNITIVELY INTACT ADULTS. SO WE DO A LOT OF CONFERENCES IN DEVELOPING COUNTRIES WE WERE IN INDONESIA SIX YEARS AGO, I GAVE A TALK SIMILAR TO THIS ONE. SOMEBODY CAME UP TO ME AFTERWARDS, THEY'RE NEUROLOGISTS, THEY DO NEUROLOGY RESEARCH AND THEY HAVE THIS RARE NEUROLOGICAL DISEASE IN INDONESIA. THEY CAN IDENTIFY PEOPLE WHO HAVE IT RELATIVELY EARLY ON. YOU GET IT FAIRLY INTACT. YOU CAN CONSENT, YOUR BRAIN IS IN GOOD SHAPE. WHAT YOU PROGRESS, IT'S A NASTY BAD DISEASE, IT'S UNDERMINES PEOPLE'S COGNITION AND THEY GET VERY SICK AT THE END OF THE COURSE OF THE DISEASE. PHASE 1 STUDY NOT DONE BEFORE BUT THOUGHT THERE WAS REASON TO TRY IT. I HAVE TWO CHOICES, GIVE IT TO PEOPLE TO CONSENT, FOCUS ON CONSENT SEEMS LIKE THE RIGHT WAY TO GO, THE PROBLEM IS PEOPLE WHO CONSENT ARE ALSO THE PEOPLE WHO HAVE MILD DISEASE ANDRAL THETIVELY INTACT BRAINS. BECAUSE THEY HAVE REEL TESTIFILY INTACT BRAINS GIVING THEM THIS DRUG POSES HIGH RISK TO THEM. IT MIGHT DO DAMAGE TO THEIR BRAINS IN A WAY THEY HAVEN'T SUSTAINED YET. O THAT'S THE FIRST OPTION. SECOND OPTION, HE CAN GIVE IT TO PEOPLE WHO FACE LOW RISK, NAMELY PEOPLE WHO HAVE ALREADY HAD THE INSULTS TO THEIR BRAINS AS A RESULT OF THE DISEASE AND BECAUSE OF THAT THEY'RE GOING TO FACE DRAMATICALLY LOWER RISK BUT AT THE SAME TIME BECAUSE OF THOSE INSULTS THEY'RE NOT GOING TO BE ABLE TO GIVE INFORMED CONSENT. SO THE QUESTIONRÖ7 IS WHAT DOES HE DO IN THIS CASE? ROUGHLY I TAKE IT -- THIS IS WHY PHILOSOPHERS THIS IS A NICE EXAMPLE BECAUSE IT'S A NICE EXAMPLE OF WHERE YOU BASICALLY HAVE TO ASK YOURSELF WHAT DO YOU CARE MORE ABOUT? DO YOU CARE MORE ABOUT MAKING SURE THAT YOU GET THE INFORMED CONSENT OF YOUR SUBJECTS OR CARE MORE ABOUT PROTECTING YOUR SUBJECTS FROM RISKS OF SERIOUS HARM? WHEN I ASK THAT QUESTION IS THERE ANYBODY THAT SAYS THAT'S OBVIOUS WHAT YOU SHOULD PREFER. ANYBODY? MAYBE THEN WE'LL GIVE YOU A CHANCE AT THE END. THAT MEANS YOU HAVE ABOUT 15, 20 MINUTES TO CON JEW AT A TIME ON IT AND GIVE AN ANSWER BEFORE THE END OF THIS. THAT'S A REALLY STRONG PUZZLE HERE. ANOTHER QUESTION, HOW ABOUT PROSPECT OF BENEFIT? NOT A PHASE 1 STUDY ANY MORE, MAYBE IT'S THAT NEUROLOGICAL DRUG, TESTED A LOT. A LOT OF EVIDENCE IT WORKS AND THE REASONABLY SAFE. WE'RE DOING A PHASE 3 TRIAL, IMPORTANT PROSPECT OF BENEFIT TO SUBJECTS. THE INVESTIGATOR COMES TO US AND SAYS I CAN ENROLL PEOPLE WHO CAN'T CONSENT AND EXCLUDE EVERYBODY -- CAN CONSENT AND EXCLUDE EVERYBODY WHO CAN'T CONSENT OR NOT WORRY ABOUT THAT IT. SCIENTIFIC REASONS I'M PERFECTLY HAPPY, SHOULD I EXCLUDE PEOPLE WHO CAN'T CONSENT. SO HERE YOU HAVE THE QUESTION WHETHER OR NOT YOU WANT A PRIVILEGE CONSENT OR WHETHER OR NOT YOU WANT TO PRIVILEGE THE OPPORTUNITY THE CHANCE OF GETTING A BENEFIT FROM BEING IN THE STUDY. I CAN TELL YOU WHEN SEEK EMANUEL, THE PREVIOUS DIRECTOR OF OUR DEPARTMENT CAME HERE, HE WAS A BREAST ONCOLOGIST WHO HAD A CASE VERY SIMILAR TO THIS ONE AND HE THOUGHT THE ANSWER TO THIS QUESTION WAS ABSOLUTELY CLEAR. HE JUST WANTED TO HAVE CONFIRMATION BEFORE HE GOT BACK TO SOMEBODY. SO HE EMAILED THIS QUESTION AROUND TO A NUMBER OF US IN THE DEPARTMENT. AND I THINK HE GOT EITHER FOUR OR FIVE DIFFERENT ANSWERS FROM JUST ABOUT 25 PEOPLE IN OUR DEPARTMENT ABOUT WHAT THE RIGHT THING WAS TO DO IN A CASE LIKE THIS. WE STILL DISAGREE ABOUT WHAT THE RIGHT THING TO DO IN THIS CASE IS. SO THIS BRINGS ME BACK TO MINIMIZING RISK THAT I HIGHLIGHTED AT THE BEGINNING TO MAKE AT LEAST ONE ARGUMENT HERE WHICH ALMOST NOBODY IN OUR DEPARTMENT AGREES WITH ME ON. SO HERE IS THE THING TO NOTICE FIRST, NOTICE THAT -- RISKIER SUBJECTS. I'M GOING TO TAKE THAT IN A VERY GENERAL SENSE FOR A MINUTE. EXAMPLE BEFORE OF SOMEBODY WHO HAS POOR KIDNEY FUNCTION. THE FIRST THING TO NOTICE, REMEMBER I SAID DOESN'T EVERYBODY THINK IT'S OBVIOUS? THEY HAVE POOR KIDNEY FUNCTION, WE SHOULD EXCLUDE THEM, OTHER PEOPLE HAVE GOOD KIDNEY FUNCTION. THEY HAVE HIGHER RISK. I TAKE IT ALMOST EVERYBODY THOUGHT THAT SEEMS EXACTLY RIGHT. NOTICE I DIDN'T SAY WHETHER OR NOT THE TRIAL OFFERED THE PROSPECT OF BENEFIT TO THOSE INDIVIDUALS. IT MIGHT BE DESPITE THE FACT THEY HAVE POOR KIDNEY FUNCTION, IT MIGHT BE BEING IN A STUDY IS IN THEIR MEDICAL INTEREST. IT MIGHT BE BETTER FOR THEM TO ENROLL IN THE TRIAL THAN NOT ENROLL IN THE TRIAL. THAT'S PARTICULARLY TRUE WHEN THERE'S SOME EVIDENCE THAT IT WORKS AND THEY HAVE A BAD DISEASE AND THEIR OPTIONS ARE FAIRLY LIMITED OR NON-EXISTENT. IN THOSE CASES THEY MIGHT BE BETTER OFF IF YOU ALLOW THEM TO ENROLL IT IN A TRIAL. THE CONCLUSION, AT LEAST IN SOME CASES YOU CAN'T JUSTIFY EXCLUDING RISKIER SUBJECTS ON THE GROUNDS OF SUBJECT PROTECTION. IT'S NOT ABOUT PROTECTING THEM IN THESE CASES. TWO CHOICES. TOUGH SAY OKAY, ALL I CAKE ABOUT IS SUBJECT PROTECTION, YOU MAKE A GOOD POINT, I WON'T EXCLUDE THEM OR YOU HAVE TO THINK ABOUT SOME OTHER REASON IT MAKES SENSE TO EXCLUDE THEM. THAT'S WHAT I'M GOING TO ARGUE FOR. SO HERE IS AT LEAST THE POSSIBLE ARGUMENT, THE REASON WHY OR AT LEAST ONE REASON WHY I THINK WE EXCLUDE PEOPLE WHO FACE SIGNIFICANTLY HIGHER RISK, IT'S NOT JUST A MATTER OF PROTECTING THEM FROM RISK OF HARM BUT THERE'S ANOTHER IMPORTANT GOAL IN THE PROCESS OF CONDUCTING CLINICAL RESEARCH WE DON'T JUST WANT TO PROTECT INDIVIDUAL SUBJECTS, WE WANT TO DO SOMETHING ELSE, WE WANT TO MINIMIZE AGGREGATE HARMS, MINIMIZE THE MAXIMUM NUMBER OF PEOPLE WE HURT AND NUMBER OF PEOPLE WHOLE DIE AS A RESULT OF BEING IN OUR TRIALS. THAT'S AN INDEPENDENT IMPORTANT ETHICAL GOAL AND THE WAY WE REALIZE THAT IS BY EXACTLY THIS MANEUVER. EXCLUDING PEOPLE WHO FAY SIGNIFICANTLY HIGHER RISK. SO RISKIER THERE WAS IN TERMS OF GREATER RISK OF PHYSICAL HARM OR MEDICAL OR CLINICAL HARM. SO THE NEXT QUESTION, LET'S TALK THE PERSON WHO CAN'T GIVE INFORMED CONSENT. WHAT'S THE WORRY THERE? ONE WAY TO DESCRIBE THE WORRY, THERE'S INCREASED CHANCE TO ENROLL THEM IN A STUDY THEY DON'T WANT TO BE IN OR A STUDY THEY WOULDN'T HAVE AGREED TO BE IN IF THEY HAD BEEN ABLE TO GIVE INFORMED CONSENT. THEN THERE'S A SENSE IN WHICH YOU'RE EXPLOITING THE FACT THEY CAN'T GIVE INFORMED CONSENT. IF THEY UNDERSTOOD THEY WOULD HAVE SAID3nm NO. SO I'M GOING TO CALL THIS A MORAL RISK OF ENROLLING PEOPLE WHO CAN'T GIVE INFORMED CONSENT. SO THE QUESTION HERE, THE ARGUMENT I TRY TO MAKE IS THE SAME PRINCIPLE WE SHOULD MINEMIZE AGGRATE HARMS APPLIES NOT JUST TO PHYSICAL HARMS BUT ALSO MORAL RISK AND MORAL HAMS. WE SHOULD MINIMIZE MORAL RISK AND HARMS OF OR STUDY, INCLUDING MINIMIZING THE EXTENT TO WHICH WE ENROLL PEOPLE IN STUDIES INCONSISTENT WITH THEIR COMPETENT PREFERENCES AND VALUES AND ONE WAY TO DO HA IS TO EXCLUDE PEOPLE WHO CAN'T GIVE INFORMED CONSENT WHEN WE CAN DO THE STUDY WITH PEOPLE WHO CAN GIVE INFORMED CONSENT EVEN THOUGH ENROLLING IN THE STUDY MIGHT BE IN THE MEDICAL INTERESTS OF THE PEOPLE WHO CAN'T GIVE INFORMED CONSENT. THAT'S BASICALLY THE ARGUMENT, HOPEFULLY NOT TOO FAST BUT WE CAN TALK ABOUT IT. HOPE -- PROBABLY HAVEN'T CONVINCED ANYBODY HISTORY IS A GUIDE BUT MAYBE SOMEBODY HELP ME MAKE IT MORE CONVINCING. ADDITIONAL SAFEGUARDS. INFORMED CONSENT IS PRIMARY THING WE WANT TO DO. SO YOU HAVE TO HAVE PEOPLE WHO CAN'T GIVE INFORMED CONSENT OR WANT TO ENROLL PEOPLE WHO CAN'T GIVE INFORMED CONSENT YOU SHOULD HAVE ADDITIONAL PROTECTIONS. ONE WE HAVE A POLICY NOW THE CLINICAL CENTER MIGHT HAVE BEEN THE FIRST INSTITUTION IN THE COUNTRY WE SHOULD HAVE REASON TO BELIEVE THE PERSON THEMSELVES WOULD WANT TO ENROLL IN THE STUDY IF THEY COULD THE DECISION FOR THEMSELVES. IF YOU HAVE A STUDY FOR DRUG FOR ALZHEIMER'S DISEASE YOU ASK THE SURROGATE WHAT DECISION DO YOU THINK THEY WOULD MAKE IF THEY COULD MAKE IT FOR THEMSELVES, THE SUBSTITUTED JUDGMENT STANDARD. YOU HAVE REASON TO BELIEVE THEY WOULD ENROLL THEMSELVES IN A STUDY. THAT RAISES A REALLY INTERESTING QUESTION I STILL CAN'T FIGURE OUT WHAT TO DO. THIS IS ONE OF THE HARDEST QUESTIONS IN THE AREA, WHICH IS IMAGINE SOMEBODY WHO HAS NEVER BEEN COMPETENT, IMAGINE SOMEBODY WITH SOME NEUROLOGICAL DISORDER THAT'S SIGNIFICANTLY IMPAIRS THEIR COGNITION, TO TO THE EXTENT THEY CAN'T GIVE INFORMED CONSENT. THEY HAD IT THEIR OWN LIVES AND NOW THEY'RE 35. HOW DO YOU DECIDE WHETHER OR NOT IT'S ACCEPTABLE TO ENROLL THEM IN A CLINICAL TRIAL? WHAT IF THEY SAY THEY WANT TO BE IN A TRIAL BASED ON WHAT THEY UNDERSTAND ABOUT IT THOUGH THEY CAN'T UNDERSTAND THAT MUCH, IS IT AN IMPORTANT STUDY TO DO AND POSES SOME RELATIVELY LOW RISK, MAYBE A COUPLE OF BLOOD DRAW, MAYBE A LUMBAR PUNCTURE. WHEN IS IT OKAY, HOW WOULD YOU DECIDE WHEN IT'S OKAY TO ENROLL SOMEBODY IN A STUDY LIKE THAT. I'M GOING TO LEAVE -- I DON'T KNOW HAVE A POSSIBLE SUGGESTION TO THE ANSWER FOR THAT. MAYBE SOMEONE SMART CAN HELP WITH THAT ONE. SURROGATES. WHAT YOU DO TO SUBSTITUTE JUDGMENT STANDARD FOR PEOPLE WHO CAN'T GIVE INFORMED P CONSENT, YOU GET A SURROGATE WHO GIVES INFORMED CONSENT FOR THEM OR WHAT'S CALLED PERMISSION, PERMISSION FOR THEM TO ENROLL IN THE STUDY. THERE ARE A NUMBER OF QUESTIONS PEOPLE STRUGGLE WITH RIGHT NOW BASICALLY AROUND WHO COUNTS AS ACCEPTABLE SURROGATE TO ENROLL SOMEBODY INTO A CLINICAL RESEARCH STUDY. IMAGINE I HAVE, DO HAVE AN ADVANCED DIRECTIVE, EVERYBODY IN THIS ROOM SHOULD HAVE AN ADVANCED DIRECTIVE IF YOU DON'T HAVE ONE AND IF YOU TONE KNOW WHAT THEY ARE, YOU SHOULD FIND OUT. AND FILL ONE OUT SO IMAGINE YOU HAVE AN ADVANCED DIRECTIVE SOMEBODY TO MAKE CLINICAL CARE DECISIONS FOR YOU. YOU FILL OUT DOCUMENT THAT SAYS IF I'M EVER IN A POSITION WHERE I CAN'T MAKE MEDICAL DECISIONS FOR MYSELF, I APPOINT X, MY SISTER BROTHER WIFE, MOTHER, NEIGHBOR, PASTOR, TO MAKE DECISIONS FOR ME REGARDING HEALTHCARE. YOU CAN'T MAKE DECISIONS FOR YOURSELF, THERE'S A QUESTION ABOUT ENROLLENING A CLINICAL TRIAL. IS IT OKAY TO HAVE THAT PERSON YOU ASSIGNED TO MAKE HEALTHCARE DECISIONS FOR YOU, MAKE DECISIONS WHETHER OR NOT YOU ENROLL IN A CLINICAL TRIAL. THAT IS VERY LIVE QUESTION BECAUSE THE VAST MAJORITY OF ADVANCED DIRECTIVES WHICH ARE STATE BY STATE FORMS DON'T SAY ANYTHING, THEY'RE SILENT ON RESEARCH SO YOU DON'T KNOW WHETHER OR NOT THE PERSON INTENDED TO ASSIGN THAT PERSON ALSO FOR RESEARCH PURPOSES. WE HAVE OUR OWN ADVANCED DIRECTIVE AND OUR FORM EXPLICITLY TALKS ABOUT NOT JUST CLINICAL CARE DECISIONS BUT ALSO RESEARCH DECISIONS WHAT GOES ON HERE. SO WE HAVE A WAY OF ADDRESSING THAT. THAT'S NOT TRUE OF ADVANCED DIRECTIVES ACROSS THE COUNTRY. MAYBE THEY WERE MARRIED 35, 50 YEARS, MARRIED TWO MONTHS, MERTA IS UP TO FOUR DAYS NOW. SO SHE'S MARRIED FOUR DAYS. I NOT GOING TO IMAGINE HER GETTING IN A CAR ACCIDENT. SHE'LL BE UPSET WITH ME. BUT HAD BEEN IS MARRIED TWO FOUR DAYS, THEY GET IN A CAR ACCIDENT, THEY CAN'T MAKE DECISIONS FOR THEMSELVES. SHOULD THE SPOUSE DECIDE WILL TO ENROLL THE PERSON TONE MEDICAL RESEARCH. THERE'S REALLY INTERESTING DATA, I HAVE BEEN DOING THIS WITH FELLOWS IN OUR DEPARTMENT BASICALLY LOOKING AT SURROGATE DECISION MAKING. WE HAVE LEARNED A COUPLE OF THINGS. ONE THING IS THAT SURROGATES ARE NOT VERY GOOD AT PREDICTING WHAT DECISIONS WITH RESPECT TO EITHER RESEARCH OR CLINICAL CARE CHARGES WOULD MAKE. PERHAPS MORRIS DISTURBINGLY THE BETTER YOU KNOW SOMEBODY, THE LONGER YOUR RELATIONSHIP WITH THEM, THE MORE INTI ANYTIME YOUR -- INTIMATE YOUR RELATIONSHIP, THE LESS ABLE YOU ARE TO MAKE DECISIONS FOR THEM. AND IN GENERAL, THE LESS ABLE YOU ARE TO PREDICT, WHAT THEY LIKE, WHAT THEY CARE ABOUT. IS REALLY INTERESTING TO PEOPLE CARE ABOUT TALK ABOUT THIS MORE. WHAT THAT UNDERMINES EXACTLY WHAT WE TRY TO DO, WHAT WE TRY TO DO IS GET THE PERSON WHO IS CLOSEST TO THE INDIVIDUAL TO MAKE DECISIONS. BUT IF WHAT WE CARE ABOUT IS WHAT I CALL PREDICTIVE ACCURACY, PREDICTING WHAT DECISION THE INDIVIDUAL THEMSELVES WOULD HAVE MADE, THAT MAYBE EXACTLY THE WRONG WAY TO GO. GAVE A STUDY, A GROUP THAT DOES AUTISM RESEARCH LAST YEAR WITH THE UNIVERSITY OF WASHINGTON SEATTLE AND THEY PROPOSED A LOT OF HARD CASES. SO THEY'RE ENROLLING A 30-YEAR-OLD WITH SEVERE AUTISM, HAD IT THEIR WHOLE LIFE, STUDY ABOUT TWO BLOOD DRAWS AND BEHAVIORAL OBSERVATIONS. THEIR QUESTION WAS HOW DO WE DECIDE WHETHER OR NOT TO -- IT'S OKAY TO ENROLL THIS PERSON AND IF SO WHO DECIDES WHETHER OR NOT THEY CAN BE ENROLLD IF THE STUDY. SO THE PARENTS CLEARLY CARE ABOUT THEM. WE ASK THEM WHAT DO YOU THINK DECISION THIS AMERICAN WOULD MAKE. WHAT DO YOU THINK HE WOULD DECIDE FOR HIMSELF IF HE CAN MAKE THIS DECISION HERE IS THE ANSWER YOU GET A LOT OF TIMES, YOU HAVE NO IDEA, OR YOU HAVE NO IDEA IF THIS PERSON CAN UNDERSTAND WHAT THEY WOULD CHOOSE BECAUSE IF THEY CAN UNDERSTAND THEY CAN BE IN A SENSE A COMPLETELY DIFFERENT PERSON. WHO KNOWS WHAT THE DETHEY WOULD MAKE IN THE HYPOTHETICAL. ALL YOU KNOW IS WHAT THEY'RE LIKE NOW, THEY CHANT POSSIBLY UNDERSTAND THE STUDY. SO THEY SAY WE HAVE NO IDEA, BUT WE KNOW HOW TERRIBLE THIS DISEASE IS, WE WANT TO DO SOMETHING FOR THIS DISEASE, WE WOULD LIKE TO ENROLL IN THIS STUDY. DOES THAT COUNT AS A SUFFICIENT REASON, AS A GOOD REASON TO ENROLL THE 30-YEAR-OLD IN THIS STUDY. OKAY. SO THAT'S SUBJECT SELECTION, GOING TO TALK SUBJECT RECRUITMENT AND RETENTION MORE QUICKLY. SO AS I MENTIONED, NOW YOU HAVE DECIDED WHO CAN BE IN YOUR STUDY, YOU'RE TRYING TO ATTRACT PEOPLE IN YOUR STUDY. SO ALSO THERE'S A LOT OF DATA NOW, ONE BIG HURDLE TO GETTING GOOD DATA ON MEDICAL INTERVENTION IS SUBJECT RECRUITMENT AND RETENTION. GETTING PEOPLE INTO STUDIES AND KEEPING THEM IN IT FOR THE DURATION I.'S REALLY IMPORTANT BUT IT'S REALLY HARD. SO THE FACT THAT THIS -- THE FACT THAT THE SOCIAL VALUE OF THE STUDY IS AN ETHICAL PRINCIPLE, ETHICAL REQUIREMENT AND GETTING PEOPLE AND KEEPING THEM IN STUDIES IS NECESSARY TO REALIZE THE VALUE, SUGGEST THAT RECRUITMENT IN ITSELF IS AN ETHICAL REASON, IMPORTANT ETHICALLY TO E GET PEOPLE INTO STUDIES AND KEEP THEM, BUT ALSO RECRUITMENT AND MENTION IN A MINUTE RETENTION RAISE INTERESTING QUESTIONS. COUPLE OF THINGS. YOU DO DO YOU DO YOUR STUDIES. WE DON'T FOCUS TOO MUCH. PEOPLE HAVE TO COME HERE, SO P IF YOU'RE IN ONE STUDY YOU HAVE TO COME TO THE CLINICAL CENTER. OTHER CASES YOU CAN DECIDE WHAT COMMUNITY. THIS IS IMPORTANT IN DEVELOPING COUNTRIES. WHICH COMMUNITY, WHICH COUNTRY, MALARIA ENDEMIC REGION AND WE CAN PICK A DIFFERENT COMMUNITY. HOW TO DECIDE WHICH TO FOCUS ON. SO THE FIRST THOUGHT IS AS I MENTIONED BEFORE, IN ANSWERING THIS QUESTION, WE WANT TO FOCUS ON THE GOALS THAT WE HAVE, FOR SELECTION RECRUITMENT AND RETENTION. WE WANT TO PICK COMMUNITIES IN A WAY THAT TRIES TO PROMOTE OR MAXIMIZE THE REALIZATION OF THESE SIX GOALS. SO THAT'S THE FIRST THING WE WANT TO TRY TO DO. SO THERE'S BIG DEBATE IN THE LITERATURE AND MAYBE YOU GUYS WILL GET THIS OPTETHICS OF THE OF DOING RESEARCH IN DEVELOPING COUNTRIES. ONE QUESTION IS TO WHAT EXTENT SHOULD HOST COMMUNITIES BENEFIT RESEARCHERS FROM WESTERN EUROPE GO INTO THIS THIS POOR COMMUNITY AND DO HELICOPTER RESEARCH, THEY BLOW IN THERE, LAND, GET BLOOD FROM THE LOCALS THEN FLY OUT AND USE THAT TO DEVELOP AN INTERVENTION THAT'S ONLY AVAILABLE IN THE U.S.. THAT LOOKS LIKE CLEAR CASE OF EXPLOITATION. SO HOW DO YOU AVOID THAT OR ADDRESS THAT POTENTIAL? ONE WAY TO MAKE SURE THE COMMUNITIES BENEFIT FROM BEING IN THE TRIAL. ONE OF THE QUESTIONS IS THERE SPECIFIC WAY IN WHICH THEY HAVE BENEFIT. THAT'S SOMETHING PEOPLE ARE DEBATING TODAY. THIS IS THE ONE EXAMPLE FOR THEM DECLARATION OF HELSINKI, THE 2008 VERSION OF HELL KINKY, WHAT YOU SHOULD DO IS ONLY DO RESEARCH IN THOSE COMMUNITIES, IF -- HELSINKI, FOR SOMETHING IMPORTANT TO THEM. THEIR HEALTH NEEDS, SOMETHING THEY CARE ABOUT, PRIORITIZE AND THERE'S REASON TO THINK IT'S BENEFICIAL TO THEM. SO THE COMMUNITY SHOULD HAVE THIS POTENTIAL BENEFIT FROM YOUR DOING YOUR STUDY IN THEIR COMMUNITY. IT'S INTERESTING EVERYBODY THEY KNOW OF IN BIOETHICS ENDORSES THAT REQUIREMENT. THE IMMUNITY HAS TO GET SOME SORT OF BENEFIT. SO WHAT I WONDER IS IF THAT'S RIGHT, DOES IT SUGGEST INDIVIDUALS WHEN YOU ENROLL IN INDIVIDUALS WHETHER IN THE DEVELOPING WORLD, OR NIH CLINICAL CENTER DOES IT APPLY SPECIFIC INDIVIDUAL VERSUS TO BENEFIT. FOR THE MOST PART THAT'S NOT A REQUIREMENT MOST PEOPLE THINK APPLY. SO IS THERE SOME DIFFERENCE BETWEEN COMMUNITY BENEFIT AN INDIVIDUAL BENEFIT OR INCONSISTENCY THERE. SOME METHODS OF RECRUITMENT. YOU CAN ASK YOUR COLLEAGUES, YOU CAN REFER YOUR OWN PATIENTS, YOU CAN ADVERTISE, IRB SPENDS A LOT OF TIME LOOKING AT ADVERTISEMENTS YOUR OWN PATIENTS. ALL SORTS OF POTENTIAL CONFLICTS ENROLLING YOUR OWN PATIENTK IF A IF PHYSICIAN GETS $1,000 FOR FINDERS FEE FOR EVERY SUBJECT PERFECTLY ACCEPTABLE OR LEAD TO THE IF PHYSICIAN MAKING RECOMMENDATIONS THAT CLEARLY AREN'T IN THE PATIENT'S BEST INTEREST. YOU HAVE A RISKY STUDY, DON'T FOCUS ON VULNERABLE WHEN YOU HAVE A -- DON'T FOCUS ON PRIVILEGED AND POWERFUL, FAIR SUBJECT SELECTION IS THE MODE HERE FOR RECRUITMENT AS WELL. INCENTIVES, A LOT OF MUCH NOW GETS INVOLVED AT VARIOUS ASPECTS OF CLINICAL RESEARCH. PEOPLE MAKE A LOT OF MONEY OUT OF CLINICAL RESEARCH AND A LOT OF MONEY GOES INTO CLINICAL RESEARCH FUNDING IT, RUNNING IT BUT ALSO INDUCEMENTS FOR PEOPLE TO REFER THEIR PATIENTS ON THE PART OF IF PHYSICIANS INCENTIVES FOR SUBJECTS TO ENROLL. RAISES A LOT OF GREAT QUESTIONS. CRAZE TEEN IS ONE OF THE EXPERTS IN THE COUNTRY ON THIS. CHRISTINE IS ONE OF THE EXPERTS. HOW DO WE ADDRESS THE CONFLICT OF INTEREST. IF WE SAY TO PHYSICIANS $1,000 FOR A PATIENT YOU REFER, HOW DO WE MAKE SURE THAT'S DONE IN A WAY REASONABLE THAT DOESN'T UNDERMINE THE RELATIONSHIP, THE CLINICAL RELATIONSHIP WITH THAT THAT THAT IF PHYSICIAN HAS WITH THEIR PATIENTS. ADVERTISING, THIS IS A BIG ISSUE NOW, THERE'S ALMOST NO GUIDANCE, I'LL SHOW YOU IN A MINUTE BUT ALMOST NO IN IRB STRUGGLE WITH THIS. FIND WHAT TO DO, HERE IS WHENEVER WE SEE AN ADVERTISEMENT 'ALLY IMPRESS RECEIVE WE START GETTING NERVOUS. SOMEHOW THAT SEEMS INAPPROPRIATE, I DON'T THINK WE LIKE THAT ONE. THEY SAY OKAY, THEY COME BACK AND SHOW US A TERRIBLE ONE, NO ONE PAY ATTENTION, YOU'LL FALL ASLOPE WHEN I' ON, WHAT'S THE POINT OF SHOWING THAT ONE. SO WHAT ARE WE LEFT WITH? WHAT CAN WE DO? THERE'S ALMOST NO GUIDANCE ON THIS. THE FDA ON THEIR WEB SEAT HAS A LITTLE BIT OF GUIDANCE ON THIS. DIRECT ADVERTISING, AS THEY REGARD IT IS THE START OF THE INFORMED CONSENT PROCESS. NOT PRIOR TO RESEARCH, IT'S PART OF THE WHOLE PROCESS SO THINK ABOUT IT ETHICALLY, IRB REVIEW IT AND EVERYBODY SHOULD MAKE SURE IT'S DONE APPROPRIATELY, ONE OF THE THINGS FOR APPROPRIATENESS LOOK AT RELATIVE SIZE OF TYPE USE AND OTHER VISUAL EFFECTS. SEEMS LIKE A GOOD IDEA, WHAT ABOUT THE SIZE? WHAT ABOUT THE VISUAL EFFECTS? SO THESE ARE SOME ACTUALWPMx AS THEY GOT PROPOSED TO MY IRB. THE FIRST ONE HAD THIS THUMPING MUSIC, THE SWIRLING SORT OF TIE DIE COLORS ALL OVER THE PLACE, DEFINITELY WOKE UP, LOOKED AT IT, THIS BIG BOOMING VOICE, WE'RE ENROLLING MEN AND WOMEN 18 TO 40 TO STUDY HOW ALCOHOL EFFECT IT IS BRAIN. AND AS A MATTER OF FACT IT PAYS UP TO $3,500 AND INCLUDES ROOM AND BOARD, CALL US TODAY. REALLY CATCHY, GRABBED YOUR ATTENTION, SWIRLING COLORS OKAY OR DEEP BOOMING VOICES OKAY. WHAT ABOUT SAYING YOU'RE GOING TO PAY, HOW MUCH YOU'RE GOING TO PAY PARTICULARLY WHEN THIS IS AN EXTRAORDINARILY HIGH AMOUNT FOR CLINICAL STUDY. IS THAT OKAY? ROOM AND BOARD STARTS TO MAKE IT SOUND LIKE A DORMITORY. MAYBE REALLY COMFORTABLE. TRY TO GIVE YOU GOOD FOOD. HAVEN'T THOUGHT ABOUT THAT. OKAY. SO WE DON'T KNOW MUCH ABOUT. ONE THING YOU WANT TO WORRY ABOUT, DEPENDS. WHAT ARE THE IMPACT OF ADVERTISING, WE KNOW VERY LITTLE ABOUT IT. WE P DON'T KNOW EXACTLY WHO IT ATTRACTS, WE DON'T KNOW IT AFFECTS UNDERSTANDING SO ONE WORRY IS THAT IF THEY HAD SO GOOD PEOPLE ARE SAYING I'M IN THE THAT STUDY, WHEN THEY COME HAY THEIR INFORMED CONSENT FORM, THEY HEAR THE RISK, THEY'RE NOT PAYING ATTENTION, THEY MADE THEIR DECISION, MAYBE NOT GETTING A VALID INFORMED CONSENT FROM THAT PERSON. ANOTHER IS WHETHER OR NOT IT AFFECTS MOTIVATIONS. DOES IT ATTRACT PEOPLE MORE INTERESTING IN MONEY THAN PROMOTING SCIENCE AND DOES IT SWITCH OR FLIP PEOPLE'S MOTIVATIONS. YOU HAVE SOMEBODY WHO MIGHT HAVE BEEN INTERESTED IN HELPING SCIENCE BUT NOW THEY SAY WOW, $3,500, THAT SOUNDS GREAT. NOW WHAT THEY CARE ABOUT IS MAKING A LOT OF MONEY, THEY START THINKING ABOUT THE THINGS THEY COULD BUY WITH $3,500. AND THEIR MOTIVATION, SAME PERSON BUT YOU SWITCHED THEIR MOTIVATIONS FOR BEING IN THE TRIAL. DOES THAT MATTER, IS THAT SOMETHING WE SHOULD WORRY ABOUT, AT LEAST IN SOME SENSE SEEMS LIKE A GOOD IDEA TO HAVE PEOPLE WHO CARE ABOUT THE SCIENCE. WHO WANT TO CONTRIBUTE RATHER THAN JUST MAKE MONEY. PAYING SUBJECTS. WHAT ABOUT ACTUALLY NOT JUST ADVERTISING IT BUT PAYING PEOPLE. CAN WE TALK ABOUT THAT, HERE IS THE FDA. ADVERTISE IT IS STATE TO BE PAID BUT NOT EMPHASIZE THE PAYMENT OR AMOUNT. SO $3,500 IS A LOT, IS IT OKAY IF IT'S A SMALL -- I CAN TELL YOU IRB REALLY FOUGHT OVER THIS. IS IT OKAY IF IT'S IN A SMALL FONT, OKAY IF IT'S OFF TO THE SIDE. YOU CAN'T UNDERLINE IT, YOU CAN'T BOLD IT. WHAT CAN YOU DO. WHAT'S ACCEPTABLE AND NOT. SO THIS IS ANOTHER ONE. SMOKING THEY WANT TO GET CHIPPERS IN THE SMOKING LITERATURE. PEOPLE WHO SMOKE OCCASIONALLY. TURNS OUT THOSE PEOPLE OFTEN SMOKE WHEN THEY GO TO BARS, THEIR FRIENDS START SMOKING, SO ONE GOOD WAY TO ADVERTISE IS IN BARS SO THEY HAD A BAR COASTER WITH THIS INFORMATION ON IT. IF YOU WANT TO BE IN OUR STUDY, CALL. IS IT OKAY TO ADVERTISE TO PEOPLE WHEN THEY'RE IN BARS? IS THAT UNSEEMLY CONNECTION FOR CLINICAL RESEARCH. IS IT GETTING THEM IN A POINT MAYBE NOT THINKING AS CLEAR AS YOU WAP THEM TO. TRYING TO GET THIS INFORMATION TO THEM, IS THAT SOMEHOW INAPPROPRIATE H. SOME WORRY AND SAY PAYMENT IS INAPPROPRIATE BECAUSE IT COERCES SUBJECTS SO AT THE END OF ALAN'S TALK SAY ISN'T PAYMENT COERCIVE? SO ALAN WILL EXPLAIN THAT TO YOU. SO ONE THING WE KNOW AND LEARNED FROM SURVEYS IS A LOT OF CASES GETTING PEOPLE IN STUDIES TRACES MUNDANE THINGS. THERE WAS A STUDY AT THE UNIVERSITY OF PENNSYLVANIA WHO ASKED THEIR BIGGEST CONCERNS. AND ONE WAS FINDING PARKING TO GET TO THE CLINIC. OR PAYING FOR THE PARKING. IN IRB WE COULDN'T GET WOMEN INTO THE STUDY WE THOUGHT IT WAS FOR COMPLICATED REASONS. WE FINALLY ASKD THE WOMEN AND THEY COULDN'T FIND SOMEBODY TO TAKE DARE OF THEIR KIDS WHILE -- CARE OF THEIR KIDS WHILE IN THE STUDY. SO IT'S OFTEN SIMPLE REASONS. QUESTION IS WHAT CAN WOE DUO ABOUT THOSE, ARE THERE WAY IT IS ADDRESS THOSE IN A CREATIVE WAY. LAST THING IS TO MENTION RETENTION. GET PEOPLE IN THE STUDY, IS IT ENOUGH, YOU GOT TO KEEP THEM IN THE STUDIES. WE DID A SURVEY WITH COLLEAGUES IN ARGENTINA, RUNNING AN HIV STUDY THAT SUGGESTED SOMETIMES BEING IN STUDIES HAS DRAMATIC IMPACTS ON PEOPLE AND ON THEIR PERSONAL LIVES AND SOMETIMES IT AFFECTS WHAT THEY'LL TELL THE INVESTIGATORS. SO OBVIOUSLY IF WE LOSE SUBJECTS WE'RE NOT GETTING DATA OUT OF THEM, IT'S A WASTE OF RESOURCES. WE WANT TO KEEP THEM IN THE STUDY BUT WHAT'S ACCEPTABLE AND APPROPRIATE WAYS TO ENCOURAGE PEOPLE TO STAY IN STUDIES SO IT'S OKAY TO SAY THIS IS AN IMPORTANT STUDY WE WANT YOU TO STAY IN IT. THAT'S APPROPRIATE EVEN FOR HAD BEEN THINKING ABOUT WITHDRAWING BUT OBVIOUSLY THERE'S SOME POINT WHICH THAT BECOMES UNACCEPTABLE. YOU CAN'T PUSHmy OR FORCE THE PERSON, THERE OR THREATEN THEM, MAYBE REPEAT IT ONCE BUT NOT MANY TIMES. WHERE DO YOU CROSS THE LINE BETWEEN ACCEPTABLE ENCOURAGEMENT AND SOMETHING MORE SINISTER. SO HERE IS THE SUMMARY, I THINK SUBJECT SELECTION AND RETENTION HOPEFULLY ONE POINT TO MAKE IS THEY'RE REALLY CENTRAL TO THEETHICS OF RESEARCH. BASICALLY REALLY CENTRAL BECAUSE THE ONLY WAY TO DO THIS, THE ONLY WAY TO FIND THESE IMPORTANT RESULTS, ONLY WAY TO FIND NEW DRUGS TO TREAT SOMETHING LIKE ALZHEIMER'S DISEASE, A NEW VACCINE FOR SOMETHING LIKE MALARIA, THOSE THINGS REALLY IMPORTANT, WOULD HELP TENS, HUNDREDS OF MILLIONS OF PEOPLE BUT TO PEOPLE INTO TRIALS, WE NEED TO KEEP THEM INTO TRIALS. HOPEFULLY AT LEAST MADE IT CLEAR THAT SELECTION, RECRUITMENT AND RETENTION ARE CENTRAL TO NOT JUST THE SCIENCE BUT THE ETHICS OF RESEARCH BUT THERE'S A LOT OF THIS THAT NEEDS TO BE WORKED OUT. THAT'S ALL I HAVE. THANK YOU. [APPLAUSE] >> CHRISTINE WANTED ME TO REMIND YOU THESE SESSIONS GET STREAMED ON TO THE WEB SO IF YOU HAVE A QUESTION PREFERABLY CAN YOU COME TO THE AISLE AND GIVE THE QUESTION TO THE MIC AND THE AISLE. IF NOT GIVE ME A CHANCE AND REPEAT IT AND WE'LL TRY TO ANSWER IT. ANY QUESTIONS? HOW ABOUT DOES ANYBODY HAVE ANY THOUGHTS ON THE BREAST CANCER TRIAL? CHRISTINE, YOU HAD A QUESTION? >> TWO. >> TWO. >> I WAS WONDERING WHAT YOU THINK ABOUT THERE'S MOUNTING EVIDENCE THAT CLINICAL RESEARCH IS NEVER FINISHED PRIMARILY BECAUSE IT'S DIFFICULT TO RECRUIT OR RETAIN PEOPLE. DO YOU THINK THAT SUGGESTS THAT WE HAVE BEEN OVERPROTECTIVE IN TERMS OF POLICIES ON RECRUITMENT AND RETENTION AND THEREFORE OUGHT TO READJUST? OR DO YOU THINK WE'RE DOING THE RIGHT THING AND FIGURE OUT OTHER WAYS TO REGROUP IS THAT N THAT'S THE FIRST QUESTION. SECOND IS, I THINK IT'S INTERESTING TO THINK ABOUT YOU HAD A LIST OF WAYS PEOPLE MIGHT BE RECRUITED THROUGH TARGETED INVITING OTHER PATIENTS, INVITING YOUR OWN PATIENTS, THAT KIND OF THING. TODAY ONE OF THE BIGGEST CHALLENGES PEOPLE ARE FACING IS SOCIAL MEDIA. HOW THAT IS USEFUL FOR RECRUITING PEOPLE AND WHETHER OR NOT THE FULL TOOLS THAT ARE AVAILABLE THROUGH SOCIAL MEDIA ARE ACCEPTABLE FOR RECRUITING PEOPLE FOR RESEARCH. DO YOU HAVE ANY COMMENTS ON THAT? >> I TOLD CHRISTINE TO START WITH EASY QUESTIONS. FIRST WITH RESPECT TO RETENTION, ONE OF THE PEOPLE WHO GOT ME INTERESTED IN THE FIRST PLACE IS NORM FAUCET AT THE UNIVERSITY OF WISCONSIN. HE IS AT -- I HAVE TO SAY GOOD ETHICS STARTS WITH GOOD DATA. SO I THINK IN TERMS OF RETENTION, I AGREE, IT'S AN INCREDIBLE PROBLEM, TWO DSMBs ARE ON THE DATA SAFETY MONITORING BOARD. SO WE MONITOR STUDIES AS THEY GO ON, THESE ARE IMPORTANT STUDIES, BIG STUDY, DRUGS THAT HAVE POTENTIALLY BAD SIDE EFFECT, WE'RE SUPPOSED TO MAKE SURE SUBJECTS ARE PROTECTED, MAKE SURE THERE'S NOT CLEAR TON STOP THE STUDY. WE SPENT 80% TIME IN MEETING TALKING RECRUITMENT AND RETENTION. WHAT'S THE PROBLEM HERE? WE P CAN'T GET PEOPLE IN THE STUDY SO IT'S A SERIOUS PROBLEM. THE REASON I THINK DATA IS IMPORTANT BECAUSE WE KNOW VERY LITTLE BOTH ABOUT WHAT GETS PEOPLE INTO TRIALS AND WHAT KEEPS THEM INTO TRIALS SO I WOULD SAY BEFORE WE TRY TOO MUCH IN TERMS OF CHANGING OUR REQUIREMENTS, CHANGING PROTECTIONS, FIRST I WOULD LIKE TO SEE SOME REALLY GOOD DATA. I HAVE NEVER REALLY ANY. (INAUDIBLE) IS THE ONE I LIKE TO KNOW. I WOULD LIKE TO SEE MORE ON WHAT INFLUENCES PEOPLE BOTH TO GO INTO THE TRIALS AND TO STAY IN THE TRIALS. SO THAT'S THE FIRST THING. THEN WITH RESPECT TO SOCIAL MEDIA I DON'T THINK -- DOES NUMBER -- MY FRIENDS REGARDING ME AS A (INDISCERNIBLE) SO I DON'T WATCH TV, I DON'T HAVE A CELL PHONE, I TRY TO AVOID ELECTRONIC STUFF, I SPEND MOST OF MY TIME READING BOOKS. IT'S THE ONLY THING I KNOW. SO I DIDN'T -- ONE OF THE WORRIES, THIS IS WHY I MAKES IT'S SPECIALLY HARD, THE OTHER THING IS A LOT OF WORRY HAS TO DO WITH PRIVACY AND CONFIDENTIALITY. AND I THINK I'M NOT SURE I HAVE STRONG VIEWS ON EXACTLY THE EXTENT TO WHICH PRIVACY AND IMPORTANT ARE PROTECTED. ANYBODY HAVE ANY THOUGHTS ON SOCIAL MEDIA? HERE IS A RELATED -- I DON'T KNOW IF -- THIS ISN'T EXACTLY SOCIAL MEDIA BUT ONE THING IS USING THEM IN TERMS OF RECRUITMENT. SO ONE THIS CAN OUR IRB FOCUSED ON A LOT IS HOW THE INVESTIGATORS FIND SUBJECTS. ONE THING THEY DO IS THEY SAY OKAY, WHAT IF WE GO ONLINE AND TRY TO IDENTIFY PEOPLE. SEND THEM AN EMAIL AND SAY YOU WANT TO ENROLL IN OUR TRIAL. ANOTHER EXAMPLE THEY HAD, THEY WANT TO GO, DEPARTMENT OF MOTOR VEHICLE IN MARYLAND, MY IRB IS IN BALTIMORE, SO DEPARTMENT OF MOTOR VEHICLES IN MARYLAND KEEPS A REGISTRY OF PEOPLE WHO HAVE BEEN IN ACCIDENTS. THEY WANT TO FIND PEOPLE WHO SUFFERED TRAUMA. SO THE QUESTION WAS WOULD IT BE OKAY FOR THE INVESTIGATORS TO GET THIS INFORMATION FROM THE DMV, WE'RE TOLD IS PUBLICLY AVAILABLE SO THEY WOULD GO AND THE DMV WOULD GIVE IT TO THEM. OUR INVESTIGATOR HAVE A LIST OF PEOPLE WHO ARE IN MARYLAND LAST YEAR.yM AND THEN SEND LETTER. YOU WERE IN THE CAR ACCIDENT, WE'RE DOING A INTERESTING STUDY. PEOPLE HAVE SUCH DIFFERENT INTUITIONS. HALF THE IRBs SAID THAT'S A GREAT IDEA. WE DIDN'T THINK ABOUT THAT. THIS IS A HARD STUDY TO RECRUIT FOR THAT'S A GREAT WAY TO DO IT. IT'S PUBLICLY AVAILABLE. YOU'RE SENDING A LETTER THEY CAN THROW THEM IN THE TRASH WHAT'S THE HARM. THE OTHER HALF THOUGHT IT WAS A TERRIBLE IDEA, THAT IT WAS COMPLETELY UNETHICAL. IT WAS SOMEHOW VIOLATING PRIVACY OR CONFIDENTIALITY. YOU COULD TAKE WHICH SIDE I WAS ON BUT I THINK THERE ARE OBVIOUSLY REAL CONCERNS THERE AND WE DON'T HAVE A SENSE HOW TO ADDRESS IT. MORE WORK FOR SOMEBODY TO DO IN BIOETHICS. >> I HAVE TWO QUESTIONS ALSO. I HAVE BEEN IN CLINICAL TRIALS WHERE PATIENT LONG TERM STUDIES LIKE -- THEY WERE LONG TERM STUDY, TWO YEARS LONG. ONE THING WE ASKED INVESTIGATORS TO DO WAS IF A SUBJECT WAS SAYING THEY WANTED FOR EXAMPLE, THE P PEOPLE WHO HAD ISSUES WITH CHILD CARE OR GOING TO BE TRAVELING OR WHATEVER, WE WOULD SAY OKAY YOU CAN CONTINUE TO PARTICIPATE IN THE STUDY BUT ONLY COME BACK FOR SOME DATA MORE VALUABLE THAN OTHERS, OUR END POINT IS 24 MONTHS. IF YOU'RE WILLING TO COME BACK FOR THE LAST VISIT, WE'LL HAVE THAT DATA, THAT WOULD BE BETTER THAN HAVING THE PATIENT DROP OUT ALL TOGETHER. I'M WONDERING IF YOU THINK THERE ARE ANY ISSUES WITH THAT. AND THEN MY SECOND QUESTION WAS JUST IF YOU CAN TALK MORE ABOUT WHO YOU THINK THE BEST SURROGATE IS, IF IT'S NOT THE PERSON CLOSEST TO YOU. >> SO IN TERMS OF -- IN IN MOST CASES AS YOU SAY SOME DATA IS BETTER P THAN NO DATA. IF THE PERSON IS NOT GOING TO GET YOU VERY MUCH, WHAT DO YOU DO ABOUT THAT. ONE WAY THE ADDRESS THAT IS I THINK PERSPECTIVELY WHAT INVESTIGATORS NEED TO DO IN IRB IS MAKE SURE THEY'RE DOING IS TO TRY TO HAVE SOME JUDGMENT ABOUT IN EFFECT WHAT'S THE MINIMAL AMOUNT OF DATA WE NEED FROM THESE PEOPLE. MINIMAL AMOUNT OF INFORMATION WE CAN GET FROM THEM AND IT MAKES SENSE. AND IDENTIFY THAT. I THINK IF THERE IS, THE WHOLE -- THE INITIAL IMPORTANT OF DOING RESEARCH IS TO COLLECT VALUABLE INFORMATION. IF SOMEBODY IS PARTICIPATION FOR WHATEVER REASON FALLS BELOW THAT POINT, I THINK THAT'S AN ACCEPTABLE REASON TO TAKE THEM OUT OF THE STUDY. ON THE OTHER HAND, AS YOU SAY, IF YOU CAN KEEP THEM IN SUFFICIENTLY TO GET SOME OF THE DATA, THAT MINIMAL SETH FROM THEM, THAT'S A VALUABLE THING TO DO. ONE HARD QUESTION IT RAISES FOR US IS WHETHER OR NOT YOU INFORM PEOPLE OF THAT. SO WHAT WE DO IS SAY HERE IS THE WHOLE STUDY. WE DESCRIBE THE STUDY TO THEM. WHAT WE DON'T SAY IS YOU REALLY DON'T HAVE TO DO ALL THAT. IF YOU DO THE FIRST LITTLE BITS IT WILL STILL BE OKAY, WE'RE WORRIED TO ENCOURAGE PEOPLE THE MINIMAL AMOUNT BUT SOME WORRY IN CASE ABOUT WHETHER OR NOT THAT'S OKAY OR NOT. SO I THINK THAT'S IT'S PLANNING PERSPECTIVELY AN IDENTIFYING THE MEN MALL AMOUNT. IF PEOPLE FALL BELOW THAT, IF YOU HAVE IDENTIFIED IT ACCURATELY, THERE'S NO REASON TO KEEP THEM IN THE STUDY. THEN WE FACE ISSUES OF YOU PAY PEOPLE OVER THE COURSE OF THE STUDY, THEY DROP OUT IN THE MIDDLE. YOU PAY FOR THE FIRST HALF OR THE WHOLE THING. DOES IT DEPEND UPON WHY THEY DROP OUT, WHERE THEY DROP OUT BECAUSE THEY WANT TO GO TO TAHITI OR THEY DROP OUT BECAUSE OF A NASTY SIDE EFFECT OF THE DRUG AND DON'T CONTINUE. IN TERMS OF THE BEST SURROGATE -- SOMETHING THAT I'M THINKING ABOUT, WORKING A LOT RIGHT NOW, IT'S A REALLY HARD QUESTION, ONE IS I MENTION BECAUSE THERE'S AT LEAST GOOD REASON TO THINK THAT THE PEOPLE CLOSEST TO THE PATIENT AREN'T VERY GOOD PREDICTOR OF WHAT THEY WANT. SO WHEN I GIVE A TALK ON THIS, I THE TITLE IS THAT EXPLAINS IT. YOU GET THIS PRESENT FROM SOMEBODY WHO THOUGHT YOU WERE CLOSE TO AND YOU LOOK AND YOU'RE THINKING HOW COULD THEY HAVE THOUGHT THAT I WOULD LIKE THIS. IT'S JUST HAS NOTHING TO DO WITH ME. THEY DON'T EVEN KNOW WHO I AM. IT LOOKS LIKE THAT'S A PERVASIVE PHENOMENON OF THE THE PEOPLE WE'RE CLOSE TO. SO IN MAKING MEDICAL DECISIONS IT'S MORE IMPORTANT THAN GETTING THE RIGHT TIE. WHAT DO YOU DO ABOUT IT. WELL, FIRST THERE'S OTHER REASONS TO HAVE NEXT OF KIN, BE A SURROGATE DECISION MAKER INDEPENDENT OF THIS PREDICTIVE ACCURACY. BUT PREDICTIVE ACCURACY IS IMPORTANT. SO WE'RE TRYING TO COME UP WITH WAYS OF DEVELOPING A DATABASE OF INFORMATION THAT YOU COULD BASICALLY OFFER TO THE SURROGATES TO TRY TO INCREASE THEIR PREDICTIVE ACCURACY. SO MY GOAL IS TO TRY TO SEE IF THERE'S WAY TO KEEP THEM INVOLVED BUT TO HAVE THEM INVOLVED IN A WAY THAT WE ADDRESS THIS ACCURACY PROBLEM. I THINK THERE'S HOPE THAT THAT'S POSSIBLE THOUGH THERE'S STILL WORK TO BE DONE. ONE LAST QUESTION. SNOW ONE IS GOING THE TO GIVE ME AN ANSWER TO THE PERSON YOU CAN ENROLL, CAN'T GIVE INFORMED CONSENT. POTENTIAL BENEFIT STUDY BUT THERE'S NO REASON, NO NEED SCIENTIFICALLY TO ENROLL PEOPLE WHO CAN'T GIVE INFORMED CONSENT, FIND TO EXCLUDE OR FINE TO INCLUDE HER. ALL RIGHT. SAVE EVERYBODY HERE. (OFF MIC) >> YOU DON'T WANT TOO MANY PHILOSOPHERS IN YOUR AUDIENCE. >> MY QUESTION IS, I THINK THE IS A CASE YOU'RE TALKING ABOUT, WHEN YOU HAVE SOMEONE INCOMPETENT, ONE INTENTION IS WE CAN'T GET INFORMED CONSENT, WHAT ARE THE BENEFITS (INAUDIBLE) BENEFITS ARE THERE. SO THE QUESTION IS WHAT ROLE IS INFORMED CONSENT PLAYENING THAT CASE, THIS SOUND COLD BUT WHY DOES THAT PRESENT ATTENTION? IF YOU THINK INFORMED CONSENT IS THERE TO PROTECT THE AUTONOMY OF THAT PERSON BUT YOU HAVE SOMEONE WHO MAYBE NEVER HAS BEEN AUTONOMOUS SO IT'S NOT FREQUENTING AUTONOMY THERE. -- PROTECTING AUTONOMY THERE. THE BENEFITS ARE THERE OR NOT. YOU MIGHT THINK WHAT'S REALLY -- >> SO HERE IS HOW I THINK ABOUT THE TENSION. MAYBE THERE'S TWO WAYS TO THINK ABOUT, MAYBE MORE THAN TWO WAYS TO THINK ABOUT THE REASON YOU GET INFORMED CONSENT AND VALUE OF INFORMED CONSENT BUT THERE'S TWO REASON, ONE IS AS YOU SAY, TO SORT OF PROTECT THE PERSON, PROTECT AUTONOMY, DECISIONS FOR THEMSELVES, WE APSALM GIVE THEM INFORMATION AND THEY CAN DECIDE WHETHER IT MAKES SENSE TO BE IN THE STUDY. SO IT PROMOTES, PROTECTS AUTONOMY AND AT THE SAME TIME PROTECTS INTEREST. THIS PERSON CAN'T DO THIS, WAS NEVER ABLE TO DO THAT. I THINK ANOTHER WAY TO THINK ABOUT IT, INFORMED CONSENT, AUTHORIZATION. ANOTHER WAY PEOPLE TALK INFORMED CONSENT, IT'S MORALLY TRANSFORMATIVE. SO THE IDEA, IF I WALK UP TO THIS GUY AND STICK A NEEDLE IN HIS ARM I HAVE DONE SOMETHING BAD. IF I EXPLAIN IT TO THEM FIRST OKAY, IT'S REALLY IMPORTANT AND VALUABLE TO DO. THE OTHER WORRY IS THAT PERSON CAN'T GIVE ME THAT MORAL TRANSFORMATION. BUT STICKING A NEEDLE IN THE ARM MIGHT HURT HER. WHAT MAKES IT OKAY, IS IT THE PARENTS SAY WE THINK THIS IS IMPORTANT, IS THAT SUFFICIENT, DO WE NEED IT. SO THAT'S THE DILEMMA. OKAY. THANK YOU. [APPLAUSE] >> MAY THE GNATS PREVAIL. OUR NEXT TOPIC IS BUILDING ON SOME OF THE THINGS THAT DAVE STARTED ACTUALLY. WE'RE GOING TO TO TALK ABOUT COERCION, UNDUE INDUCEMENT AND INCENTIVES IN RESEARCH. WE ARE LUCKY TO HAVE WITH US ALAN BETTER HEIMER IN THE DEPARTMENT OF HIE -- WERTHEIMER AND WROTE THE BOOK ON THESE TOPICS, HAS BEEN WORKING IN THIS AREA A LONG TIME AND SINCE WE DRAGOONED THEM TO SPEND TIME WITH US, HE'S BEEN APPLYING THESE CONCEPTS TO THE SETTING OF CLINICAL RESEARCH. ALAN. >> I'M AFRAID I WAS BORN IN NEW YORK 70 YEARS AGO WAS BORN A YANKEES FAN, SORRY, DAVE. MY CHILDHOOD MEMORY OF WASHINGTON BASEBALL IS WHEN THE BASEBALL TEAM WAS THE WASHINGTON SENATORS. THE SAYING WHEN I WAS A KID, WASHINGTON WAS FIRST IN WAR, FIRST IN PEACE AND LAST IN THE AMERICAN LEAGUE. WHERE IS THE -- OKAY. I SHOULD GO BACK, IF I CAN. DISCLAIMERS CAN I GET THIS BACK? TO THE BEING SOMETHING I'M SORRY. THERE WE GO. DISCLAIMERS DAVE HAD, THOUGH THESE ARE MY VIEWS BAD NEWS. THE GOOD NEWS IS ON THIS ISSUE MY VIEWS ARE TRUE. ACKNOWLEDGEMENTS, I WANT TO ACKNOWLEDGE CHRISTINE GRADY WHO I USED A FEW SLIDES SHE DEVELOPED DATA AND INFORMATION SHE DEVELOPED, SHE WAS COLLABORATOR IN SOME RESEARCH, I WILL TELL YOU ABOUT AS WE GO ALONG. THE BASIC PROBLEM IS RESEARCH SUBJECTS AND RECRUITMENT IS OFTEN DIFFICULT. ALTRUISM IS IN LIMITED SUPPLY. WHEN RESEARCH IS BENEFICIAL TO THE SUBJECT IT'S NOT A PROBLEM. BUT WHEN RESEARCH IS A NET BURDEN OR NET RISK TO THE SUBJECT IT'S HARD TO GET PEOPLE INTO RESEARCH ACCRUAL IS VERY SLOW, MANY STUDIES DON'T COMPLETE. THERE'S ANOTHER DIMENSION OF THIS WHICH NEEDS TO BE MENTIONED IS THAT LOTS OF STUDIES AREN'T PROPOSED WHERE STUDIES WOULD BE GOOD STUDIES, AN IMPORTANT STUDY IF THEY GET SUBJECTS, BECAUSE IT'S PERCEIVED DIFFICULT TO GET SUBJECTS. SO IT APPEARS ACCORDING TO ONE ARTICLE, MORE THAN ONE FIFTH OF TRIALS SPONSORED BY NCI FAILED TO ENROLL A SINGLE SUBJECT. ONLY HALF DEVELOP DATA THAT IS OF ANY USE. 3% OF CANCER PATIENTS PARTICIPATE IN ONCOLOGY TRIALS. THE PERCENTAGE OF PARTICIPATION IN PEDIATRIC ONCOLOGY IS HIGHER FOR REASONS THAT I WON'T DO INTO NOW. THE PROBLEM RECRUITMENT SOCIAL SCIENCES, OFTEN CALL A COLLECTIVE ACTION PROBLEM. YOUYOU HAVE A COLLECTIVE ACTION PROBLEM WHEN SOMETHING IS IN HERB'S INTEREST, IT'S IN HERB'S INTEREST WHEN PEOPLE MIGHT BE SICK THAT RESEARCH BE CONDUCTED BUT IT'S IN THE VICTIM'S INTEREST OFTEN NOT -- INDIVIDUAL'S INTEREST OFTEN NOT THE PARTICIPATE. IT'S IN MY INTEREST AS AN INDIVIDUAL TO FREE ON PARTICIPATION OF OTHERS. IT'S MY INTEREST EVERYBODY ELSE PAY THEIR TAXES. IT'S IN MY INTEREST TO PAY AS LITTLE AS I CAN. TAKE SOMETHING LIKE CATALYTIC CONVERTERS ON OUR CARS, USED TO RECUSE AIR POLLUTION. IF THEY WERE CONTROL -- REDUCE AIR POLLUTION. IF CARS DIDN'T COME EQUIPPED WITH CATALYTIC CONCERTERS WHICH MAY -- CONVERTERS AND WE LEFT IT TO INDIVIDUALS TO PUT THEM ON THEIR CARS I THINK WE CAN PREDICT THAT MOST PEOPLE WOULDN'T BOTHER PUTTING THEM ON. IT'S MY INTEREST YOU PUT ONE ON YOUR CAR BUT NOT MY INTEREST TO PAY 3 OR $400 TO PUT IT ON MY CAR. THERE ARE AREAS OF SOCIAL LIFE WHEN WE HAVE A COLLECTIVE ACTION PROBLEM, WHEN IT'S IN EVERYBODY'S INTEREST, THAT SOMEBODY BE DONE BUT ANIMY INTEREST NOT TO DO IT, IN SOME AREAS OF LIFE WE USE COERCION. WE REQUIRE PEOPLE TO PAY TAXES, REQUIRE CARS HAVE CATALYTIC CONVERTERS BUT NOT RESEARCH. RESEARCH REQUIRES CONSENT. WE'RE NOT WILLING TO CONSCRIPT PEOPLE IN PARTICIPATING IN RESEARCH JUST LIKE WE CAN SCRIP PEOPLE TO PAY TAXES. WHAT CAN WE DO? WE COULD USE INCENTIVES TO GET PEOPLE TO PARTICIPATE. WE DO USE AND I'LL GIVE DATE ON THAT. THE USE OF INCENTIVES SEEMS TO BE COMPATIBLE WITH GETTING PEOPLE INFORMED, VOLUNTARY VALID CONSENT. IT'S NOT IN YOUR INTEREST TO PARTICIPATE FOR NOTHING BUT WE CAN MAKE IT IN YOUR INTEREST TO PARTICIPATE BY PAYING YOU AND GET ENOUGH PEOPLE TO PARTICIPATE. THE USE OF INCENTIVES IS ACTUALLY NOT A NEW PHENOMENA. YOU MAYBE DOING IT MORE EXPANSIVELY THAN WE USED TO BUT ACTUALLY IT'S DONE FOR A LONG TIME T FAMOUS STUDIES BY WALTER REED PAID $100 IN GOLD TO PEOPLE WILLING TO BE INTENTIONALLY EXPOSED. THIS WAS A CHALLENGE STUDY. EXPOSED TO YELLOW FEVER. THEY WERE PAID $100 IN GOLD IF THEY WERE ACTUALLY INFECTED THEY GOT ANOTHER $100. IN CASE THEY DIED THEN THE MONEY WAS PAID TO THEIR FAMILIES. IT WAS USE OF INCENTIVES TO GET PEOPLE TO PARTICIPATE. TODAY WE PAY PEOPLE SOMETIMES MODEST AMOUNTS SOMETIMES SIGNATURE P CAN'T AMOUNTS FOR PARTICIPATING IN STUDIES. SO THERE IS THIS WEBSITE, RXGETPAID.COM WHERE YOU CAN FIND OUT ABOUT STUDIES THAT PAY PEOPLE TO PARTICIPATE. THERE ARE OTHER INCENTIVES TO GET PEOPLE TO PARTICIPATE. FOR SOME IT'S THE CHANCE FOR FREE TREATMENT, OR CHANCE OF TREATMENT IN MASS BOW CONTROL TRIAL. PERHAPS FINANCIAL AND OTHER REASONS TREATMENT WAS UNAVAILABLE TO THEM. SOMETIMES PEOPLE USE RESEARCH TO GET FREE MEDICAL EXAM AS PART OF THE SCREENING OR ACCESS TO AN EXPERIMENTAL TREATMENT THAT'S NOT OTHERWISE AVAILABLE OR TO GET POST TRIAL TREATMENT. BECAUSE THE PROTOCOL SPECIFIES AFTER THE TRIAL IS OVER TREATMENT WILL CONTINUE. ANCILLARY CARE OR PERHAPS FINDING OUT STUFF YOU WOULDN'T FIND OUT. THERE'S OTHER INCENTIVES THAN FINANCIAL INCENTIVES. THAT GET PEOPLE TO PARTICIPATE. TODAY I'M GOING TO FOCUS ON FINANCIAL INCENTIVES. THE FACT IS, PAYMENT MAYBE MOST COMMON, IN SOME KINDS OF TRIALS OR MORE COMMON IN SOME KINDS OF TRIAL THAN OTHER, PAYMENTS ARE MADE IN PHASE 1, PHASE 2 AND PHASE 3 STUDY. AT LEAST 23% ON STUDY THAT CHRISTINE AND FORMER FELLOW AND ZEKE EMANUEL DID ACADEMIC INSTITUTIONS PAID SUBJECT AND MY BEST GUESS IS THAT IN COMMERCIAL RESEARCH THE PROPORTION OF STUDIES THAT PAY PEOPLE IS MUCH HIGHER THAN IN ACADEMIC OR GOVERNMENTALLY SPONSORED RESEARCH. THIS STUDY WITH WAS SOME YEARS AGO, THEY TEND TO BE MODEST BUT THERE ARE STUDIES THAT PAY $1,000, $2,000 TO PEOPLE TO PARTICIPATE. WHY DO WE PAY PEOPLE? IT'S IMPORTANT TO NOTE THERE ARE DIFFERENT JUSTIFICATIONS FOR PAYING PEOPLE. THE LEAST CONTROVERSIAL IS REIMBURSEMENT. WE CAN PAY PEOPLE TO REIMBURSE EXPENSES. NOBODY OBJECT T TO PAYING PEOPLE FOR REIMBURSEMENT, WE CAN COMPENSATE PEOPLE FOR TIME AND BURDENS OF RESEARCH, I DISTINGUISH BETWEEN BURDENS AN RISK. THERE ARE BURDENNINGS ASSOCIATED WITH PARTICIPATING. THERE'S TIME. THERE'S INCONVENIENCE, THERE'S WAITING THERE IS PAIN OF SOME PROCEDURES BUT I DON'T THINK OF PAIN AS A BIG RISK. IF IT'S SHORT DURATION AND DOESN'T POSE ANY NET TO ONE'S LONG TERM HEALTH. WE CAN COMPENSATE PEOPLE FOR RISK. AS WELL. AS I WILL SHOW, I -- IN A MINUTE OR SO. PEOPLE ARE MUCH LESS INCLINED TO SUPPORT COMPENSATING PEOPLE FOR RISK THAN COMPENSATING PEOPLE FOR TIME AND CONVENIENCE, BURDENS OR FOR REIMBURSING OF PEOPLE. INTERESTINGLY, THERE ARE MANY PEOPLE WHO WORRY ABOUT PAYING PEOPLE BECAUSE OH, IF WE PAY PEOPLE TO PARTICIPATE, RESEARCH EXLOYALING THEIR NEED FOR THE MONEY. THAT'S ONE WAY TO THINK ABOUT IT BUT IT'S ALSO PAYING PEOPLE TO AVOID EXPLOITATION. THE RESEARCHERS ARE GETTING PAID. WHY AREN'T THE SUBJECTS GETTING PAID? WHY ARE THEY DOING THIS FOR NOTHING MAYBE PAYING PEOPLE A FAIR AMOUNT FOR THEIR PARTICIPATION IS A WAY NOT TO EXPLOIT THEM. SO WE CAN THINK OF JUSTIFYING PAYMENT FOR THAT REASON. WHAT WE'RE GOING TO TALK ABOUT TODAY IS MAINLY USING PAYMENT AS AN INCENTIVE FOR RECRUITMENT. CHRISTINE, FRANK MILLER AND I AND FORMER FELLOW IN THE DEPARTMENT, EMILY DID A STUDY A FEW YEARS AGO WHICH WE SURVEYED THE VIEWS OF IRB MEMBERS ACROSS THIS COUNTRY. WE DID THIS IN CON JUNCTION WITH AN OUTFIT CALLED PUBLIC RESPONSIBILITY AND MEDICINE RESEARCH WHICH IS AN ORGANIZATION THAT BASICALLY SERVES EDUCATIONAL FUNCTIONS FOR IRB MEMBERS AN PEOPLE IN THE COUNTRY WHO ARE INTERESTED IN SUBJECTS PROTECTION AND WANTED TO FIND OUT WHAT THEY THOUGHT ABOUT INCENTIVES. WE HAD SUSPICIONS ABOUT WHAT THEY THOUGHT BUT NO GOOD HARD DATA. THESE ARE PEOPLE WHO DECIDE WHETHER WHETHER PROTOCOLS GO FORWARD OR NOT. WE THOUGHT IT IMPORTANT TO FIND OUT. WITHIN MORE CONTROVERSIAL PART OF THE STUDY IS WE STENT PEOPLE A LETTER TELLING THEM THEY WERE GOING TO GET AN EMAIL ASKING THEM TO PARTICIPATE IN RESEARCH BY CLICKING ON THE THING AND DOING IT, IT WAS A WEB-BASED. OUR ENVELOPE TO THEM SAID AS A TOKEN OF APPRECIATION, HERE IS $5. THE ENVELOPE CONTAINED A $5 BILL. YOU CAN KEEP IT WHETHER OR NOT YOU PARTICIPATE IN THE STUDY. MANY RESPONDENTS HAD INTENTION REACTIONS TO THAT. SOME THOUGHT IT WAS COERCIVE, THAT WE WERE -- AND THAT THEY PARTICIPATED IN THE RESEARCH THEY SAID BUZZ THEY FELT GUILTY HAVING RECEIVED THE $5. SO IN ANY CASE, OUR STUDY SHOWED SOME INTERESTING THINGS. WE ASKED PEOPLE WHETHER THEY AGREED OR STRONGLY AGREED THEY'S ACCEPTABLE OR SHOULD WE COLLAPSE THE DATA. WE ASKED THEM DID THEY AGREE OR NOT AGREE, AGREE STRONGLY, SO FORTH. IS IT OKAY TO OFFER MONEY? WHEN PUT THAT WAY, THERE WAS A TENDENCY TO THINK IT WAS OKAY TO OFFER MONEY TO HEALTHY VOLUNTEER S, WHAT ABOUT PATIENT SUBJECT WITH PROPROSPECT OF BENEFIT? 80% THOUGHT IT WAS OKAY. WHAT ABOUT PATIENT SUBJECTS WITH PROPECK OF DIRECT BENEFIT? SLIGHTLY LESS BUT NOT MAJOR DIFFERENCES ACROSS THIS CATEGORY OF SUBJECTS. REIMBURSING EXPENSE? EVERYBODY THOUGHT THAT WAS OKAY. WHAT ABOUT COMPENSATING FOR TIME? EVERYBODY THOUGHT THAT WAS OKAY BUT WHEN PUT AS INCENTIVE AS YOU CAN SEE THE LEVEL OF AGREEMENT GOES DOWN SHARP SLIGHTLY LESS FOR PATIENT SUBJECTS WITH RESPECT -- NOT A MAJOR DIFFERENCE, WHAT ABOUT COMPENSATING PEOPLE FOR RISK? THERE THE PERCENTAGE GOES DOWN EVEN LOWER. ONLY A THIRD OF OUR RESPONDENTS THOUGHT THAT IT WAS OKAY TO PARTICIPATE TO OFFER PARTICIPANTS MONEY TO COMPENSATE THEM. FOR RISK. SO THE STATE OF PAYMENT IN THE UNITED STATES, VERY COMMON, ALL KINDS OF SUBJECTS ARE PAID, THERE'S NOT A LOT OF GUIDANCE HOW MUCH TO BE PAID OR BUT THERE'S DISAGREEMENT AS TO USING PAYMENT FOR INCENTIVE FOR COMPENSATING RISK. A LOT OF WORRY ABOUT PAYMENT. WE ASKED IN GENERAL TERMS ARE YOU WORRIED ABOUT PAYMENT? ARE YOU CONCERNED ABOUTETHICS OF PAYING PEOPLE? AS YOU CAN SEE, WHEN WE ASKED PEOPLE ABOUT TOKEN PAYMENT IT IS LEVELS OF WORRIES WERE NOT VERY GREAT. BUT PRETTY SIGNIFICANT PROPORTION OF OUR SUBJECT POOL WAS EITHER SOMEWHAT CONCERNED OR MODERATELY CONCERNED OR VERY CONCERNED WHEN THERE WERE SUBSTANTIAL PAYMENT OFFERED TO SUBJECTS. IT'S -- WHAT ARE THE WORRIES? I THINK THERE ARE BASICALLY TWO CATEGORIES, TWO LARGE CATEGORIES. ONE OF THE WORRIES ABOUT PAYMENT IS OFFERING PAYMENT CAN COMPROMISE THE VALIDITY OF CONSENT BECAUSE PAYMENT COERCES OR BECAUSE PAYMENT CONSTITUTES AN UNDUE INFLUENCE. ISLE TRY TO SAY SOMETHING ABOUT THE DIFFERENCE BETWEEN THOSE CONCEPTS AS WE GO FORWARD. THERE ARE OTHER KINDS OF WORRIES, THOUGH OUR SUBJECTS DIDN'T MENTION THIS, I SHOULD SAY BECAUSE WE DIDN'T ASK. THERE ARE PEOPLE WHO WORRY ABOUT WHAT SOMETIMES CALLED CO-MODIFICATION. THERE'S SOMETHING UNSEEMLY ABOUT IT'S LIKE PROSTITUTION, ABOUT PAYING PEOPLE TO BE RESEARCH SUBJECTS. THERE'S SOMETHING UNSEEMLY ABOUT GETTING PEOPLE TO PUT THEIR BODIES AT RISK IN EXCHANGE FOR MONEY. SOME WORRY ABOUT -- USING MONEY TO TREAT PEOPLE -- ANOTHER WORRY, IT'S A VERY DIFFERENT WORRY THAN OUR CONSENT WORRY, IS WHEN WE PAY PEOPLE IT MIGHT UNDERMINE GENERAL SOCIAL TRUST IN THE RESEARCH ENTERPRISE. WE NEED SOCIETY TO REMAIN CONFIDENT THAT RESEARCH IS ETHICAL AND PAYING PEOPLE MIGHT UNDERMINE TO TRUST. FINALLY, THERE ARE SCIENTIFIC WORRIES ABOUT PAYING PEOPLE. YOU MAYBE INDUCING SUBJECTS TO CONCEAL INFORMATION IN ORDER TO GET INTO THE STUDY. THEY MAY WITHHOLD INFORMATION, MAY LIE. THEY MAY FEIGN ILLNESS. IN A RECENT ARTICLE IN SCIENTIFIC AMERICAN MIND THE AUTHOR PINTED OUT THAT IN PSYCHIATRIC RESEARCH, WE USE SUBJECTS REPORTING TO FIGURE OUT WHETHER THE SUBJECT IS SICK. WE OFTEN DON'T HAVE INDEPENDENT MEASURES OF ILLNESS. THE SUBJECT MAY SAY YES, I'M DEPRESSED. IN ORDER TO GET INTO THE STUDY. MAYBE THEY AREN'T DEPRESSED BUT WANT THE MONEY. THIS HAS INTERESTING CONSEQUENCE, IF YOU GET THE WRONG PEOPLE INTO THE STUDY, NOT ONLY ARE YOU IN THE GETTING USEFUL DATA BUT MAY EXAGGERATE THE PLACEBO EFFECT. THIS PERSON GOT ALL BETTER. THEY WERE NEVER SICK TO BEGIN WITH. THAT'S WHY IT SHOWS A BOUNCE IN THEIR WELL BEING. IN ANY CASE, WHAT I WANT TO KNOW IS WORRIES, SCIENTIFIC WORRIES, WORRIES ABOUT HOW PAYING PEOPLE COULD SCREW UP THE SCIENCE ARE VERY DIFFERENT WORRIES THAN WORRIES ABOUT THE VALIDITY OF A SUBJECT CONSENT. I WANT TO TALK ABOUT THE CONSENT BASED WORRY. IF PAYING PEOPLE SCREWS UP THE SCIENCE, THAT IS A GOOD REASON NOT TO PAY PEOPLE. THE QUESTION IS, WHETHER WE HAVE REASON TO WORRY THAT PAYING PEOPLE COMPROMISES VALIDITY OF THEIR CONSENT. THERE IS A LOT OF ANECDOTAL EVIDENCE THAT WE HAVE THE ANECDOTAL EVIDENCE THAT IRB MEMBERS AND PEOPLE IN THE SUBJECT PROTECTION COMMUNITY, ARE VERY CONCERNED THAT PAYMENT DOES IN FACT COERCE OR CONSTITUTE UNDUE INFLUENCE. OUR STUDIES SHOWED THAT WHAT WE THOUGHT WAS TRUE ACTUALLY WAS TRUE. THERE ARE A LOT OF PEOPLE WHO THINK THAT PAYMENT CONSTITUTES OR CAN CONSTITUTE COERCION OR UNDUE INFLUENCE. WHAT'S THE PROBLEM? TO THE EXTENT THAT THESE ATTITUDES ABOUT PAYMENT, THESE VIEWS ABOUT COERCION AND UNDUE INFLUENCE ARE CORRECT, THEN THEY DO APPROPRIATELY LIMIT THE PRACTICE OF PAYMENT, IF PEOPLE ARE RIGHT THINKING THE PAYMENT IS COERCIVE OR CONSTITUTES UNDUE INFLUENCE IF YOU PAY PEOPLE TOO MUCH, THAT IS A GOOD REASON NOT TO PAY PEOPLE OR NOT TO PAY TOO MUCH. BUT IF THE VIEWS OF IRB MEMBERS, IF THE WAY THEY THINK ABOUT COERCION AND UNDUE INFLUENCE ARE BASED ON CONCEPTUAL OR ETHICAL MISCONCEPTION, THEN THEY MAYBE UNNECESSARILY PUTTING LIMITS ON RESEARCH. IF THEIR VIEWS ARE WRONG, THEY VIEWS ARE BASED ON MISCONCEPTIONS ABOUT THE CONCEPTS OF COERCION AND UNDUE INFLUENCE, THEN WE GET A SITUATION WHICH RESEARCH DOESN'T GO FORWARD OR TAKE AS LONG TIME TO COMPLETE, BECAUSE RESEARCHERS ARE NOT PERMD TO PAY OR PAY ENOUGH. RESEARCH TAKES A LONG TIME TO COMPLETE OR DOESN'T COMPLETE AT ALL. THE SUBJECTS WHO MIGHT WANT TO GET PAID OR PAID MORE DON'T GET PAID MORE, IF VIEWS ABOUT COERCION OF INDUE INFLUENCE ARE ON MISTAKE, WE THINK IT BAD FOR THE SCIENCE AND FOR THE SUBJECTS. WE WOULD BE IN EFFECT STOPPING A KIND OF WIN WIN SITUATION. WE NEED TO BE DAREFUL. SOMEBODY MIGHT SAY -- CAREFUL. THESE COERCIONS AND UNDUE INFLUENCE ARE NOT HAVING IMPACT BUZZ YOU TOLD US PEOPLE ARE ACTUALLY PAID. SO CLEARLY RESEARCHERS ARE ALLOWED TO PAY PEOPLE. BUT THAT'S NOT QUITE RIGHT. I'M GOING TO MAKE A CONFESSION HERE I PROBABLY SHOULDN'T MAKE. BUT THINK ABOUT SPEED LIMITS FOR A MINUTE. SPEED LIMITS I VIOLATE THE SPEED LIMIT. WHEN I GO ON -- I STILL FLIVVER MONT, WHEN I GO ON THE INTERSTATE IN VEER MON, THERE'S A 65-MILE AN HOUR SPEED LIMB, I SET MY CRUISE CONTROL AT 72. DOES HA SHOW ME THE SPEED LIMB ISN'T HAVE AN EFFECT ON MY BEHAVIOR. IT DOESN'T SHOW THAT. I DON'T SET IT AT 80. I SET IT AT 72. BECAUSE I HAVE REASON TO BELIEVE THEY WON'T STOP ME AT 72. BUT I'M SUSPICIOUS THEY WOULD STOP ME AT 80, RIGHT? SO THE SPEED LIMIT IS HAVING AN EFFECT ON MY BEHAVIOR EVEN THOUGH I SPEAK. THAT'S THE POINT THAT I WANT TO MAKE. THE SAME I THINK IS TRUE OR MIGHT BE TRUE FOR WORRIES ABOUT PAYMENT. THE FACT PEOPLE ARE PAID DOESN'T SHOW WORRIES AREN'T HAVING AN EFFECT ON THE KINDS OF PROTOCOLS THAT ARE APPROVED OR THE KINDS OF PROTOCOLS THAT ARE SUBMITTED OR AMOUNT OF PAYMENT ALLOWED. THEREFORE, THE SUCCESS IN RECRUITMENT. WORRIES ABOUT PAYMENT, WE DON'T ACTUALLY KNOW, WE KNOW PEOPLE HAVE THE WORRIES. THAT OUR STUDY WAS ABLE TO ESTABLISH. I'LL TELL YOU MORE ABOUT THAT AS AS WE GO FORWARD. BUT WE DON'T KNOW TO WHAT EXTENT HOW THESE INFLUENCED DECISIONS. AND WE ALSO DON'T KNOW HOW MANY STUDIES ARE NEVER PUT FORWARD BECAUSE RESEARCHERS IT AFFECT SAY WE'LL NEVER GET PEOPLE IF WE DON'T PAY THEM QUITE A BIT TO PARTICIPATE AND THE IRB WILL NEVER APPROVE IT IF WE PUT THIS -- SO WE MIGHT AS WELL NOT BOTHER. THAT'S A POSSIBLE COST OF WORRIES ABOUT PAYMENT. IT'S QUITE HIDDEN. WHAT MAKES IT HIDDEN IS THAT NOTHING HAPPENS. THE RESEARCH ISN'T PROPOSED, IRB NEVER SEES IT AND WE DON'T KNOW. THEREFORE, WHAT THE AFFECTS ARE. SO OUR THESIS IS, MY THESIS, THIS WAS THE THESIS THAT EMILY LARGE AND CHRISTINE FRANK MILLER AND I DEFENDED IN A RECENT ARTICLE, THE ARTICLE IS NOW AVAILABLE ONLINE IN THE JOURNAL BIOETHICS, MANY OF THE PREVALENT CONCERNS ABOUT PAYMENT ARE MISGUIDED. OUR VIEW IS THE PAYMENT NEVER COERCES. DON'T COERCE. IT'S A CONCEPTUAL MISTAKE TO THINK PAYMENT CAN COERCE. CAN RAISE ETHICAL CONCERN WITH RESPECT TO CONSENT, WHEN IT UNDULY INFLUENCES RESEARCH PARTICIPANTS BY DISTORTING THEIR PERCEPTION OF RESEARCH RISK AND BENEFITS. WE THINK NEVER COERCION, THERE CAN BE UNDUE INFLUENCE, WHEN PAYMENT DISTORTS SUBJECTS ABILITY -- PARTICIPATION. BUT THERE'S LITTLE EVIDENCE THAT PAYMENT HAS DISTORTED EFFECT. SO IN THE ABSENCE OF EVIDENCE THAT SUCH DISTORTIONS OCCUR, OUR VIEW IS THAT IRB SHOULD BE VERY RELUCTANT TO CONCLUDE THAT OFFERS OF PAYMENT UNDERMINE THE VALIDITY OF CONSENT. HERE ARE SOME REGULATORY STATEMENTS ABOUT COERCION. COMMON RULE, WHICH YOU'RE FAMILIAR WITH RIGHT NOW. INVESTIGATORS SEEK CONSENT ONLY UNDER CIRCUMSTANCES THAT PROVIDES RESPECTIVE SUBJECT OR REPRESENTATIVE SUFFICIENT OPPORTUNITY TO CONSIDER WHETHER OR NOT TO CONSIDER TO PARTICIPATE AND MINIMIZE THE POSSIBILITY OF COERCION OR UNDUE INFLUENCE. THE FDA HAS A SIMILAR STATEMENT. NEITHER WHERE PAYMENT SHOULD BE NEITHER COWE ARESIVE OR PRESENT UNDUE INFLUENCE. OFFICE OF HUMAN RESEARCH PROTECTION HAS AGAIN, A VERY SIMILAR STATEMENT ABILITY COERCION AND UNDUE INFLUENCE. HOW DO IRB MEMBERS ACTUALLY NONE WE ALL AGREE IF THERE'S COERCION THE CONSENT WOULDN'T BE VALID, QUESTION IS HOW DO PEOPLE UNDERSTAND WHAT IS COERCION AND ARE THERE UNDERSTANDINGS OF THAT CORRECT? WE ASKED PEOPLE HOW THEY UNDERSTOOD COERCION IN THIS STUDY. WE ASKED THEM ARE YOU -- DO YOU THINK THAT SOMEBODY IS COERCED IF THREATENED WITH HARM? 91% AGREED. WE ASKED ARE PEOPLE COERCED IF PAYMENT GETS THEM TO PARTICIPATE WHEN THEY OTHERWISE WOULD NOT PARTICIPATE? 65% SAID THAT WAS COERCION. 80% SAID UNDUE INFLUENCEMENT IF PAYMENT GETS SOMEBODY TO PARTICIPATE OTHERWISE WHEN THEY WOULDN'T PARTICIPATE. WHAT ABOUT IF A PERSON FEELS THEY DON'T HAVE ANY REASONABLE ALTERNATIVE BUT TO ACCEPT THE OFFER OF PAYMENT GIVEN WHERE THEY IN LIFE, GIVEN THE NEED FOR THE MONEY, GIVEN WHAT RESEARCH PARTICIPATION WOULD MEAN TO THEM, WHAT IF THEY FELT GIVEN THE OFFER, I DON'T HAVE A REASONABLE CHOICE. I HAVE TO TAKE THE MONEY. 81% THOUGHT THAT WAS COERCION, 80 THOUGHT IT WAS UNDUE INFLUENCE. IS IT UNDUE INFLUENCE IF IT -- IF PAYMENT DISTORTS PEOPLE'S ABILITY TO PERCEIVE RISKS AND BENEFITS. EVERYBODY AGREE WITH THAT. THIS IS WHAT PEOPLE THINK ABOUT COERCION. I THINK THE FIRST VIEW, I'LL GET TO THE BUSINESS ABOUT THREAT PEN WITH HARM WHICH IS CORRECT. SOME PEOPLE AS WE JUST ESTABLISHED THINK OFFERS OF PAYMENT ARE COERCION IF THEY GET PEOPLE TO PARTICIPATE WHEN THEY OTHERWISE WOULDN'T. THE FACT TO USE A PHILOSOPHERS TECHNICAL TERM, THAT VIEW IS CRAZY. I MEAN, THERE ARE WAYS TO GET PEOPLE TO DO SOMETHING THEY OTHERWISE WOULDN'T DO THAT DON'T INVOLVE COERCION. IF I PERSUADE YOU TO DO SOMETHING, I SAID YOU REALLY OUGHT TO GIVE BLOOD, IT'S NOT VERY PAINFUL, IT DOES A LOT OF GOOD, YOU'RE WISE -- I HAVE GOT TO DO SOMETHING YOU'RE WISE WOULDN'T DO. THAT'S NOT COERCION. IF I OFFER SOMEBODY $20 TO SHOVEL MY DRIVEWAY OR MOW MY LAWN WHEN THEY OTHERWISE WOULDN'T, THEY'RE NOT GOING TO DO IT IF I DON'T PAY THEM. I COERCED THEM TO DO SOMETHING. RIGHT? AS A GENERAL PROPOSITION, OFFERS DON'T COERCE. IF I OFFER YOU SOMEBODY, I'M GIVING YOU ANOTHER OPTION YOU DIDN'T HAVE BEFORE. I HAVEN'T REDUCED IT FOR YOU, I PUT ANOTHER OPTION ON, YOU MIGHT DECIDE IT'S AN UNATTRACTIVE OFFER, YOU MIGHT REJECT THE OFFER BUT I HAVEN'T LIMITED YOUR FREEDOM WHEN I OFFER YOU SOMETHING THAT WAS OTHERWISE NOT OFFERED. OFFERS CAN BE IMMORAL AND THEY CAN BE INDECENT, A BRIBE IS AN IMMORAL OFFER. IF I I ACCIDENTLY DO GO TOO FAST AND THE COP STOPS ME AND I OFFER $100 NOT TO GIVE ME TICKET. IT HASN'T HAPPENED BECAUSE I HAVEN'T BEEN STOPPED. THAT'S AN IMMORAL OFFER, IT'S IMMORAL TO OFFER IT, IT'S IMMORAL TO ACCEPT IT. IF HE DOES ACCEPT IT, HE HASN'T BEEN COERCED TO ACCEPT IT, HE'S ACCEPTED IT VOLUNTARILY. WE WOULDN'T HIM AFTER THE HOOK, YOU SEE I HAD TO CHOICE BUT TO ACCEPT THE BRIBE. NO. OFFERS DON'T COERCE. OFFERS CAN BE IMMORAL. BUT THEY DON'T COERCE OR THAT IS THE VIEW. WHAT IS COERCION? WE GO BACK TO THE THREAT OF HARM. SOMEBODY COERCES SOMEBODY TO DO SOMETHING IN A WAY THAT INVALIDATES COP SENT ONLY -- CONSENT ONLY IF THEY PROPOSE TO HARM THEM, IF THEY DON'T AGREE. DO THIS CONSENT TO DO THIS OR I WILL HURT YOU? HARM YOU? COULD BE PHYSICAL HARP, COULD BE I'M GOING TO DAMAGE YOUR REPUTATION. COULD BE ALL KINDS. THAT'S COERCION. WHEN WE GET SOMEBODY TO DO SOMETHING BY THREATENING THEM WITH A HARM IF THEY DON'T DO IT. THAT IS COERCION. SO WHAT ARE SOME EXAMPLES? THE EXAMPLE OF THE GUNMAN THE MUGGER WHO SAYS GIVE ME YOUR MONEY OR I'M GOING TO SHOOT YOU. THAT'S COERCION. OR EXTORTION. THE EXTORTIONIST SAYS TO THE STORE OWNER, LOOK, I WANT YOU TO HIRE MY SANITATION COMPANY, WE'LL TAKE CARE OF YOUR GARBAGE. BUT I THINK I HAVE SOMEBODY ELSE. YOU BETTER HIRE US BECAUSE IF YOU DON'T WE'RE GOING TO HAVE TO -- SOMEHOW WINDOWS ON YOUR RESTAURANT WILL BE BROKEN. THAT'S EXSTORGES. IF I AGREE TO HIRE THEM, THAT'S COERCION. MY CONSENT ISN'T VALID IN THAT CASE. I MAY DECIDE TO GO WITH IT ANYWAY. OR THE GODFATHER'S OFFER, YOU MAY REMEMBER THE VERY -- RIGHT NEAR THE OPENING SCENE IN THE MOVIE THE GODFATHER, WHERE THERE'S THE SINGER THAT COMES -- APPEARS AT THE WEDDING JOHNNY UPONTAIN AND MICHAEL, THE AL PACINO CHARACTER TELLS DIANE KEATON WELL HOW DO YOU KNOW? MY FATHER HELPED HIM OUT, HE HAD THIS CONTRACT WITH A BAND LEADER AND WANTED OUT. AND MY FATHER OFFERED THE BAND LEADER $10,000, THE BAND LEADER SAID NO, I WON'T RELEASE JOHNNY FONTAIN. THE NEXT THEY THE BAND LEADER SIGNED A CONTRACT FOR A THOUSAND DOLLARS, HOW DID HE DO THAT? MY FATHER MADE AN OFFER HE COULDN'T REFUSE. BUT IT WASN'T REALLY AN OFFER, THAT'S THE POINT. IT WAS COERCION. YOU SEE, NAYTHER WENT TO SEE -- MY FATHER WENT TO LUKABROSI AND HE HELD A GUN TO THE HEAD AND HE SAID EITHER YOUR BRAINS OR SIGNATURE WILL BE ON THE CONTRACT. BUT IT WASN'T AN OFFER, IT WAS A THREAT. SO THREATS COERCE. IN GENERAL, OFFERS DO NOT. THREATS REDUCE THE OPTIONS. BEFORE THE MUGGER GAME -- APPROACHED YOU, YOU HAD THE OPTION OF KEEPING YOUR MONEY AND YOUR LIFE THE THREAD SAID YOUR MONEY OR YOUR LIFE. YOU HAVE FEWER OPTIONS BEFORE THE THREAT. I'M SORRY MORE OPTIONS BEFORE THE THREAT. THE THREAT REDUCED YOUR OPTION, OFFERS, EXPAND OPTIONS THAT ARE AVAILABLE. THEY DON'T RESTRICT YOUR FREEDOM. THEY ENHANCE YOUR FREEDOM. SO SOME PEOPLE, REMEMBER THERE WAS THIS OTHER DEFINITION WE ASKED PEOPLE ABOUT. SOME THINK THAT OFFERS ARE COWE ARESIVE WHEN PEOPLE HAVE NO REASONABLE ALTERNATIVE BUT TO CONSENT TO PARTICIPATE WHEN CONFRONTED WITH AN OFFER OF PAYMENT. IN A RECENT ARTICLE CALLED COWE ARESIVE THREATS AND OFFERED IN SEW COARSESIVE THREATS, BACK TO THE GUNMAN CASE, WE COULDN'T SAY MY HANDING OVER THE WALLET WAS AN AUTONOMOUS LET ALONE A CONSENTING ACT SINCE I WAS AFTER ALL UNDER A THREAT. I HAD NO OTHER REAL OR REASONABLE ALTERNATIVE. IN THIS ARTICLE I MENTIONED PAYING PEOPLE IN PSYCHIATRY RESEARCH, GABRIELLE LA ROSEN QUOTES A BIOEST CYST DAVID ROTHMAN WHO SAYS MANY IN THE FIELD WORRY THAT LOWER INCOME PATIENTS THIS IS ROSEN SPEAKING IN, MANY IN THE FIELD WORRY THAT LOWER INCOME PATIENT WHOSE NEED THE MONEY OR CANNOT AFFORD CONVENTIONAL TREATMENT ARE SUBJECT TO A DIFFERENT KIND OF PRESSURE. IT IS COERCION THROUGH LACK OF INCOME, EXPLAINS DAVID ROTHMAN. MONETARY NEED MAY CLOUD A PATIENT'S DECISION MAKING EXPOSING THE INDIVIDUAL TO A GREATER LEVEL OF RISK THAN HE OR SHE MIGHT OTHERWISE ACCEPT. THERE'S A NOTION THAT PEOPLE CAN BE COERCED BY LACK OF INCOME, BUZZ THEY DON'T HAVE ANY REASONABLE ALTERNATIVE BUT TO AGREE TO PARTICIPATE. I THINK THE NO REASONABLE ALTERNATIVE VIEW OF COERCION, IS AN ATTRACTIVE VIEW BUT I THINK IT'S MISTAKEN. IT'S ATTRACTIVE BECAUSE IT IS TRUE THAT IN MOST CASES OF COERCION IT IS TRUE YOU DON'T HAVE ALTERNATIVE BUT TO --v ? SO WHEN THE GUNMAN SAYS YOUR MONEY OR YOUR LIFE, I DON'T HAVE ANY REASONABLE ALTERNATIVE BUT TO AGREE. BUT IT DOESN'T FOLLOW, THIS IS MY POINT, I WILL HOPE TO CONVINCE YOU OF IT WITH MY NEXT SLIDE, IT DOESN'T FOLLOW THAT THE PERSON IS COERCED BECAUSE THEY DON'T HAVE ANY REASONABLE ALTERNATIVE. TO AGREE. THAT'S NOT WHY THE GUNMAN COERCES, THEY COERCE BECAUSE THEY'RE THREATENING YOU WITH A HARM. WHY IS IT NOT COERCION? WHEN YOU DONE HAVE ANY REASONABLE ALTERNATIVE? CONSIDER ONE CASE. CONSIDER THE CASE OF SOMEBODY WHO SERIOUSLY IS ILL. THE DOCTOR SAID HERE ARE YOUR CHOICES. YOU CAN AGREE TO THIS TREATMENT, SURGERY, MAYBE CHEMOTHERAPY, OR YOU'RE GOING TO DIE. YOU DON'T WANT TO DIE. IT'S TRUE IN THIS CASE THAT YOU DON'T HAVE ANY -- YOU MAY FEEL YOU DON'T HAVE ANY REASONABLE ALTERNATIVE BUT TO AGREE. PEOPLE ARE NUN THAT SITUATION. WHERE THEY DONE -- BUT WE WOULDN'T SAY THAT THE PATIENT IS COERCED TO CONSENT TO THE CHEMOTHERAPY. BECAUSE THEY DON'T HAVE ALTERNATIVE BUT TO AGREE. IN FACT YOU HAVE SIGNED A CONSENT FORM. FOR THE SURGERY. WE WOULDN'T ASK FOR PEOPLE'S CONSENT, IT WOULD BE RIDICULOUS, CONSENT SUSPECT NECESSARY, WHY ISN'T IT NECESSARY? BECAUSE CONSENT IS COERCED, WHY COERCE BUZZ THEY'RE SICK AND DON'T HAVE ALTERNATIVE. I UNDERSTAND WHERE THAT VIEW COMES FROM BUT THINK IT'S A MISTAKE. WE DON'T SAY BECAUSE PEOPLE WHO ARE UNEMPLOYED AND CAN'T PROVIDE THEIR FAMILIES AN THEREFORE ACCEPT AN OFFER OF PAYMENT FOR TAKING, WE DON'T THINK THEY'RE COERCED THOUGH THEY MAY FEEL THEY DON'T HAVE REASONABLE CHOICE. MAY THINK IT'S NOT A GOOD SITUATION. BUT THEY'RE NOT -- THEY'RE NOT COERCED. OR SO I THINK. NOW, THIS VIEW ABOUT COERCION, THE NO REASONABLE ALTERNATIVE VIEW ABOUT COERCION, ACTUALLY HAS IMPACT. ONE CASE IN WHICH I HAD IMPACT IS THIS VERY FAMOUS CASE, HAVE YOU ENCOUNTER THE GELSINGER CASE IN THE COURSE OF TODAY? VERY FAMOUS CASE INVOLVING AN ADOLESCENT BY THE NAME OF YES, SIRIE GELSINGER. I DON'T WANT TO GO INTO DETAILS ABOUT THE CASE, BUT WHAT WAS INTERESTING ABOUT THE CASE WAS THAT RESEARCHERS CONNECT WITH SOMETHING DAVE WAS SAYING, THE RESEARCHERS HAD AL TEN TESTIFY OF DOING RESEARCH WITH NEONATES WHO HAD A SERIOUS FORM OF THE DISEASE AND WERE GOING TO DIE SOON REGARDLESS OF WHAT HAPPENED IN THE RESEARCH OR DOING IT WITH SOMETHING LIKE JESSIE GELSINGER WHOED HAD A MILD FORM OF DISEASE AND THEREFORE WAS ACTUALLY A GREATER RISK. JESSIE HAD MORE TO LOSE THAN THE NEONATES WHO WERE GOING TO DIE SOON. BUT THEY DECIDED TO DO THE RESEARCH WITH JESSIE GELSINGER OR SUBJECTS WHO COULD CONSENT. WHY? IT WASN'T SO MUCH INFANTS COULDN'T CONSENT BUT JESSIE COULD, BECAUSE THE PARENTS AFTER ALL COULD CONSENT ON BEHALF OF THEIR CHILD. THE VIEW OF PROBABLY AMERICA'S -- ZEKE EMANUEL, OUR FORMER DIRECTOR, I DON'T KNOW THE MOST FAMOUS AMERICAN BIOETHICIST BUT AUTHOR KAPLAN WHO COMPETE FOR TITLE OF THE MOST FAMOUS AMERICAN BIOETHICIST OFTEN QUOTED IN NEWS MAGAZINES AND NEWSPAPER SAID THAT THE PARENTS OF THE -- THE PARENTS OF THE DYING INFANT ARE INCAPABLE TO GIVE CONSENT BECAUSE THEY'RE COERCED BY THE ILLNESS, THEY MAY FEEL THEY HAVE NO CHOICE GIVEN THEY HAD A SLIM PROSPECT OF BENEFIT. BUT IT WAS A PHASE 1 TRIAL. THERE WAS STILL -- THEY SAID THESE PARENTS ARE COERCED BY ILLNESS. AND THEREFORE THE TRIAL WAS DONE. GOOD CONSENT BY JESSIE. NOT TRYING THE TO SUGGESTOZ[ THAT IT'S MISTAKE IN COERCION THAT SOMEBODY DIED. I AM TRYING TO SUGGEST THAT THOUGH I THINK IT'S TRUE IN THIS CASE, THAT THE ISSUE IS NOT MERELY SEMANTIC, NOT SEMANTIC WHETHER WE THINK THE PAYMENT COERCES OR ADOPT THE VIEW WHEN THERE'S NO REASONABLE ALTERNATIVE. PEOPLE'S VIEWS ABOUT THESE MATTERS HAVE IMPACT. IT AFFECTS THE DECISIONS THAT THEY MAKE OR REGULATORY EFFECTS LABELING PAYMENT. SO THERE CAN BE COERCION AND RESEARCH. OFFERS OF PAYMENT ARE EVER COERCED. PEOPLE THINK THEY'RE COERCED BY SIMPLY MAKING A CONCEPTUAL MISTAKE. THERE CAN BE COERCION IF A SUBJECT IS EITHER EXPLICITLY OR IMPLICITLY THREATENED WITH HARM. A DOCTOR WHO IMPLICITLY OR EXPLICITLY THREATENS TO AMAN DAN A PATIENT I THINK THAT MIGHT BE COERCION. THEN YOU HAVE CASES WHERE PEOPLE FEEL COERCED EVEN WHEN THEY WERE NOT. IF SHE DONEN'TN'T AGREE TO PARTICIPATE WHERE THE DOCTOR WON'T AND MADE NO SUGGESTION TO THAT EFFECT BUT THEY FEEL COERCED. THAT'S A WORRY, THAT'S SOMETHING I THINK WE NEED TO WORRY ABOUT WHEN WE ASSESS THE VALIDITY OF THEIR CONSENT. IN GENERAL, I THINK COERCION IS RARE. SO ONE OF AMERICA'S WELL KNOWN BIOETHICISTS HOW LARGE A PAYMENT CONSTITUTES UNDUE INFLUENCE OR COWE ARESIVE OFFER TO PARTICIPATE IN RESEARCH IS A QUESTION WHICH NO CLEAR ANSWER IS FORTHCOMINGING. A CLEAR ANSWER IS FORTHCOMING, OFFERS OF PAYMENT DON'T COERCE. YOU HAVE ENOUGH TO WORRY ABOUT IN YOUR LIFE, PEOPLE INVOLVED WITH RESEARCH AND RESEARCHthICS HAVE ENOUGH TO WORRY ABOUT. I'M HERE THE TAKE AWAY ONE O YOUR WORRIES. YOU DON'T NEED TO WORRY, OFFERS OF PAYMENT THE TO RESEARCH SUBJECTS COERCE. THEY MIGHT CONSTITUTE UNDUE IN NUANCE. WHEN DO PAYMENT CONSTITUTE UNDUE INFLUENCE? DIFFERENT QUESTION THAN COERCION. LET'S BEAR IN MIND THAT AS GENERAL MATTER, GO BACK TO THAT DEFINITION OF UNDUE INFLUENCE. PEOPLE INDUCEMENT AND INCENTIVE THAT THEY OTHER WEE WOULDN'T DO, THAT'S WHAT INCENTIVES ARE ABOUT, GETTING PEOPLE TO DO THINGS THEY OTHERWISE WOULDN'T DO. THAT'S WHY WE GIVE PEOPLE INCENTIVES, WHETHER JOB OR MARKET TRANSACTION. I GIVE YOU THIS PRODUCT IF YOU PAY MONEY. WHAT'S THE INCENTIVE? GETTING THE PRODUCT. GETTING YOU GIVE MONEY TO THIS PERSON THAT YOU'RE WISE WOULDN'T GIVE THAT. TEST WAY THE WORLD WORKS. NOTHING PROBLEMATIC AS A GENERAL MATTER THERE'S NOTHING ABOUT USING INCENTIVES TO GET PEOPLE TO DOING SOMETHING THEY WOULDN'T OR WISE WOULDN'T DO, PARENTS OFTEN GIVE INCENTIVES TO THEIR CHILDREN TO GET CHILDREN TO DO THINGS THAT THEY OTHERWISE WOULDN'T DO. WHAT IS UNDUE INDUCEMENT? SCOTT HALPER AND OTHERS IN AN ARTICLE GAVE AN ACCOUNT, MONETARY INDUCEMENTS MAYBEN DUE P IF THEY ALTER PATIENT DECISION MAKING PROCESS SUCH THAT THEY DON'T APPROPRIATELY CONSIDER RISK OF PARTICIPATING. THAT WOULD BE UNDUE INFLUENCE. THAT IS A WORD. THIS IS WHAT THE OHRP, BY ACTUALLY DON'T AGREE WITH PART OF THE STATEMENT AS YOU CAN SEE. AN OFFER OF ONE COULD NOT REFUSE IS ESSENTIALLY COWE ARESIVE OR UNDUE. ACTUALLY A MR. JENKINS: WIN A GENERAL, GENUINE OFFER. P IF SOMEONE WERE TO OFFER ME A MILLION DOLLARS TO GO TO THE BIOETHICS DEPARTMENT AT JOHNS HOPKINS, I MIGHT GO. IT'S AN OFFER I COULDN'T REFUSE. BUT THAT'S NOT COWE ARESIVE. PSEUDOOFFERS MIGHT BE COEROSIVE. UNDUE INDUCEMENTS MAYBE TROUBLESOME BECAUSE OFFERS TOO I TRACKTIVE MAY BLIND PERSPECTIVE SUBJECTS TO THE RISKS OR IMPAIR ABILITY TO EXERCISE PROPER. THAT'S WHEN THOSE ARE THE CONDITIONS CONSTITUTES UNDUE PAYMENT. WHEN THEY DISTORT OR IMPAIR PERSPECTIVE SUBJECTS DECISION MAKING OR OR JUDGMENT HOW CAN THEY DO THAT? I WOULD LIKE JUST TO GIVE THINGS A LABEL. INTERESTING THEY USE THE LANGUAGE BLIND OR DISTORT, TO USE A KIND OF VISION-BASED CONCEPTION OF DISTORTION. I THINK OFFERS OF PAYMENT COULD DISTORT, NOT SAYING THEY DO DISTORT, COULD DISTORT IN ONE OF TWO WAYS. ONE WHICH I CALL TUNNEL VISION. A PERSON GETS TUNNEL VISION WHEN THEY FOCUS ON ONE COMPONENT IN WHAT WOULD BE A RATIONAL DECISION PROCESS AND IGNORE OTHER COMPONENTS THAT MIGHT THAT THAWING TO CONSIDER IN MAKING A RATIONAL DECISION. IF YOU HAVE TUNNEL VISION WHEN PERIPHERAL VISION IS LOST AND YOU FOCUS TOO MUCH ON ONE DIMENSION. SO IF THE OFFER OF MONEY GETS PEOPLE TO FOCUS ONLY ON THE MONEY, SUCH THAT THEY DON'T EVEN SEE RISK OF PARTICIPATION, OR TAKE ACCOUNT OF THE BURDENS OF PARTICIPATION, THAT WOULD BE A WORRY. THAT WOULD BE A WAY IN WHICH MONEY MIGHT DISTORT PEOPLE OR JUDGMENT OR BLIND THEN THERE'S A RELATED PHENOMENA, IT'S'S A LITTLE DIFFERENT, MYOPIA BUT ANOTHER DISTORTEDED VISION, WHERE WE TEND -- THIS OF COURSE IS A GENERAL PROBLEM IN HUMAN DECISION MAKING, WHERE WE FOCUS ON SHORT TERM AND DISCOUNT THE LONG TERM. Y'ALL PROBABLY MANY FAMILIAR WITH FAMOUS MARSHMALLOW EXPERIMENT, BASICALLY A MARSHMALLOW NOW BUT IF YOU'LL WAIT UNTIL THE EXPERIMENTER RETURNS YOU CAN HAVE MORE. YOU CAN HAVE TWO MARSHMALLOWS. THERE WAS A TENDENCY FOR CHILDREN, YOUNG CHILDREN ANYWAY, TO NOT WAIT, THEY FOCUS SHORT TERM, THEY IGNORE THE LONG -- THE POTENTIAL BENEFITS LONG TERM, OR WE CAN IGNORE THE POTENTIAL COST LONG TERM. WHY DO I HAVE THAT ICE CREAM? BECAUSE I'M FOCUSING ON THE SHORT TERM IGNORING THE LONG TERM. RIGHT? MONEY COULD DO THAT. IT'S NOT THAT MONEY NECESSARILY MAKES YOU UNAWARE OF THE RISKS BUT THE MONEY IS COMING RIGHT NOW, THE RISKS ARE IN THE FUTURE. SO YOU TEND TO UNDERWEIGHT THE LONG TERM RISKS AND OVERWEIGHT THE SHORT TERM BENEFITS AND PARTICIPATION. IF OFFERS OF PAYMENT DISTORT PEOPLE'S JUDGMENT BY GETTING THEM TO UNDERWEIGHT LONG TERM RISK RELATIVE TO SHORT TERM BENEFIT, THEN I THINK THAT WOULD BE A PROBLEM. ACTUALLY, THAT QUOTE I READ YOU EARLIER FROM DAVID ROTHMAN SORT OF HALF AGREES WITH THAT. NOTE THE SENTENCE, MONETARY NEED MAY CLOUD PATIENT DECISION MAKING EXPOSING THE INDIVIDUAL TO A GREATER LEVEL OF RISK THAN HE OR SHE MIGHT OTHERWISE ACCEPT. I THINK THAT STATEMENT IS HALF RIGHT. THE HALF RIGHT IS THAT MONEY IS A PROBLEM IF IT DISTORTS. CLOUDS A PATIENT JUDGMENT. IF IT DOES THAT, WE HAVE REASON TO WORRY ABOUT OFFERS OF PAYMENT. THE FACT IT GETS SOMEBODY TO ACCEPT A LEVEL OF RISK THEY OTHERWISE WOULDN'T ACCEPT, THAT I THINK IS A MISTAKE. OF COURSE PAYMENT CAN GET PEOPLE TO ACCEPT LEVELS OF RISK THEY OTHERWISE WOULDN'T ACCEPT. IT HAPPENS IN RESEARCH, AND JUST AS IMPORTANT, THINK JOBS. THERE ARE JOBS THAT ARE RISKY JOBS. COAL MINING. LOGGING. COMMERCIAL FISH, TURNING OUT LOBSTER FISHING IS ONE OF THE MORE DANGEROUS JOBS IN THIS SOCIETY. WHY DO PEEP DOLL IT? ACCEPT THERYKS. GET -- PAYMENT GETS THEM TO ACCEPT RISK THEY OTHERWISE WOULDN'T ACCEPT. WE DON'T THINK PEOPLE SHOULDN'T BE ABLE TO TAKE RISKY JOBS IN EXCHANGE FOR PAYMENT. AN ACCEPT RISK THEY OTHER WAY WOULDN'T ACCEPT IF WE THINK THEY'RE MAKING REASONABLE JUDGMENT THAT THE PAYMENT COMPENSATES THEM FOR THE LEVELS OF RISK. IT IS AN INTERESTING QUESTION, SOMETHING THAT I HAVE BEEN THINKING ABOUT EVER SINCE I JOINED THE DEPARTMENT AFTER I THOUGHT I WAS RETIRING. AS TO WHETHER PAYING PEOPLE TO ACCEPT RISK IN RESEARCH IS MORALLY DIFFERENT THAN PAYING PEOPLE TO ACCEPT THE RISKS OF EMPLOYMENT. WHICH WE READILY ACCEPT. NOW, YOU MIGHT SAY WE SHOULDN'T ACCEPT IT THERE. MAYBE WE SHOULDN'T LET PEOPLE ENGAGE IN LOBSTER FISHING, STRUCTURAL STEEL WORK, COAL MINING, FIRE FIGHTENING EXCHAIN FOR MONEY BECAUSE THEY GET INTO A LEVEL OF RISK THEY OTHERWISE WOULDN'T -- THAT WOULD BE SILLY. YOU MIGHT THINK PAYING PEOPLE TO BE RESEARCH PARTICIPANTS IS DIFFERENT. IT MAY WELL BE DIFFERENT. BUT IN GENERAL, WE HAVE NO REASON TO THINK, THE EVIDENCE ON THIS THIS IS CLEAR. I SAID THAT PAYMENT MIGHT BE A WORRY IF IT DISTORTS PEOPLE'S JUDGMENT BUT THE EVIDENCE THAT WE HAVE SO FAR IS PAYMENT DOES NOT IN FACT DISTORT PEOPLE'S JUDGMENT. PEOPLE WHO PAID ARE VERY SENSITIVE TO THE RISKS OF PARTICIPATION. THEY THINK ABOUT THEM. THEY KNOW ABOUT THEM. I'M GETTING A TIME. CHRISTINE IS POINTING TO HER WATCH SO I'M GOING TO STOP IT AT THIS POINT. AND I WILL SKIP A FEW SLIDES JUST TO SAY DOES PAYMENT OR PAYING MORE COMPROMISE THE VOLUNTARINESS OF CONSENT? IT MIGHT. PROBABLY MUCH LESS THAN IS OFTEN THOUGHT, THERE IS ANOTHER WORRY, HOWEVER, THAT MAYBE NOT PAYING PEOPLE OR PAYING TOO LITTLE EXPLOITS THEM. AND I HAVE BAD NEWS YOU HAVE TO HEAR ME ABOUT EXPLOITATION IN A COUPLE OF WEEKS. AND THEN I'LL SEGUE ABOUT EXPLOITATION AT THAT TIME BUT THIS IS WHAT I HAVE TO SAY ABOUT COERCION. AND UNDUE INDUCEMENT. THANK YOU. [APPLAUSE] >> IN TERMS OF BETWEEN RESEARCH ANURIAS CAN BE JOBS SOME PEOPLE ARGUE MORALLY RELEVANT THE COLLECTIVE ORGANIZATION OF PEOPLE LIKE MINE WORKERS AND FIREFIGHTERS VERSUS A LACK OF COLLECTIVE ORGANIZATION OF RESEARCH PARTICIPANTS AS ENTITY OR PROFESSIONAL CLASS TO ORGANIZE THEMSELVES AND GAIN COLLECTIVE AWARENESS, THERE IS LOBBY FOR MEASURES TO REDUCE RISK. DO YOU SEE THAT AS SOMEBODY WE CAN SEE OR DO YOU THINK THAT'S NOT -- >> THERE IS A FELLOW WHO STARTED A WEB-BASED -- I THINK CALLED GUINEA PIG ZERO, IS THAT RIGHT? THAT WAS PRECISELY WHAT HE WAS ABOUT. TO IN EFFECT CREATE A PSEUDO UNION OF PROFESSIONAL RESEARCH PARTICIPANTS, THOSE WHO ENGAGE IN LOTS OF CASES. AND I THINK THAT MIGHT BE A GOOD THING. I'M NOT AVERSE TO THE NOTION CERTAIN KINDS OF RESEARCH PARTICIPANTS DESERVE MORE PROTECTION AND THEY MAY NOT AS INDIVIDUALS BE ADEQUATELY CAPABLE OF PROTECTING THEIR OWN INTEREST. THAT'S A DIFFERENT QUESTION WHETHER PAYMENT COERCES. BUT I THINK THAT'S A DISTINCTION POSSIBILITY. >> HELLO. HOW ARE YOU? >> I'M FINE. >> PERSPECTIVE OF IRB, IRB ADMINISTRATOR. AND ONE IRB A LOT OF OUR STUDIES WERE NCI. I WOULD SAY OUT OF 90 PROBABLY 45 FOR NCI OUT OF 45 FIVE IN ENROLLMENT BUT FIVE HAVE SLOW ENROLLMENT, 10, 12, 15 YEARS. THEY ENROLLED IN TWO PATIENTS. IT GOT TO THE POINT IRB REBELLED BECAUSE THEY DIDN'T REVIEW STUDIES THAT HAVE BEEN OVER SO LONG BUT WEREN'T RECRUITING. SO WE SENT A LETTER TO THOSE RECRUITMENT -- TO THOSE RESEARCH TEAMS ASKING WHAT TYPE OF RECRUITMENT STRATEGIES WOULD YOU USE TO UP ENROLLMENT. SOME OF THE IRB MEMBERS THOUGHT WOULDN'T THAT BE COWE ARESIVE IF THEY COME BACK AND SAY WE'RE GOING TO OFFER THEM MONEY. WOULD THAT BE INDO YOU KNOW INFLUENCE, HOWEVER THAT'S THE ONLY WAY FOR THEM TO INCREASE ENROLLMENT. SO THE QUANDARY WAS DO WE KEEP A STUDY OPEN KNOWING THAT RECRUITMENT IS SLOW, DO WE KEEP IT OPEN KNOWING EVENTUALLY FOR THEM TO IN-- UP THEIR ENROLLMENT WE HAVE TO OFFER INCENTIVES. ONE THING WHEN I WAS IN COLLEGE YEARS AGO, THERE WAS A RECRUITMENT STUDY. ONE OF THE REQUIREMENTS OR WHAT YOU WOULD GET IF IN THE STUDY, YOU MIGHT WIN A CAR. AND SO OF COURSE I DID CALL. THEY SAID IT WAS A RAFFLE BUT HOW IT WAS WORDED IT WAS LIKE YOU WOULD GET A CAR. SO SOMETIMES HOW THINGS ARE WORDED AS WELL THAT COULD BE COWE ARESIVE. COWE ARESIVE -- COERCIVE. >> WHAT YOU HAVE SAID ACTUALLY CONFIRMS WHAT OUR STUDY WAS ABOUT. P IRBs DO WORRY WHETHER PAYMENT COERCES. THIS ARTICLE WHICH YOU HEARD SOME TODAY, MISCONCEPTIONS ABOUT COERCION ARGUES THEY SHOULD STOP -- THEY'RE NOT THINKING RIGHT WHEN THEY THINK OFFERS OF PAYMENT COERCE. UNDUE INFLUENCE SHOULD ASK WHETHER PEOPLE WHO -- THIS WOULD BE THE QUESTION. IF SOMEBODY PARTICIPATES IN EXCHANGE FOR THE MONEY, DO WE HAVE REASON TO THINK THEY'RE MAKING A REASONABLE JUDGMENT, THAT THE VALUE OF THE PAYMENT COULD ADEQUATELY COMPENSATE THEM FOR RISK. IF THEY ARE, THERE'S NO UNDUE INFLUENCE AND I WOULD SAY GO FOR IT. IF YOU'RE WORRIED THE PAYMENT IS GOING TO DISTORT PEOPLE'S JUDGMENT, THEN THAT WOULD BE A WORRY, A REASON TO SHY AWAY. BUT THERE'S IN EVIDENCE IT DOES ACTUALLY DISTORT. I THINK THESE TEND TO BE SORT OF VERY -- THE WORRIES ARE THERE. BUT I THINK THE WORRIES -- THERE ARE PEOPLE THAT DISAGREE WITH ME, OBVIOUSLY, ABOUT MY ANALYSIS OF COERCION UNDUE INFLUENCE. I THINK THEY'RE MISTAKEN BUT I NEED TO TELL YOU IN HONESTY, THERE ARE PEOPLE THAT DISAGREE AND HAVE A DIFFERENT VIEW ABOUT IT. BUT I THINK MOST ARE JUST MISPLACED. ONCOLOGY STUDIES ARE NOT THE BEST ARENA FOR GETTING PEOPLE TO PARTICIPATE IN EXCHANGE FOR MONEY. IT MAY NOT BE HELPFUL IN CERTAIN KINDS OF RESEARCH. BUT THAT WOULD BE AN EMPIRICAL QUESTION, NOT A MORAL QUESTION. >> DO WE KNOW STUDY THAT SHOWS RECRUITMENT WILL BE DIFFERENT OR WAS DIFFERENCE WHEN YOU DISCUSSED BEFORE THE CONSENT AND AFTER THE CONSENT. >> BEFORE THE CONSENT AND AFTER CONSENT. IN OTHER WORDS WE DON'T TELL THEM THEY'RE PAID BUT THEN WE PAY THEM MINI? >> YOU TELL THEM AFTER THE CONSENT. DO THEY RECRUIT DIFFERENCE? IF WE PAY AFTER CONSENT WE'RE NOT USING PAYMENT AS INCENTIVE. WE MIGHT SOMETIMES JUST AS TOKEN OF APPRECIATION OR GRATITUDE PAY PEOPLE, AND I CAN'T SEE WHY THERE WOULD BE ANY PROBLEM IN GENERAL WITH THAT. THE WORRIES THAT I'M WORRYING ABOUT ARE THE WORRIES ABOUT PAYMENT COMPROMISING THEIR CONSENT BEFORE THEY CONSENT. NOW, ANOTHER WORRY RELATES TO SOMETHING DAVID WENDLER SAID, WHAT ABOUT STUDIES THAT PAY COMPLETION BONUSES. WHAT ABOUT SAYING YOU'RE GOING TO GET $1,000 IF YOU ENROLL IN THE STUDY AND GET ANOTHER $1,000 IF AND ONLY IF YOU COMPLETE. DOES THAT COMPROMISE FOR EXAMPLE THE RIGHT TO WITHDRAW FROM THE STUDY AT ANY TIME? IS IT COERCING THEM TO STAY IN THE STUDY? THERE MAYBE WORRIES ABOUT COMPLETION BONUSES BUT I DON'T THINK COMPLETION BONUSES COERCE. >> THANK YOU. JUST WANT TO FOCUS MORE ON THE BENEFITSES, SO IS IT MORALLY ETHICAL TO NOT PAY SOMEONE AND RESEARCHERS HAVE A HUGE FINANCIAL GAIN AFTERWARDS? WHAT ARE YOU THOUGHT'S >> I'M SORRY. YOU'RE NOT GOING TO -- >> YOU'RE NOT PAYING ANY RESEARCH SUBJECTS BUT SAY IT'S A NEW INTERVENTION OR SORT OF GENETIC TEST OR SOMETHING. AND RESEARCHERS STAND TO GAIN A LOT OF MONEY IF HYPOTHESIS TURN OUT TRUE, IS IT ETHICAL TO NOT PAY -- >> RIGHT. THERE YOU HAVE WHAT I WOULD CALL NOT A CONSENT WORD BUT A FAIRNESS WORD. YOU HAVE -- IS IT FAIR, IS IT JUST WHEN RESEARCHERS MIGHT MAKE A LOT OF MONEY ON THE RESEARCH BUT THE PARTICIPANTS DON'T GET ANY BENEFIT FROM WHAT THEY HAVE CONTRIBUTED TO THE RESEARCH. THAT'S A DIFFICULT QUESTION, WE HAVE AN IMPORTANT LEGAL CASE THAT CAME OUT OF RESEARCH IN CALIFORNIA IN WHICH THAT QUESTION WAS MORE I THINK IS IT VERSUS CALIFORNIA IT WOULD TAKE LONGER THAN YOU WANT TO SPEND TO GIVE AN ADEQUATE -- >> CAN WE SAVE IT FOR ANOTHER TIME. >> SAVE IT FOR ANOTHER TIME. >> WE'RE EATING UP THE BREAK. IF WE HAVE TWO SHORT QUESTIONS WE'LL TAKE THEM. >> HOW DO YOU DETERMINE A PATIENT MAKING A REASONABLE JUDGMENT? FIRST OF ALL. THEN IS ALL OF THIS THINKING ABOUT CONCERNS FOR THE PATIENT OR THINKING LEGAL REPERCUSSIONS LIKE PROIT CANNING -- PROTECTING YOURSELVES AN RESEARCH BECAUSE IF SOMETHING GOES WRONG THE PATIENT CAN COME BACK AND SUE. WHAT'S THE MOTIVE? Q. I WASN'T WORRIED. I WASN'T TALKING ABOUT THE LEGAL -- ABOUT THE LEGAL DIMENSION. THE FIRST QUESTION CONCERNED? >> WHAT'S REASONABLE. >> I'M SORRY. YES. (OFF MIC) >> YEAH. THAT'S VERY TRICKY. IT'S VERY TRICKY. HOW DO WE DETERMINE WHETHER SUBJECTS ARE MAKING A REASONABLE JUDGMENT? I DON'T KNOW QUITE HOW TO DO THAT. WE CAN FINE OUT WHETHER SUBJECTS ARE PAYING ATTENTION TO THE RISK OF PARTICIPATION, THAT WE CAN FIND OUT. AND WE CAN I THINK AT LEAST ASSUME IF THEY'RE PAYING ATTENTION TO THE RISK AND ACTUALLY WE HAVE GOOD REASON TO THINK WHEN YOU PAY PEOPLE THEY'RE MORE SENSITIVE TO THE RISK THAN WHEN YOU'RE NOT. IF THEY'RE PAY MEG TO DO THIS WHY ARE THEY PAYING ME? I BETTER THINK ABOUT THAT. SO WE HAVE GOOD REASON TO THINK -- REASON TO THINK SUBJECTS WHO ARE PAID ARE IN FACT SENSITIVE TO RISK. THERE'S GOOD STUDIES THAT SHOWS WHEN YOU INCREASE PAYMENT IT DOES NOT IN FACT LEAD TO MYOPIA OR TUNNEL VISION THAT I DESCRIBED. >> ANY STUDIES LOOKING HOW RESEARCH ENROLLMENT RELATES TO UNEMPLOYMENT? IN THE HARD TIMES OF UNEMPLOYMENT IF THERE ARE MORE THAT ENROLL IN RESEARCH STUDY, VICE VERSA. >> I DON'T KNOW. INTERESTING AREA FOR RESEARCH. >> THANK YOU VERY MUCH. WE'RE GOING TO BREAK. WE'RE ALREADY PAST THE TIME SO MAKE IT SHORT. TEN MINUTES, PLEASE. AND THEN WE'LL DO THE LAST SESSION. >> PEDIATRIC INTENSIVE CARE AND RESIDENCES KNEW IF I EVER SAT DOWN ROUNDS WOULD NEVER END SO THEY HAD TO KEEP ME WALKING. SO I'M GOING TO BASICALLY WALK THROUGH THESE CONCEPTS. LET ME TIE IT TO SOMETHING AL ALABAMA LISTEN SAID. THE ISSUE IS NOT WHETHER PARENTS COULD CONSENT TO ENROLL CHILDREN WITH DEFICIENCY INTO THE STUDY. THE DIFFICULTY WAS THAT THAT WASN'T APPROVABLE UNDER THE DETECTION BUT THE PARENTAL PERMISSION WAS AN IRRELEVANT CONSIDERING. SO I'M GOING TO WALK THROUGH WHY THAT'S THE CASE. THAT'S THE LAST PROTECTION WE GET TO, WE HAVE OTHER ADDITIONAL SAFEGUARDS. THE SLIDES WILL BE AVAILABLE SO IF I SKIP THROUGH THEM, BEAR WITH ME. SO THERE'S FOUR BASIC ETHICAL PRINCIPLES BEHIND THE PEDIATRIC REGULATIONS. YOU HEARD DAVE TALK ABOUT SCIENTIFIC NECESSITY. THE FIRST IS, IS IT NECESSARY TO USE CHILDREN IN RESEARCH OR NOT? IF THE ANSWER IS NO, DON'T DO IT. IF YOU CAN GET THE ANSWER BY ENROLLING ADULTS WHO CAN CONSENT YOU SHOULD DO THAT. ALSO SPOKE ABOUT ENROLLING ADOLESCENTS BUT ADDITIONAL PROTECTIONSTOR CHILDREN COVER ANYONE WHO IS A CHILD WHICH BY DEFINITION UNDER MOST CIRCUMSTANCES ARE THOSE WHO ARE LESS THAN 18 YEARS OF AGE. THE SECOND ONE, ABSENT A PROSPECTIVE OF DIRECT THERAPEUTIC BENEFIT TO THAT CHILD, RISK MUST BE LOW. ISLE SHOW YOU HOW THAT WORKS OUT IN THE REGULATIONS. THIRD IS CHILDREN SHOULDN'T BE PLACED AT A DISADVANTAGE BY BEING ENROLLED IN A CLINICAL TRIAL. AS OPPOSED TO WHAT THEY OTHERWISE MIGHT RECEIVE. BOTH ARE ADDITIONAL PROTECTIONS BEYOND WHAT WE OFFER ADULTS WHO ENROLL IN CLINICAL RESEARCH. HOW CAUSE APPLY? HERE IS THE GENERAL REGULATIONS FOR THOSE WHO ARE USED TO SEEING 45CFR-46 SINCE I JOINED THE FDA I STARTED AS A MATTER OF PRINCIPAL TO ONLY USE THE FDA ONES BECAUSE PEOPLE FORGET THERE ARE FDA REGULATIONS WHICH READ EXACTLY THE SAME. THESE ARE CITATIONINGS. 21CFR-561,182, THIS WOULD OTHERWISE BY 45-CFR-111A-2. SO HERE WHAT'S IMPORTANT? YOU CAN ENROLL SUBJECTS IF ANTICIPATEED BENEFITS, IFNY, WHAT THAT IFNY MEANS IS YOU CAN -- IF ANY. YOU CAN BALANCE RISK AGAINST KNOWLEDGE SO YOU CAN ASK A COMPETENT ADULT TO GIN TO PHASE 1 TRIAL TO SEE IF THAT -- LOOK AT THE PHARMACOKINETIC OF THAT PRODUCT, MAYBE TOXICITY, MAXIMUM TOLERATED DOSE. YOU CAN DO PHASE 1 TRIALS, YOU CAN DO CHALLENGE EXPOSURES, YOU CAN DO PESTICIDE RESEARCH, GIVE ADULTS PESTICIDES. WITH THEIR CONSENT. BOTTOM LINE IS, YOU CAN'T DO THAT WITH KIDS. WE HAVE THESE ADDITIONAL PROTECTIONS. WHAT ARE THESE? FIRST IS, IF THERE'S NO POTENTIAL FOR DIRECT BENEFIT, THE CHILD GOING IN THAT RESEARCH WILL NOT RECEIVE POTENTIAL FOR DIRECT BENEFIT THE RISK MUST BE LOW AN LANGUAGE WE USE IS MINIMAL OR MINOR INCREASE OVER MINIMAL. TWO REGULATIONS HERE, OR IF THERE IS POTENTIAL FOR DIRECT BENEFIT FOR THE CHILD, THE RISKS MUST BE JUSTIFIED BY THE BENEFIT AND THE BALANCE MUST BE FAVORABLE AS AVAILABLE ALTERNATIVES. IF YOU LOOK BACK AT THE NATIONAL COMMISSION'S REPORT IN THE '70s AS THEY WERE THINKING ABOUT THIS, THEY ARGUED THIS IS SIMILAR TO THE CLINICAL DECISION MAKING. HOW YOU UNDERGO ANY INTERVENTION. ARE THE RISKS REASONABLE IN TERMS OF WHAT YOU ANTICIPATE HOPING TO ACHIEVE AND IS IT EQUAL TO THE OTHER ALTERNATIVES. THE FOURTH PRINCIPLE IS PERMISSION. SO MY ARGUMENT IS AS YOU WALK THROUGH THESE PROTECTIONS, FIRST IS SIGN ACTIVIC NECESSITY, DO YOU NEED TO USE CHILDREN TO ANSWER THAT QUESTION, YES OR NO. THE SECOND IS APPROPRIATE BALANCE OF RISK AND BENEFIT AND ONLY THEN DO YOU GET TO PARENTAL PERMISSION AND CHILD DECENT. MOST MY WORK T A FDA IS AROUND THE FIRST THREE. IF YOU SOLVE THOSE YOU CAN FIGURE OUT THE AACCEPT AND PERMISSION COMPONENT. THE FIRST THREE THAT ARE HARD. THESE SUB PART D, NOT GOING THROUGH THAT AND I TALK ABOUT PRINCIPLES OF SCIENTIFIC NECESSITY. WHERE IS THIS IN THE REGULATION REGULATIONS. IN THE EQUITABLE SELECTION. YOU HEARD DAVID TALK SELECTION. WE THINK ABOUT SELECTION IN IN TERMS OF ECONOMIC, ETHNICITY, GENDER. THE NATIONAL COMMISSION WHEN TALKING ABOUT EQUITABLE SELECTION IN PEDIATRICS TALKED ABOUT ADULTS BEFORE CHILDREN. THAT'S HOW THAT WAS INTERPRETED. SO THAT'S WHERE I PERMLY LINK IT IN THE REGULATIONS. BEING AD THE FDA IF I CAN'T LINK TO THE REGULATIONS I'M IN TROUBLE. SO THE WAY I CONSIDER THIS IS THERE'S TWO PATHWAYS ONE CAN GO IN TRYING TO DO PEDIATRIC PRODUCT DEVELOPMENT. ONE IS LOW RISK PATHWAY, THE OTHER IS THE HIGHER RISK PATHWAY. SO WITH THIS PATHWAY, YOU NEED INFORMATION THAT TELLS YOU THE RISKS ARE LOW ENOUGH YOU DON'T HAVE TO WORRY ABOUT BENEFIT TO THE CHILD. I'LL SHOW YOU AN EXAMPLE LATER. THIS ONE, HIGHER RISK PATHWAY, YOU NEED EVIDENCE THAT THAT CHILD MAY BENEFIT FROM THAT INTERVENTION, THIS IS IS PROBLEM WITH JESSIE GELSING WE ARE THE GENE TRANSFER STUDY OF OTC DEFICIENCY. THEY DIDN'T HAVE AN ANIMAL MODEL. THEY DIDN'T HAVE SUFFICIENT EVIDENCE, IF THEY GAVE IT TO A NEONATE THAT THERE BE PROSPECT OF DIRECT BENEFIT. WHAT DO THEY DO? ENROLLED ADULTS. WE OFTEN FORGET BECAUSE JESSIE'S DAD AT THE TIME THIS HAPPENED, LESS SO RECENTLY BUT OVER ENSUING DECADE WE FORGET JESSIE WAS AN ADULT, HE'S 18 YEARS OLD. SO THE PEDIATRIC REGULATIONS DIDN'T APPLY. HE WAS CONSENTED LIKE THE OTHER INDIVIDUALS IN THAT TRIAL AS AN ADULT. TWO KEY CONCEPTS. PROSPECT OF DIRECT BENEFIT AND THE OTHER P COMPONENT ANALYSIS. WHAT'S THE DIRECT BENEFIT? LET'S START FIRST IF YOU GIVE ME $20, IS THAT A BENEFIT TO ME? IS IT? IF ALL GAVE ME $20, THAT WOULD BE GREAT BENEFIT THOUGH VIOLATION OF FEDERAL REGULATION REGULATIONS. I CANNOT ACCEPT THAT. 15 I COULD ACCEPT INDIVIDUALLY BUT I THINK NOT 20. THE POINT IS, IT'S MY BENEFIT. SO IF YOU'RE TALKING DIRECT BENEFIT WITH MY BENEFIT, NOT YOUR BENEFIT, WE GENERALLY TALK ABOUT FROM THAT RESEARCH INTERVENTIONS. IN OTHER WORDS, IF I SAY THERE'S DIRECT BENEFIT OF ENROLLING IN A TRIAL, IF YOU GET THAT RESEARCH INTERVENTION THERE'S A POTENTIAL FOR BENEFITING. I'M PILEING A LOT OF HEALTHCARE IN THAT TRIAL. IN OTHER WORDS THERE'S A BENEFIT BECAUSE I'M GOING TO -- WE'RE GOING TO DO A PHYSICAL AND I'M GOING TO TREAT YOUR SORE THROAT, ET CETERA. WHAT WE'RE REALLY TALKING ABOUT IS BENEFIT FROM THE INTERVENTION BEING STUDIED. IT HAS NOTHING TO DO WITH MY INTENTION AS CLINICAL INVESTIGATOR. IT HAS TO DO WHAT I'M PLANNING TO DO. AS DAVID ALLUDED, EVERYBODY IS OPTIMISTIC. IF YOU ASK ANY INVESTIGATOR, THEIR INTERVENTION WILL OFFER BENEFIT TO ANYONE WHO GETS IT. THE QUESTION IS HAVE THEY STRUCTUREDED IT THAT WAY. WHAT'S THE DOSE, DURATION, WHAT'S THE EVIDENCE. IN ORDER Y'ALL CAN JUDGE WHETHER OR NOT WHAT I'M PLANNING TO DO DOES OFFER DIRECT BENEFIT OR NOT. SO IT'S BASED ON THE STRUCTURE OF THE INTERVENTION, NOT MY INTENTIONS. THAT GETS YOU TO LEVEL OF EVIDENCE. WHAT THE LEVEL OF EVIDENCE. YOU DON'T NEED EVIDENCE THAT IT'S EFFECTIVE. THAT WOULD CREATE A STANDARD NO RESEARCH PROJECT COULD MEET. YOU NEED SOME EVIDENCE THERE'S A PROSPECT OF DIRECT BENEFIT. YOU'RE TESTING WHETHER IT'S EFFICACIOUS. THAT'S THE CHALLENGE, HUMAN DATA, PEDIATRIC, WHATEVER HUMAN DATA YOU HAVE, YOU MAY HAVE OFF LABEL DATA IF IT IS A MARKETED PRODUCT. ANIMAL MODEL THAT'S GREAT. THE BEST ANIMAL MODEL FOR HUMAN CHILD, IS ADULT HUMAN WITH THE SAME DISEASE. SO P IF YOU HAVE THAT, EVEN BETTER. WHAT'S THE DATA. CAN DOES IT MAKE YOU REASONABLY COMFORTABLE. THAT'S SQUISHY LANGUAGE BUT HEAR O TO MAKE IT MORE PRECISE. IS IT ADEQUATE TO PROVIDE BENEFIT. WHEN I ASK QUESTIONS ABOUT IS IT ETHICAL TO DO THIS PHASE 1 TRIAL IN PEDIATRICS, THE QUESTION IS, WHAT'S THE EVIDENCE THERE'S PROSPECT OF DIRECT BENEFIT AND IS THE DOSE CORRECT AND TO WHAT EXTENT IS THAT PROVIDED. WHAT'S COMPONENT ANALYSIS. YOU NEED TO LOOK AT THE INDIVIDUAL INTERVENTIONS IN THE TRIAL THE AND NOT THE OVERALL PROTOCOLS ITSELF. WHAT YOU AVOID IS THE FALLACY OF PACKAGE DEAL. I CAN HAVE THIS INTERVENTION WHICH IS RISKY AN OFFERS NO BENEFIT AT ALL. BUT I'M GOING TO IN THAT TRIAL PACKAGE ALL OF THESE OTHER THINGS IN IT LIKE HEALTHCARE, FREE THIS, FREE THAT. WHATEVER. IF PHYSICIAN VISITS. SO FORTH. FREE CARE FOR A YEAR. I CAN'T JACK UP THE BENEFIT TO COVER RISK OF THE PROCEDURE. YOU HAVE TO LOOK AT THESE INDIVIDUALLY. SO YOU HAVE TO LOOK AT EACH RESEARCH INTERVENTIONS AND ASSESS THEM INDIVIDUALLY AS TO WHETHER OR NOT THEY DO OR DO NOT OFFER PROSPECT OF DIRECT BENEFIT. HOW MANY ARE IRB MEMBERS HERE? DO YOU DO THIS? NOW, THIS COULD BE OWNERSOME. I'M NOT BURDEN DENSOME, NOT SAYING YOU NEED TO LOOK AT EVERY SINGLE BLOOD TEST BUT YOU GROUP THEM BLOOD TESTS, ET CETERA, GENERALLY GROUP THEM. AND YOU ASSESS THESE DIFFERENTLY. THERE WAS A PROTOCOL THAT SINCE THIS IS IN PUBLIC DOMAIN, I'LL MENTION THAT RANDOMIZED PLACEBO CONTROLLED TRIAL OF A PRODUCT THAT REQUIRED INFUSION EVERY DAY FOR TWO WEEKS, FOUR HOURS A DAY. SOMEI NOT ALL, 80% DID IT BUT 20% DID. AT THE REQUEST OF THE INVESTIGATORS THAT THEY ALLOWED THE PLACEMENT OF A PERCUTANEOUS CENTRAL LINE, DWELLING CENTRAL LINE FOR ADMINISTRATION OF THE INVESTIGATIONAL PRODUCT. WHAT WAS THE PROBLEM? IT WAS A BLINDED PLACEBO CONTROLLED TRIAL. SO THE KIDS GETTING THE PLACEBO HAD THE RISK OF A CENTRAL CATHETER WITH NO POTENTIAL BENEFIT OF RECEIVING THE INVESTIGATIONAL PRODUCT. AND THEY DIDN'T THINK THAT THROUGH TO ASK IS THAT AN APPROPRIATE RISK TO THE PLACEBO GROUP. THEY THOUGHT THROUGH THE FACT THAT PEDIATRICS LIKE TO DO THAT TO SAVE ADDITIONAL STICKS AND SO ON P AND SO FORTH. BUT THE MISTAKE THERE WAS THEY DIDN'T SEPARATE IT OUT AND LOOK AT THOSE TWO GROUPS SEPARATELY. AND ASK IS THAT APPROPRIATE RISK FOR PLACEBO GROUP TO UNDERGO. THIS IS A DEFINITION OF MINIMAL RISK IT'S MEANT TO SAY WHAT'S THE RISK GOING TO SEE YOUR PEDIATRICIAN FOR ROUTINE HEALTHCARE. OFFER RISK OF DAILY LIFE. THE NATIONAL COMMISSION PUT THE PHRASE OF HEALTHY CHILDREN IN THERE WHICH WAS REMOVED FROM REGULATION WHEN PUBLISHED IN 1,983. FDA DIDN'T ADOPT THESE UNTIL 2001 BUT ON THIS POINT THEY'RE THE SAME. EVERY COMMISSION SINCE THEN THINKS IT OUGHT TO BE LINKED TO HEALTHY CHILDREN. WHY? FROM THE PERSPECTIVE OF JUSTICE, TO ALLOW AGAIN RESEARCH THAT DOESN'T OFFER BENEFIT TO HAVE HIGHER RISK BECAUSE CHILDREN ARE EXPOSED TO HIGHER RISK IN DISEASE WAS THOUGHT PROBLEMATIC. AND THEY -- THERE'S ANOTHER CATEGORY WE'LL GET TO TO ALLOW THAT. NOW, LET'S TALK RISK OF EVERY DAY LIFE. WHAT DOES THAT TELL US ABOUT THE APPROPRIATE RISK THAT CAN BE ALLOWED IN THE RESEARCH PROJECT? ANYBODY HERE FROM THE MIDWEST? PRACTICES AND ALLOWING CHILDREN TO DRIVE FARM VEHICLES ON LOCALLY OWNED CURRENT OWNED FARMS. RISKY. THEY'RE DRIVING COMBINE, ATVs, ALL SORTS OF THINGS. IT'S RISKY. THERE'S SOME I SAW ON TV A COUPLE OF YEARS AGO IN ATV RODEO. PARENTS LETTING THEIR KIDS DRIVE ATVs OVER JUMPS AND THINGS. KID DOWN TO 6 AND 7 YEARS AND WENT FROM THAT PICTURE, KID WAS WEARINGING A HELMET TO A KID IN A WHEELCHAIR. DO WE THINK EVEN THOUGH WE ALLOW PARENTS TO MAKE THE DECISION TO LET KIDS RIDE ALL TERRAIN VEHICLES OFF ROAD IN THESE ACTIVITIES OR ON THE FARM DOING LABOR, WOULD THAT BE AN APPROPRIATE LEVEL OF RISK TO ALLOW A MINIMAL RISK RESEARCH STUDY TO INVOLVE? NOT ASKING FOR AN ANSWER, MY POINT IS THAT THIS IS MEANT TO BE AN APPLICATION WHICH REQUIRES SOME JUDGMENT, NOT PURELY DATA-DRIVEN ASSESSMENT, IT'S NOT JUST A QUESTION OF LOOKING AT PROBABILITY AND MAGNITUDE AND DOING THE MATH AND SAYING THAT RESEARCH IS THE SAME. MY ARGUMENT WHICH WOULD TAKE LONGER IS THAT IN FACT THIS MINIMAL RISK DEFINITION IS MEANT TO BE A MORAL DEFINITION. IT LOOKS STATISTICAL BUT MEANT TO BE A MORAL DEFINITION TO CAPTURE THE BOUNDARIES THAT WE NORMALLY ALLOW PARENTS TO MAKE AROUND THE DECISIONS FOR CHILDREN. THE KIND OF DECISIONS. WALK TO SCHOOL, TAKE A BUS TO SCHOOL, RIDE BICYCLE TO SCHOOL. THAT WOULD BE A DECISION EACH ONE OF THOSE RISK, LOCATION AND ROUTES, ET CETERA. WE LET PARENTS MAKE THAT E DECISION. SO THIS RISK CATEGORY IS MEANT TO CAPTURE BOUNDARIES AROUND PARENTAL DECISION MAKING WE ALLOW PARENTS TO MAKE. THE MERE FACT THAT A RISK OCCURS DOESN'T MEAN THAT ESTABLISHES MINIMAL RISK. THE NUMBER OF INJURIES IN CAR ACCIDENTS WITH CHILDREN THOUGH WE ALLOW PARENTS THE PUT KIDS IN CARS AN DRIVE THEM DOESN'T MEAN THAT'S THE LEVEL OF INJURY TO ALLOW MANY MINIMAL RISK RESEARCH. WE HAVE THIS OTHER CATEGORY, MINOR INCREASE OVER MINIMAL RISK SLIGHTLY BEYOND, NO CLEAR DEFINITION OF THIS T. IMPORTANT ONE HERE IS THAT CATEGORY IS LIMITD TO CHILDREN WITH A DISORDER OR CONDITION. DEBATE WHETHER OR NOT THIS IS APPROPRIATE, WHAT'S THE JUSTICE OR FAIRNESS OF EXPOSING CHILDREN WHO HAVE A DISEASE, GREATER THAN MINIMAL RISK TO RESEARCH. I WON'T GET TIN TO THAT DEBATE, ONLY POINT OUT THE COMPLEXITY IS AROUND THE DISORDER OR CONDITION AS WELL. HERE IS ONE DEFINITION, AN ESTABLISHED BODY OF SCIENTIFIC EVIDENCE OR CLINICAL KNOCK SHOWN TO NEGATIVELY EFFECT CHILDREN'S HEALTH AND WELL BEING OR DECREASE RISK OF DEVELOPING A HEALTH PROBLEM IN THE FUTURE. HOW MANY OF YOU WERE FOLLOWING OVER THE PAST YEAR OVER DEBATE IN TESTING ANTHRAX VACCINE IN CHILDREN ABSENT ANTHRAX EXPOSURE? ANYONE FAMILIAR WITH THAT DISCUSSION? YOUR OWN CHRISTINE GRADY IS ON THE PRESIDENTIAL COMMISSION OF BIOETHICS AND ASKED THE TO PRODUCE A REPORT ON THAT, SUPPOSEDLY COMING OUT IN DECEMBER OR JANUARY. QUESTION IS, ARE CHILDREN AT RISK FOR ANTHRAX? ARE THEY? SOME SAY YES, SOME SAY NO. NO MORE THAN ANYONE ELSE THAN WHAT'S OUR ANYONE ELSE RISK. POINT IS, THIS IS A COMPLEX QUESTION. HOW ABOUT SMALLPOX? ARE SMALLPOX? WHY DO WE SAY YES? WE SAY YES BECAUSE THEY'RE NOT IMMUNOCOMPETENT AGAINST SMALLPOX BUT WHAT'S THE REALITY OF A SMALLPOX EXPOSURE? EXCUSE ME? IT'S ERADICATED EXCEPT WHERE? IN TWO LABS TO OUR KNOWLEDGE. ONE IN ATLANTA, THE OTHER IN RUSSIA. SO MY POINT BEING, THE ASSESSMENT OF RISK OF SMALLPOX IS FIRST CLASSIFIED BUT SECOND OF ALL ASSUMES A BREECH IN SECURITY. ANTHRAX IS AVAILABLE AND CAN BE WEAPONNIZED. WE KNOW THAT. SO THAT RISK IS DIFFERENT. WHAT ABOUT MEASLES? ARE CHILDREN AT RISK FOR MEASLES? PERTUSSIS. LOOK WHETHER'S GOING ON IN WASHINGTON STATE, ABSENT VACCINATION. SO MY POINT IS, EVEN IF YOU LOOK AT INFECTIOUS DISEASE IN VACCINATION YOU HAVE THIS COMPLEX QUESTION OF RISK AND EXPOSURE AND DO THEY HAVE A CONDITION. ALL I'M SAYING IS THIS -- WHEN YOU GET INTO THE WEEDS, OF WHETHER CHILDREN DO OR DO NOT HAVE A CONDITION, IT CAN GET FAIRLY COMPLICATED. ONE EXAMPLE. OVER THE COUNTER COUGH AND COLD PRODUCTS NO PEDIATRIC DATA THAT JUSTIFY EFFICACY OR SAFETY OF OVER THE COUNTER COUGH AND COLD PRODUCTS. WE DON'T KNOW IF THEY WORK. THEY WERE GRANDFATHERED IN WHEN THE AMENDMENTS OF 1,962 WERE PASSED. AND GO INTO THE MONOGRAPH. SO THEY GET MARKETED. BUT WE HAVE NO DATA. AT ALL. SO IN AN ATTEMPT TO GET DATA PHARMACEUTICAL COMPANIES ARE DOING SOME OF THESE STUDIES SO THE QUESTION IS CAN YOU TAKE ANY CHILD AT ALL AND GIVE THEM A SINGLE DOSE OF AN ANTI-HISTAMINE IN A PHARMACOKINETIC STUDY? WELL, FOR BEAR OR WORSE, WE DECIDED THAT GIVING A DOSE OFFICIOUSAL DRUG IS NOT MINIMAL RISK. SOME MIGHT DISAGREE AND THE QUESTION IS WHAT'S THEIR CONDITION? POINT IS NOT ALL CHILDREN ARE EQUALLY AT RISK FOR COLDS. I DON'T KNOW, ANYONE, YOU'RE HERE SO ODDS ARE YOU MAY NOT BUT ANYONE HOME SCHOOL THEIR CHILDREN OR DID HOME SCHOOL THEIR CHILDREN? OR KNOW OF ANYONE THAT HOME SCHOOL THEIRS CHILDREN? MY BROTHER AND HIS WIFE HOME SCHOOL THEIR CHILD. AND I DONE -- SHE'S NOW 13. I DON'T THINK SHE'S EVER HAD A COLD IN HER LIFE. BECAUSE SHE'S NOT EXPOSED TO ANYBODY AT ALL. IF YOU LOOK AT THE RISK OF GETTING A COLD IT'S DAY CARE, SCHOOL SETTINGS, NUMBER OF CHILDREN IN THE HOME. ET CETERA. SO ONE CAN COME UP WITH A CHARACTERISTIC OF WHY ONE IS AT RISK OR IS NOT AT RISK. SO THAT'S THE LOW RISK PATHWAY. LET'S TALK ABOUT THE HIGHER RISK PATHWAY. RISK IS JUSTIFIED BY ANTICIPATED BENEFITS TO THE CHILD BALANCE WHICH IS AT LEAST AS FAVORABLE AS AVAILABLE ALTERNATIVES. SO THERE ARE TWO QUESTIONS HERE. FEST IS WHETHER OR NOT THE INTERVENTION OFFERS A PROSPECT OF DIRECT BENEFIT. THAT'S QUESTION ONE. QUESTION TWO, WHETHER THAT BENEFIT IS SUFFICIENT TO JUSTIFY THE RISKS. THE POINT IS, THIS IS A COMPLEX JUDGMENT. IT'S A JUDGMENT THAT HAS TO LOOK AT THE DISEASE STATE, SEVERITY OF THE DISEASE, ALTERNATIVES, SAME KINDS OF QUESTION, IS IT WORTH DOING IN A CLINICAL SETTING. DISEASE SEVERITY, ET CETERA. SO THAT'S WHAT WE'RE TALKING ABOUT WHEN WE TALK PROSPECT OF DIRECT BENEFIT. DEFINITELY A JUDGMENT CALL, WHAT IS THE ROLE OF ADULT HUMAN DATA? PEDIATRICS OVER THE YEARS AND CHILDREN OVER YEARS HAVE SUFFERED IN MY VIEW FROM LACK OF DATA ON THE USE OF PRODUCTS TREATING CHILDREN. PEDIATRICSES WENT OFF LABEL. -- PEDIATRICIANS GO OFF LABEL. IT'S MARKETED, AND IT WAS -- THAT WAS A RESULT OF OVERPROTECTED CHILDREN SAYING WE SHOULD ENROLL THEM IN PEDIATRIC STUDY, ONLY GET ADULT DATA. SO THE QUESTION IS HOW MUCH ADULT DATA DUE DOW NEED BEFORE INITIATING CLINICAL TRIAL? EFFICACIOUS IN ADULTS BEFORE YOU INITIATE A TRIAL WITH PEDIATRICS? THE ARGUMENT IS I THINK NO. OR MY ARGUMENT IS NO, EQUITABLE SELECTION DOESN'T IMPLY YOU HAVE TO HAVE COMPLETED ALL YOUR ADULT STUDIES BEFORE YOU START PEDIATRIC STUDIES. WHAT YOU DOA – NEED IS SUFF ICIENT PROOF OF CONCEPT, DIRECT BENEFIT THAT JUSTIFIES THE RISKS. SO YOU NEED SOME INFORMATION ON THE BENEFIT SIDE, ALSO FROM NON-CLINICAL ANIMAL STUDIES. IF OFF GOOD MODEL. YOU DONE, THAT'S A PROBLEM. YOU NEED SOME INFORMATION ON SAFETY SIDE. YOU SHOULD ENROLL ADULTS IF APPROPRIATE PRIOR TO ENROLLING CHILDREN NORTH TO GET THAT INFORMATION BUT IT'S NOT TO WHERE YOU HAVE TO PROVE IT'S EFFICACIOUS. JUST GETTING INFORMATION TO BE ABLE TO MOVE FORWARD DONE ERR ADDITIONAL SAFEGUARDS FOR CHILDREN AND RESEARCH. ONCE SUFFICIENT ADULT DATA EXISTS YOU CAN MAKE THIS DEVELOPMENT. WHETHER OR NOT YOU NEED FULLY ADEQUATE AND WELL CONTROLLED STUDY IN PEDIATRICS DEPENDS WHERE YOU CAN OR CAN'T EXTRAPOLATE. I'LL TALK ABOUT EXTRAPOLATION, IT AFFECTS HOW WE DECIDE AT THE FDA TO REQUIRE PEDIATRIC STUDY. SO EXTRAPOLATION IS DEFINED AS IF THE COURSE OF THE DISEASE AND RESPONSE THE TREATMENT IS THOUGHT SUFFICIENTLY SIMILAR. YOU MAYBE ABLE TO CONCLUDE THE PRODUCT WILL WORK PROVIDED YOU HAVE EVIDENCE ON THE APPROPRIATE DOSE TO USE. AND SAFETY DATA. YOU CAN EXTRAPOLATE EFFICACY. HOW THAT LOGIC WORKED OUT, THIS IS A FEW YEARS OLD BUT IT ACTUALLY INVOLVES NIAID. HIV VACCINE TRIALS. SO FDA WAS ASKED BACK IN AUGUST 2,007 ABOUT WHETHER OR NOT ADOLESCENCE COULD BE ENROLLED IN A TRIAL OF A VACCINE FOR HIV. THIS WAS THE ANSWER. DO NOT ENROLL ADOLESCENTS UNTIL AFTER INTERIM EFFICACY AND CELL IMMUNE MEDIATED DATA WERE AVAILABLE AND THERE WOULD BE A TREND. SO THERE WAS THE IDEA TO SHOW EFFICACY IN ADULTS BEFORE YOU ENROLL ADOLESCENTS BUT YOU HAVE TO SHOW A TREND IN FAVOR OF THE VACCINE. SO ONE CONCLUDES IF YOU'RE ENROLLED IN ADOLESCENT THERE'S PROSPECT OF DRUG BENEFIT. I DIDN'T TAKE A POSITION WHAT THAT TREND MIGHT BE POINT 2, POINT 3, WHAT'S THE P VALUE OF TREND. BUT THERE SHOULD BE A TREND. IF EXTRAPOLATION IS APPROPRIATE IMMUNE RESPONSE TO ADOLESCENT WOULD BE THE SAME AS ADULT, WHICH IS PROBABLY A REASONABLE ASSUMPTION, YOU WOULDN'T NECESSARY HI NEED TO HAVE ENOUGH ADOLESCENTS TO CONCLUDE ABOUT EFFICACY. BUT YOU WOULD WANT ENOUGH AD LESSENS TO MAKE CONCLUSIONS ABOUT THE IMMUNOGENICITY OF THE THE PRODUCT. SO YOU USE CELL MEDIATED IMMUNITY AND IMMUNOGENICITY DATA TO DO A COMPARISON AND DO WHAT'S DONE IN INFLUENZA VACCINE RESEARCH, BRIDGE USING THAT IMMUNOGENICITY DATA. RATHER THAN PEDIATRIC EFFICACY TRIAL. THAT WOULD BE BASED ON EXTRAPOLATION. THE RECOMMENDATION WAS NOT TO ENROLL ADOLESCENTS AT THIS TIME BUT WAIT UNTIL IT REACHED IT. THIS TURNED OUT TO -- THIS WAS THE SAME VACCINE WHICH RESULTED IN THOSE WHO WERE ADINOVIRAL 5 POSITIVE HAVING HIGHER INCIDENCE OF HIV INFECTION AND THE TRIAL WAS STOPPED SIX MONTHS LATER FOR THAT SIGNAL. LET'S TALK BRIEFLY ABOUT CHOICE OF CONTROL GROUP. THIS JUST LISTS THE DIFFERENT KIND OF CONTROLS THAT I WON'T GO INTO. THIS IS GOLD STANDARD BUT JUST AS GOOD. THERE ARE SOME OTHER ALTERNATIVES THAT EXIST. AS I MENTIONED IN THE EXAMPLE I GAVE ABOUT COMPONENT ANALYSIS, WHAT WE WANT TO BASICALLY SEE IS AN ANALYSIS BASED OF THE PLACEBO CONTROL GROUP ITSELF THAT HAS MORE NUANCE THAN LOOKING AT TWO GROUPS AS A WHOLE. SO THERE'S TWO TYPES OF RISK TO PLACEBO. RISK OF PLACEBO ITSELF, MAYBE MINIMAL, BUT THERE MAYBE -- MAY NOT BE MEN MALL. LET'S TAKE AN EXAMPLE OF SHAM INJECTIONS THE TRIAL IS A SHAM INJECTION, A FOUR HOUR INFUSION OF PLACEBO EVERY DAY FOR TWO WEEKS. SO THAT'S A SHAM INJECTION. THERE'S STUDY OF GROWTH HORMONE WHERE IT REQUIRED A WEEKLY INJECTION OF GROWTH HORMONE FOR TWO YEARS. YOU'RE YOU CANNING 104 SHAM INJECTIONS. -- YOU'RE TALKING 104 SHAM INJECTIONS. THAT'S THE FIRST RISK, PALACE BEACH THE SECOND IS RISK OF HARM FROM NOT RECEIVING PROVEN OR EFFECTIVE TREATMENT. SO THE PLACEBO GROUP HAS TWO RISKS, WHAT'S THE RISK OF PLACEBO AND WHAT'S THE RISK OF NOT RECEIVING THE ACTIVE COMPOUND NORTH RECEIVING WHAT WOULD BE OTHERWISE STANDARD OF CARE IF NOT IN THE TRIAL. BOTH TYPES MUST BE MINOR INCREASE OVER MINIMAL RISK. THE RISK TO WHICH CHILDREN EXPOSED WHEN THEY HAVE NO PROSPECT OF DIRECT BENEFIT TRUE FOR PLACEBO GROUP, NO NEURON A MINOR INCREASE OVER MINIMAL RISK. SO THAT'S THE SAME STANDARD THAT SHOULD BE APPLYD TO THE CONTROL GROUP. I WOULD ARGUE I'M NOT GOING TO SHOW YOU THE QUOTATIONS BUT THIS IS INTERNATIONAL CONFERENCE ON HARMONIZATION, CHOICE OF CONTROL GROUP, FOR THOSE INTERESTED IN TOPIC OF CHOOSING CONTROL GROUPS, I THINK THAT IS A GOOD READ, A FAIRLY COMPLEX DOCUMENT. THE WEIGHT DECLARATION OF HELSINKI, THIS IS ALSO CONSISTENT AT THIS POINT THOUGH THE WORLD MEDICAL ASSOCIATION IS OPENING UP THE DECLARATION OF HELSINKI FOR ANOTHER ROUND OF REVISIONS GIVEN 2014 IS THE 50th ANNIVERSARY OF DECLARATION OF HELSINKI. WHAT'S ACCEPTABLE PLACEBO REIS INCOME ONE IM INJECTION? STUDY OF (INDISCERNIBLE) WHICH IS GIVEN MONTHLY FOR INFANTS WHO ARE PREMATURE WHO HAVE OTHER KINDS OF CONGENITAL HEART DISEASE TO REPRESENT RSV INJECTION. THAT WAS INJ FOUR TIME AS MONTH. ONCE A MONTH INJECTION FOUR TIMES, PROBABLY NO BIG DEAL. MINOR INCREASE OVER MINIMAL RISK. 50 IM INJECTIONS, GROWTH HORMONE TRIAL, TWO YEARS, 104, ONCE A WEEK? PERIPHERAL IV LINES, WE OFTEN PLACE THEM TO DRAW CATHETERS. SHAM SURGERY. SHOULD WE ALLOW PEDIATRICS WHAT IS DONE IN ADULTS. PARKINSON'S DISEASE RESEARCH, BURR HOLES. SHAM KNEE SURGERIES. ET CETERA. SHOULD THAT BE DONE IN PEDIATRICS. SO LET'S TALK PARENTAL PERMISSION AN CHILD ASSENT. THE FIRST QUESTION IS WHO IS A CHILD? THE DEFINITION IS NOT OBTAIN LEGAL AGE FOR CONSENT. THE REASON THIS IS IMPORTANT IS 45 CFR-46 ALLOWS IRBs TO WAVE PERMISSION IF IT'S NOT A REASONABLE REQUIREMENT FOR PROTECTING CHILDREN. HAVE YOU WAIVED PARENTAL PERMISSION? WHAT WAS THE TRIAL. (OFF MIC) RIGHT. SEXUALLY TRAN MITTED DISEASE IN BIRTH CONTROL, DID YOU USE THE WAIVER UNDER 408C. MY POINT IS YOU DON'T HAVE TO DO THAT. THE WAY A CHILD IS DEFINED, I ASSUME IN STATE OF MARYLAND THOUGH NOT FOR SURE, IT WAS TRUE IN PENNSYLVANIA, TRUE IN WISCONSIN WHERE I WAS PREVIOUSLY. ADOLESCENT HAS A RIGHT TO CONSENT FOR TREATMENT OF HAS A LEGAL RIGHT TO CONSENT ORAL CONTRACEPTIVES AND FAMILY PLANNING, SO FORTH. THAT 14-YEAR-OLD OR 15-YEAR-OLD IS NOT A CHILD. ACCORDING TO THIS DEFINITION OF RESEARCH. THEY HAVE OBTAINED THE LEGAL AGE OF CONSENT. SO INSTEAD OF WAIVING PARENTAL PERMISSION UNDER FDA REGULATION, WHAT YOU'RE DOING IS NOT REQUIRED BECAUSE THAT CHILD CAN CONSENT FOR THEMSELVES. THAT MINOR IS NOT A CHILD FOR PURPOSES OF CONDUCTING RESEARCH. IT'S A DIFFERENT APPROACH, YOU ENUP IN THE SAME PLACE. MOST IRBs ONLY WAIVE PARENTAL PERMISSION GENERALLY IN CIRCUMSTANCES WHERE THEY BELIEVE THEY HAVE RIGHT TO ACCESS FOR THAT INTERVENTIONS. FDA REGULATIONS DO NOT INCLUDE THAT WAIVER, THAT'S THE ONLY DIFFERENCE BETWEEN FDA SUB PART D AN HHS SUB PART D. PARENTAL PERMISSION, AGREEMENT TO PARTICIPATE IN THE TRIAL, A WAIVER ONLY UNDER EXCEPTION FOR EMERGENCY RESEARCH, THERE'S WAVERS FOR INFORMED CONSENT, 45CFR 46 THINGS LIKE MINIMAL RISK SO FORTH, THERE IS NO WAIVER OF INFORMEDED CONSENT UNDER FDA REGULATIONS. HISTORICALLY THAT'S DUE TO THE FACT THAT CONGRESS PASSED THE FDA INFORMED CONSENT LEGISLATION IN RESPONSE TO THALIDAMIDE IN THE 1960S BEFORE THE RULE EXIST SOD THE FDA REQUIREMENT FOR INFORMED CONSENT GOES TO 1960S PRIOR TO WHEN THE NATIONAL COMMISSION MET AND FORMULATED THE COMMON RULE TO MAKE IT MORE -- THE FDA SNOT A SIGNATORY TO THE COMMON RULE. THAT'S WHY WE HAVE OUR OWN REGULATIONS. THERE IS A FEW DIFFERENCES YOU MIGHT FIND. CHILD ASSENT IS JUST DEFINED AFFIRMATIVE AGREEMENT. THERE'S NO DISCUSSION ABOUT WHAT IT IS, WHAT IT'S NOT. JUST SAYS THE CHILD MUST AGRIA, AFFIRMATIVELY. SO THE QUESTION IS, IF YOU ASK A 6-YEAR-OLD, MAY I DRAW A BLOOD TEST AND THE SIX YEAR OLD GOES WHAT IS THAT? IS THAT AFFIRMATIVE AGREEMENT? HARD TO SAY, I PREFER YES LIKE THAT. YOU COULD EVEN SAY TO THE CHILD IT'S FINE IF I DRAW YOUR BLOOD, WHAT SHOULD I DO IF YOU FLINCH? SHOULD I ASSUME YOU HAVE CHANGED YOUR ANSWER TO NO AND LET THE KID SAY, GO AHEAD AND TAKE THE BLOOD. THE PROBLEM WITH THIS, YOU CAN DEBATE WHEN YOU LIMIT -- WHEN YOU DECIDE A CHILD IS NOT CAPABLE, SINCE THAT'S NO DEFINITION OF WHAT ASSENT IS, THERE'S VARIABILITY ASSENT MUST BE THE SAME AS CONTENT, IN OTHER WORDS THE RISK BENEFIT ANALYSIS AND SO FORTH THE AGE WHICH AN ADOLESCENT CAN DO THAT IS PROBABLY AROUND 13, 14, 15, YEARS OF AGE. THAT'S WHAT THE DATA WOULD SUGGEST. AD LESSEN OF THAT AGE IS JUST AS GOOD AS ADULT. FLIP SIDE TO SAY JUST AS BAD ADULT BECAUSE THE DATA SUGGESTS THAT WE'RE NOT VERY GOOD AT RISK ASSESSMENTS IT WOULD BE INTERESTING THAT ALAN WAS SAYING LOOK AT IMPACT OF INCENTIVES ON DECISION MAKING BECAUSE THAT DECISION MAKING IS BAD ANYWAY. COULD BE MAKE IT BETTER IF PEOPLE PAID MORE ATTENTION. MY OWN BIAS IS IT HAS AN EXPERIENCE OF THIS CHILD. THE ONLY DIFFERENT IS THIS CHEMOTHERAPY DRUG VERSUS THAT ONE THAT'S THE DIFFERENCE? YOU MIGHT WAIVE ASSENT DEPENDING ON THE DISEASE. BUT MY POINT IS FROM THE EXPERIENCE OF A CHILD IS TRIVIAL. BECAUSE THEY'RE GOING TO BE INTERIM LOCKED UP UNDER ISOLATION, SICK, LOSING THEIR HAIR, VOMITING, MUCOUS ITIS, NO MATTER WHAT THEY DECIDE. WHAT DO YOU TELL THEM? NO MATTER WHAT YOU DECIDE, IT WILL BE THE SAME. IT WILL SUCK. IS THAT OKAY? IF YOU'RE GOING TO GET A SENSE. MY POINT IS ASEPTEMBER SHOULD BE REALLY -- ASSENT SHOULD BE GEARED TOWARDS THAT. PART OF MY ARGUMENT FOR THAT IS YOU NEED THE LOOK AT CHILD ASSENT AND PARENTAL PERMISSION TOGETHER. WE'RE NOT EXPECTING THE CHILD TO MAKE DECISION THAT PARENT IS GOING TO BE MAKING. THE PARENT SAYS I THINK THIS IS AN APPROPRIATE PROTOCOL FOR MY CHILD TO BE IN AND THEN YOU APPROACH THE CHILD. I'M NOT -- THE PROCESS OF HOW YOU DO THIS IS COMPLEX. SO SOME CHILDREN WAN TO BE APPROACHED SEPARATELY, SOME WAN TO BE APPROACHED TOGETHER. I THINK PEDIATRIC RESEARCHERS, THE PLEXTY OF TRYING TO DECIDE IF THAT CHILD IS BEING, QUOTE, UNDULY INFLUENCED BECAUSE OF THEIR KNOWLEDGE OF THE PARENT'S DESIRE TO BE IN THE PROTOCOL IS COMPLEX. THERE'S SOME CHILDREN WHO WOULD BE UNABLE TO SAY NO IF THEY KNOW THEIR PARENT SAYS YES. THAT'S VERY COMPLEX. THE POINT IS YOU NEED TO VIEW THESE THINGS TOGETHER TO GO TOGETHER CONCEPTUALLY. THE BURDEN ON ASSENT IS NOT THE SAME AS BURDEN ON PARENTAL PERMISSION. THAT'S PART OF THE ARGUMENT WHY ASSENT IS A MUCH MORE MINIMALIST APPROACH BUZZ YOU'RE ASSUMING PARENTAL PERMISSION LOOKING AT THE OTHER PLEXES. -- COMPLEXES. I'M NOT GOING TO GO THROUGH ASSURING COMPLIANCE BECAUSE THAT'S MORE FDA KIND OF THING. SO I'LL JUST END AND WE HAVE GOT NINE MINUTES FOR QUESTIONS, AT LEAST BY THAT CLOCK. [APPLAUSE] IF THERE ARE I'LL TRY TO SAY SOMETHING MORE CONTROVERSIAL. >> >> THE DEFINITION OF CHILDREN -- >> LEGAL AGE TO CONSENT. WHAT IT DOES RAISE IS AN INTERESTING QUESTION. SO IF YOU'RE CONDUCTING RESEARCH WHERE PROTECTING AD LESS ISN'T CONFIDENTIALITY IS IMPORTANT, THEN PART OF THE CONSENT PROCESS WITH THAT ADOLESCENT YOU DECIDED HAS THE RIGHT TO SAY GET FAMILY PLANNING SERVICES AND SO FORTH, IS THE INSURANCE. BECAUSE THE LAST THING YOU WANT TO HAVE HAPPEN IS THEY COME IN FOR A VISIT THAT GETS CHARGED TO PARENT'S INSURANCE BILL AND UP COMES GEE, WHAT IS THIS THAT HAPPENED? ET CETERA. SO THERE ARE SOME VERY INTERESTING QUESTIONS AROUND CONFIDENTIALITY INSURANCE PAYMENTS BUT IT DOESN'T CHANGE THE CONSENT STATUTES. CHILDREN ARE STILL CHILDREN, THE THEY'RE IN THE HOME, THAT'S TRUE TO PROBABLY 40 AND 50. CERTAINLY DIDN'T CHANGE AT 26 BASED ON MY MOTHER'S (INAUDIBLE). >> I WAS HOPING YOU CAN TALK MORE ABOUT THE RELATIONSHIP BETWEEN THE DIRECT BENEFIT AND THE PHASE 1 TRIALS. BECAUSE THAT SEEMS COMPLEX. MY SECOND QUESTION, IS ALSO I WOULD BE INTERESTED IN YOUR THOUGHTS THE REAL REASONS WE HAVE A LACK OF RESEARCH WHETHER IT'S A REGULATORY ISSUE OR BROADER ISSUES OF DRUG COMPANIES BEING CONCERNED ABOUT LIABILITY, NOT WANTING TO CUT INTO THEIR MARKET. >> FIRST IS AN EASIER QUESTION. PHASE 1 RESEARCH IS MORE THAN MINIMUM RISK. I THINK WE'RE -- SO PHASE 1 PEDIATRIC RESEARCH FALLS UNDER THE SAME OBLIGATION AS PHASE 2 AND PHASE 3, TO MEET THE STANDARD OF PROSPECT OF DIRECT BENEFIT THAT JUSTIFIES THE RISK. THAT CAN BE A CHALLENGE. SO IF YOU LOOK AT THE ADULT -- THE WAY ADULT PHASE 1 TRIAL IS DESIGNED IS TO START AT SAY -- THEY MAY HAVE AN ANIMAL DOSE THAT (INAUDIBLE) LEVEL AND GO DOWN 1 HUB FOLD. THEY'LL GO REALLY SMALL AND -- 100 FOLD START SMALL AN GOWN FROM THERE. WITH PEED WHERE TRICK YOU CAN'T BE SO LOW THERE'S RACE AND NO BENEFIT SO IT'S TRYING TO -- NO RISK THERE'S RISK AND NO BENEFIT. SO YOU'RE NOT STARTING ABOVE A DOSE THAT MIGHT BE TOXIC BUT STILL GETTING DOSE RANGES RANGES SO MAYBE 80% TO 20% AROUND THE DOSE. WHAT DATA DO YOU HAVE TO SUPPORT THAT. IS THERE A NON-CLINICAL ANIMAL MODEL TO GIVE YOU THAT INFORMATION? SO THAT'S THEœ T:URJN„ I THINK YES, IT CAN. BUT THE BURDENNEN OF EVIDENCE ON INVESTIGATORS TO SAY YOU CAN DO THAT IS IMPORTANT. ON THE SECOND QUESTION, IF THE PHARMACEUTICAL -- WHAT'S CLEAR FROM THE EXPERIENCE OVER THE LAST 15 NOW ALMOST 20 YEARS INCENTIVES FOR DOING PHARMACEUTICAL RESEARCH PEDIATRICS IS ECONOMIC INCENTIVES WORK. PRIOR TO 199 # NO INCENTIVES AFTER 1997 SPONSORS GET MARKET EXCLUSIVITY ADDED. IF THEY DO IT'S ON REQUEST OF THE FDA. NICHD, THEY DONE GET EXCLUSIVITY BUT THERE'S A PROCESS,. THAT EXPLODED PEDIATRIC RESEARCH. THERE'S 400 SOME ODD LABELS SO THAT'S A LOT OF RESEARCH HAPPENING UNDER THAT. SO ECONOMIC INCENTIVES WORK. SO I GUESS -- I THINK THAT'S A LARGE PART, THERE WAS A CONSERVATISM ABOUT DOING ADULTS BEFORE KIDS. AND THEN ON TOP OF THAT, IF PEDIATRICIANS WERE WILLING TO USE PRODUCTS OFF LABEL WHICH THEY ARE, THERE'S NO INCENTIVE THEN TO WORRY BECAUSE THEY STILL MAKE MONEY OFF THE REVIEW. >> HI. I LIKE TO ASK HOW WOULD YOU HANDLE A SITUATION YOU PICTURE THE CHILD THAT LOSE HIS HAIR AND HAVE ALL THE SIDE EFFECTS OF THE TREATMENT. HOWEVER, THE PARENT WOULD RECOMMEND ONE,THE CHILD BEING A YEAR OLD IN THE CLINICAL TRIAL WHILE THE CHILD FEEL STRONGLY THAT'S NOT GOING TO PARTICIPATE IN IT. HOW WOULD YOU HANDLE SOMETHING LIKE THAT? >> IF I UNDERSTAND -- THE CHALLENGE IS THIS. WE CAN'T WAIVE PARENTAL PERMISSION BUT ALLOWD THE WAIVE CHILD ASSENT T. QUESTION IS, WOULD WE WAIVE IT? I THINK GENERALLY IF YOU'RE LOOKING AT ONCOLOGY RESEARCH, PARTICULARLY PHASE 3 ONCOLOGY RESEARCH, IS GENERALLY THE CHILDREN THAT ARE GOING INTO THOSE TRIALS, IT'S A STANDARD ARM AGAINST A NEW ARM. THE QUESTION IS, THE WAIVER IS IF THE BENEFIT IS NOT OTHERWISE AVAILABLE OUTSIDE THE RESEARCH, THE QUESTION IS, IF THEY DIDN'T GO INTO RESEARCH THEY CAN GET THE OLD STANDARD ARM. SO ARE YOU GOING TO GIVE THEM A SENSE OR NOT? EYE I'M NOT AN ONCOLOGIST. MY IMPRESSION IS THEY SPEND A LOT OF EFFORT RESPECTING THE CHILD'S VIEWS. AND THE LAST THING YOU WANT TO HAVE ON ANY PROTOCOL IS AN UNWILLING CHILD INSIDE THAT ISOLATION ROOM. SO WHETHER OR NOT IRBs DO OR DO NOT WAIVE ASSENT, RESPECT FOR CHILD'S WISHES IS HONORED IN MANY WAYS. SO I'M IN THE AWARE THAT THERE IS A BIG DIFFERENCE THERE BUT THERE'S A CHALLENGE. WOULD YOU WAIVE ASSENT. WAIVING ASSENT DOESN'T MEAN YOU DON'T LISTEN TO THE CHILD, IT JUST MEANS THAT YOU DON'T REQUIRE IT TO MOVE FORWARD WITH THE RESEARCH. COMPLEX QUESTION ABOUT HOW THAT WORKS OUT. I THINK PEDIATRIC ONCOLOGISTS ARE ADEPT AT MANEUVERING AROUND THOSE ISSUES. >> CAN YOU TALK MORE ABOUT DIVIDING I GUESS CHILDREN ADOLESCENTS VERSUS ADULTS? FOR EXAMPLE, IF YOU'RE TALKING ABOUT THE HIV VACCINE AND THE QUESTION OF REASONABLE TO ASSUME THAT ADOLESCENTS ARE THE SAME AS ADULT AND IF YOU EXTEND THAT WHEN DOES ADOLESCENTS BEGIN AND CHILDHOOD END? AND WHAT IS A REASONABLE AMOUNT OF EVIDENCE THAT YOU CAN ASSUME BIOLOGICALLY THEY'RE THE SAME? >> SO THE QUESTION YOU'RE GETTING AT IS EXTRAP PLACE. >> RIGHT. >> THE BOTTOM LINE, IT'S COMPLEX AND DEPENDS SOMEWHAT ON THE SPECIFIC PRODUCT. IF YOU LOOK -- IF YOU LOOK AT WHAT IS RECENT PUBLICATION IN PEDIATRICS IN THE LAST YEAR WITH JULIA DUNN WAS PRIMARY AUTHOR, DUNNE, THAT LOOKEDED AT WHAT FDA HAD DONE WITH STUDIES THAT WERE DONE UNDER A WRITTEN REQUEST, THE EXCLUSIVITY, THAT I MENTIONED. AND BY AND LARGE ABOUT 15% OF THEM WERE NO EXTRAPOLATION, MEANING TWO FULL RANDOMIZED CONTROL STUDIED, GOLD STANDARD, ET CETERA. ONLY 15% WERE COMPLETE EXTRAPOLATION. MEANING JUST GET PK DATA AND SOME SAFETY AND YOUR EAR DONE. THE -- YOU'RE DONE. MAJORITY, 70% WERE WHAT WE CALLED PARTIAL EXTRAPOLATION. THE WAY YOU COULD UNDERSTAND THAT IS WE THINK WE CAN EXTRAPOLATE BUTœG& WE'RE NOT SURE. SO THEREFORE WE DID SOMETHING TO IMPROVE OUR CONFIDENCE AROUND OUR ABILITY TO EXTRAPOLATE THE ADULT EFFICACY DATA TO PEDIATRICS. SO WHAT ARE SOME OF THOSE SOMETHINGs? IT COULD RANGE FROM ONE CLINICAL TRIAL TO VERIFY IT WORKS IN KIDS OR SOMETHING LIKE AN EXPOSURE RESPONSE STUDY. SO YOU HAVE A BIOMARKER AND THEN YOU DO EXPOSURE RESPONSE TO THAT BIOMARKER, USE THAT TO BRIDGE AND DO PARTIAL EXTRAPOLATION. A LOT OF WHAT'S GOING ON FALLSES INTO MIDDLE GROUND. WE THINK WE CAN EXTRAPOLATE BUT NOT SHOWER BECAUSE THE DATA IS NOT ROBUST, SO LET'S DO SOMETHING TO SUPPORT EXTRAPOLATION. RATHER THAN FULL GOLD STANDARD TWO PEDIATRIC TRIALS AN SUBSTANTIAL EVIDENCE OR NOTHING AT ALL. THAT REALLY IS PRODUCT SPECIFIC. SO IF YOU LOOK AT THE ARTICLE YOU SEE HOW IN THE DIFFERENT PRODUCT AREAS IT GOES THROUGH THE DIFFERENCE DIVISION, ALL THE WAYS THAT PLAYED OUT, IT DEPENDS ON THE DISEASE AND PRODUCT. IS IT A NEW MOLECULAR ENTITY, THE THINK ONE ALONG? WHAT EXPERIENCE. SO IT'S A COMPLEX QUESTION. >> THANKS. [APPLAUSE] >> FOR A GREAT LECTURE AND ALSO ENDING ON TIME.