TODAY THE THEME IS RISKS AND BENEFITS, AND THE ETHICS OF RESEARCH WITH CHILDREN. AND WE'RE GOING TO START OUR FIRST SESSION WITH A DISCUSSION OF RISKS AND BENEFITS, A REALLY IMPORTANT PART OF HOW WE THINK ABOUT THE ETHICS OF RESEARCH, AND OUR RESIDENT EXPERT IN OUR DEPARTMENT, DAVE WENDLER, WHO IS A PHILOSOPHER AND A SENIOR INVESTIGATOR IN THE INTRAMURAL PROGRAM, IS GOING TO TALK WITH YOU ABOUT RISKS AND BENEFITS. >> GOOD MORNING. ANYBODY AWAKE? SOMEBODY? ALL RIGHT. SO, CHRISTINE HAS BEEN DOING A SPECTACULAR JOB OF RUNNING THIS COURSE FOR A NUMBER OF YEARS NOW, AND I'VE BEEN GIVING SOME OF THE TALKS AND I REALIZE THERE ARE A LOT OF PEOPLE WHO TAKE THE COURSE WHO THINK, YOU KNOW, TWO, THREE HOURS OF BIOETHICS IN THE MORNING JUST ISN'T ENOUGH, WOULDN'T IT BE NICE IF THERE WERE JUST A CONTINUATION, SAY, AT NOON, AND FOR ALL OF YOU WHO HAVE BEEN THINKING THAT LAST WEEK AND YOU'RE GOING TO CONTINUE TO THINK THAT, WE'VE GOT GOOD NEWS NOON, SAME PLACE, RIGHT HERE, ETHICS GRAND ROUNDS, THE ETHICS OF ENROLLING PREGNANT WOMEN IN VACCINE TRIALS. SO I THINK YOU JUST GO GET YOURSELF A QUICK LUNCH AND COME BACK FOR THAT. IT SHOULD BE A GREAT SESSION. THAT'S THE WORD FROM THE SPONSOR. OKAY. I'M GOING TO TALK ABOUT RISK/BENEFIT ASSESSMENT AS CHRISTINE SAID, AND AT LEAST IN MY VIEW, THIS IS THE HEART OF RESEARCH ETHICS. BASICALLY WHAT CLINICAL RESEARCH INVOLVES IS, IT INVOLVES EXPOSING PARTICIPANTS TO RISKS AND BURDENS, SOMETIMES FOR THEIR OWN BENEFIT, BUT PRIMARILY TO TRY TO LEARN THINGS THAT CAN BENEFIT FUTURE SPAISHTS AND SO THE WHOLE PATIENTS, SO THE WHOLE QUESTION IS WHEN DO YOU FIGURE OUT WHEN THAT WHOLE PROCESS IS ETHICALLY ACCEPTABLE, WHEN IS IT ACCEPTABLE TO EXPOSE CURRENT PARTICIPANTS TO RISKS AND BURDENS TO LEARN THINGS THAT MIGHT BENEFIT PEOPLE IN THE FUTURE. THAT'S THE CHALLENGE BOTH OF RESEARCH ETHICS PRIMARILY AND ALSO THE CHALLENGE OF DOING AN APPROPRIATE RISK/BENEFIT ASSESSMENT. AND AS YOU'LL SEE ALTHOUGH IT'S THE HEART OF THIS, IT'S, A, VERY HARD, AND B, THERE'S A LOT OF IT THAT WE HAVEN'T WORKED OUT YET. SO FOR ANYBODY WHO'S INTERESTED IN BIOETHICS RESEARCH, THERE'S LOTS OF RICH OPPORTUNITIES HERE. ONE WARNING, THAT'S WHY I WAS MAKING SURE PEOPLE ARE AWAKE, I'VE SEEN THIS LECTURE GIVEN. THERE'S THE RESEARCH ETHICS 101 VERSION OF THIS LECTURE WHERE THEY SORT OF GIVE YOU THE BASICS AND IT'S GREAT BECAUSE THE SPEAKER THEN FEELS REALLY SMART BECAUSE THEY UNDERSTAND EVERYTHING THEY SAID AND THE AUDIENCE FEELS SUPER SMART BECAUSE THEY GOT EVERYTHING THE FIRST TIME THEY HEARD IT. THIS IS NOT THAT VERSION OF THE TALK UNFORTUNATELY. THIS IS THE VERSION OF THE TALK THAT INCLUDES THE BASE A BASICS BUT GOES BEYOND THOSE TO THINGS I DON'T UNDERSTAND AND HAVEN'T FIGURED OUT AND HOPEFULLY YOU GUYS CAN HELP ME WITH. SO EVERYBODY NEEDS TO BE A LITTLE BIT AWAKE, SO MAYBE YOU WANT TO SHAKE YOURSELF, OR MAYBE YOU SHOULD BE COMPLETELY ASLEEP SO YOU DON'T GET A HEADACHE FROM THIS. SO JUST TO START, BELMONT REPORT IS ONE OF IF NOT THE PRIMARY DOCUMENT ON THE ETHICS OF CLINICAL RESEARCH. THIS IS FROM THE 1970s, A RESULT OF THE NATIONAL NATIONAL COMMISSION'S WORK, AND BASICALLY WHAT THEY SAY IS WE'VE GOT TO FIGURE OUT HOW TO DO RISK/BENEFIT ASSESSMENT IN A SYSTEMATIC ACCURATE WAY, SO WHEN CHRISTINE FIRST CHARGED ME WITH GIVING THIS TALK I THOUGHT, WELL, THEY'VE BEEN DOING THIS FOR 40, 50 YEARS, PEOPLE HAVE COME UP WITH A SYSTEMATIC FRAMEWORK, I'LL JUST LECTURE ON IT AND I WON'T HAVE TO DO A WHOLE LOT OF WORK. UNFORTUNATELY IT TURNS OUT THAT THERE AREN'T ANY EXISTING FRAME WORKS, SO WHAT I'VE BEEN TRYING TO DO AS PART OF THIS TALK OVER THE YEARS IS TO DEVELOP AND REFINE A FRAMEWORK, WHICH I'LL PRESENT TODAY. SO A COUPLE THINGS, LIMITS ON THE SCOPE OF THIS TALK, I'M ONLY GOING TO -- OR AT LEAST PRIMARILY TALK ABOUT THE RISKS AND BENEFITS TO INDIVIDUAL SUBJECTS. THERE ARE OTHER RISKS, BENEFITS AND BURDENS ASSOCIATED WITH CLINICAL RESEARCH THAT ARE ETHICALLY IMPORTANT. I'LL TALK A LITTLE ABOUT AGGREGATE RISK, SORT OF THE OVERALL TOTAL RISKS TO THE ENTIRE POPULATION, AGGREGATE BENEFITS, THERE'S ALSO THIRD PARTIES THE, YOU DO AN INFECTION CHALLENGE STUDY AND YOU INFECT SOMEBODY WITH A DISEASE, THEN THEY GO HOME AFTER THE STUDY, MAYBE THEY INFECT THE PEOPLE WHO THEY LIVE WITH SO THERE'S A POTENTIAL RISK TO THIRD PARTIES. THERE'S ALSO THE QUESTION PARTICULARLY A BIG DEAL, YOU'LL HEAR MORE ABOUT THIS LATER IN THE COURSE, ON BENEFITS AND OBLIGATIONS TO PARTICIPANTS AFTER A TRIAL IS OVER, DO YOU HAVE ANY OBLIGATIONS TO CONTINUE TO GIVE THEM THE DRUG, TO FIND THEM HEALTHCARE, TO TRANSITION THEM. SO I'M GOING TO START -- I DON'T START COUGHING ON YOU GUYS TOO MUCH HOPEFULLY. SO I'M NOT GOING TO TALK ABOUT ALL THOSE THINGS BUT THEY'RE IMPORTANT. I WAS YELLING AT ONE OF OUR FELLOWS FOR DRINKING WATER DURING THE TALK. WHAT THAT SHOWS IS SOMETIMES I KNOW THE RIGHT THING BUT I DON'T DO IT. OKAY. SO QUICK THING IS THAT THESE ARE TERMS OF ART, RISKS AND BENEFITS, AND THEY DON'T REFER -- SO TYPICALLY WHEN YOU THINK OF A RISK, FOR INSTANCE, THE PAIN OF A NEEDLE STICK, IT SEEMS A LITTLE ODD TO REGARD THAT AS A RISK BECAUSE IT BASICALLY IS CERTAIN TO HAPPEN, AT LEAST WHEN I UNDERGO A NEEDLE STICK, ALL THE TIME, BUT IN THE PARLANCE OF RESEARCH ETHICS, THAT COUNTS AS A RISK. SO THE RISKS ARE JUST ANY OF THE POTENTIAL OR ACTUAL BAD THINGS THAT CAN HAPPEN TO PARTICIPANTS AS A RESULT OF THEIR BEING IN A TRIAL, AND THE BENEFITS ARE BOTH THE THINGS THAT CERTAINLY WILL HAPPEN AND ALSO THE THINGS THAT MAY HAPPEN, LIKE MAYBE THE EXPERIMENTAL TREATMENT WILL IMPROVE THEIR CONDITION. SO THESE ARE TERMS OF ART THAT ARE SUPPOSED TO BE VERY BROAD, BROADER THAN THE WAY THEY'RE USED IN ORDINARY ENGLISH. SO HERE'S THE FRAMEWORK, AND I'LL TALK A LITTLE BIT ABOUT THIS, THE FIRST AUTHOR IS A COLLEAGUE IN OUR DEPARTMENT WHO I'VE BEEN WORKING ON THIS WITH FOR MAYBE THE LAST FIVE YEARS OR SO. SO THIS SHOULD LOOK SIMILAR TO THE FRAMEWORK FOR THE ETHICS OF RESEARCH IN GENERAL, IT'S BASICALLY MODELED ON THAT FRAMEWORK, SO THE CLAIM IS THAT TO DO RISK/BENEFIT ASSESSMENT SYSTEMATICALLY, YOU'VE GOT TO GO THROUGH THESE SIX STEPS. THE SO I'M GOING TO TAKE THEM THROUGH THE SIX STEPS, EXPLAIN THEM AND THEN TRY TO HIGHLIGHT SOME OF THE CHALLENGES THAT I THINK GET RAISED WHEN YOU TRY TO IMPLEMENT, FOR INSTANCE, WHEN AN IRB TRIES TO IMPLEMENT EACH OF THESE STEPS. SO QUICK NOTE ABOUT CLINICAL RESEARCH THAT MOST PEOPLE HERE ARE FAMILIAR WITH. A CLINICAL RESEARCH STUDY, AS ANYBODY WHO READ THE PROTOCOL THAT YOU'RE GOING TO BE DISCUSSING IN A COUPLE OF HOURS, RESEARCH PROTOCOLS AREN'T JUST ONE THING, THEY INVOLVE LOTS OF THINGS. THERE'S LOTS OF INTERVENTIONS, THERE'S LOTS OF TESTS, THERE'S BLOOD DRAWS, SCANS, EXPERIMENTAL TREATMENTS, BEING WEIGHED, BEING SEEN BY THE NURSE. THERE'S LOTS OF COMPONENTS THAT MAKE UP INDIVIDUAL STUDIES. SO WHY THAT'S IMPORTANT FOR OUR PURPOSES IS, WHAT YOU'RE SUPPOSED TO BE DOING WHEN YOU DO RISK BENEFIT ASSESSMENT IS FIRST LOOKING AT THE RISKS AND BENEFITS OF THE INDIVIDUAL INTERVENTIONS THAT ARE INCLUDED IN THE STUDY, AND THEN ONCE YOU'VE DONE THAT, LOOKING AT THE WHOLE PACKAGE, ALL OF THE RISKS AND BENEFITS OF ALL THE INTERVENTIONS TAKEN TOGETHER. SO FIRST THE INDIVIDUAL INTERVENTIONS, THEN THE ENTIRE STUDY. SO ANOTHER THING ABOUT PROTOCOLS, THEY OFTEN INVOLVE BOTH RESEARCH INTERVENTIONS AND STANDARD OF CARE CLINICALLY INDICATED INTERVENTIONS. SO YOU HAVE PATIENTS WHO HAVE A CERTAIN KIND OF LEUKEMIA YOU AND WANT TO TEST AN EXPERIMENTAL TREATMENT, THAT STUDY MIGHT INVOLVE FIRST GIVING THEM STANDARD TREATMENT, MONITORING IT IN A STANDARD WAY, ALL OF WHICH WOULD HAVE BEEN EXACTLY WHAT THEY WOULD HAVE GOTTEN IF THEY HAD JUST GONE TO A DOCTOR OUTSIDE OF THE RESEARCH CONTEXT, AND THEN YOU ADD IN SOME RESEARCH THINGS, EXPERIMENTAL TREATMENT, SOME RESEARCH BLOOD DRAWS. SO THE IDEA IS FOR THE MOST PART, WHEN YOU'RE DOING RISK BENEFIT ASSESSMENT OF THE INDIVIDUAL COMPONENTS, YOU SHOULD FOCUS ON THE RESEARCH COMPONENTS AND FOR THE MOST PART, ASSUME THAT THE CLINICALLY INDICATED COMPONENTS HAVE ACCEPTABLE RISK BENEFIT PROFILES, THAT'S WHY THEY'RE REGARDED AS CLINICALLY INDICATED. SO THIS IS FROM THE U.S. REGULATIONS BASICALLY SAYING THIS. IRBs SHOULD BE FOCUSING ON THE RESEARCH PARTS OF THE PROTOCOL AND NOT THE STANDARD OF CARE PARTS, WHICH THEY DESCRIBE AS THE RISKS AND BENEFITS OF THERAPIES SUBJECTS WOULD RECEIVE EVEN IF NOT PARTICIPATING IN THE RESEARCH. ONE COMPLICATION HERE IS THAT AT LEAST IN SOME CASES, THE RESEARCH INTERVENTIONS MIGHT ALTER THE RISKS OR PEN FITS OF A STANDARD TREATMENT. SO IF YOU HAVE A STUDY WHERE EVERYBODY GETS STANDARD TREATMENT AND THEY DO WHAT'S CALLED AN ADD-ON STUDY, ONE ARM GETS A PLACEBO AND THE OTHER ARM GETS THE STANDARD PLUS SOME EXPERIMENTAL TREATMENT, THAT COMBINATION OF THE EXPERIMENTAL TREATMENT AND THE STANDARD MIGHT SOMEHOW INFLUENCE THE RISKS AND BENEFITS OF THE STANDARD GIVEN ALONE. IT MIGHT MAKE IT POTENTIALLY MORE BENEFICIAL, IT MIGHT MAKE IT RISKIER, SO AT LEAST THAT PART OF IT, IRBs NEED TO BE COGNIZANT OF WHEN THEY'RE DOING RISKS BENEFIT ASSESSMENT. OKAY. SO THAT'S THE BACKGROUND, SO STEP ONE IS ASSESSING TO ENSURE THAT THE STUDY -- EACH INDIVIDUAL INTERVENTION THAT'S INCLUDED IN THE STUDY AND THEN THE STUDY AS A WHOLE HAS SUFFICIENT SOCIAL VALUE TO JUSTIFY THE RISKS THAT EACH OF THOSE INTERVENTIONS AND THE STUDY AS THE WHOLE POSES. THIS, I THINK, IS CRITICAL AND I THINK THERE'S A LOT OF THINGS THAT IRBs DO REALLY WELL. I THINK THIS, THEY DON'T DO AS WELL. I THINK IRBs FOCUS A LOT ON RISKS, PROTECTING SUBJECTS FROM RISKS, IT'S OBVIOUSLY IMPORTANT, BUT THE WHOLE JUSTIFICATION FOR EXPOSING SUBJECTS TO RISKS IS THE POTENTIAL TO GATHER VALUABLE INFORMATION, SO I THINK WE NEED TO TAKE THIS STEP MORE SERIOUSLY THAN SOMETIMES -- YOU'VE GOT TO MAKE SURE THAT IT'S A REALLY VALUABLE STUDY. I THINK ONE OF THE REASONS WHY PEOPLE MAYBE DON'T TAKE THIS AS SERIOUSLY AS THEY SHOULD IS THAT IT'S REALLY HARD TO GET IT RIGHT, TO FIGURE OUT WHETHER OR NOT SOME NEW EXPERIMENTAL TREATMENT FOR LEUKEMIA MIGHT HAVE IMPORTANT SOCIAL VALUE, YOU HAVE TO KNOW A LOT THAT PEOPLE LIKE ME WHO SIT ON IRBs DON'T KNOW. YOU NEED TO KNOW, WELL, OKAY, HOW BAD IS THAT TYPE OF LEUKEMIA? WHAT ARE THE CURRENT TREATMENTS FOR THAT TYPE OF LEUKEMIA? HOW AVAILABLE ARE THOSE TREATMENTS? HOW EXPENSIVE ARE THOSE TREATMENTS? HOW TOXIC ARE THOSE TREATMENTS? YOU NEED TO KNOW A LOT THAT YOU NEED EXPERTS TO HELP YOU WITH. THEN ALSO YOU OBVIOUSLY HAVE TO BE PREDICTING INTO THE FUTURE AND WE'LL COME BACK TO THIS IN A SECOND. IT'S NOT JUST WELL, WE COULD USE ANOTHER TREATMENT, IT'S WHAT'S THE CHANCES THAT THIS ONE IS GOING TO TURN OUT TO BE SUCCESSFUL, AND THAT MIGHT TAKE INTO ACCOUNT A LOT OF COMPLICATED QUESTIONS ABOUT HOW IT GETS MANUFACTURED, HOW IT GETS DISTRIBUTED, WILL DOCTORS USE IT, IF IT WORKS BUT DOCTORS AREN'T GOING TO USE IT FOR SOME REASON, THEN IT'S NOT GOING TO BE BENEFICIAL IN THE WAY WE HAD HOPED. SO A LOT OF DETERMINATIONS THAT SOMEBODY NEEDS TO BE MAKING. SO I THINK THERE'S A COUPLE IMPORTANT QUESTIONS HERE, SO TYPICALLY THE IRBs LIKE YOU GUYS, YOU'VE GOT A SPECIFIC PROTOCOL, AND THE CHARGE IS USUALLY CHARACTERIZED AS ASSESSING THE RISKS AND BENEFITS OF THAT INDIVIDUAL PROTOCOL, DO THE POTENTIAL BENEFITS, JUSTIFY THE RISKS. THAT'S IMPORTANT BUT IT RAISES THIS OTHER QUESTION THAT IRBs FACE -- OUR IRB FACES A LOT ABOUT WHETHER OR NOT YOU SHOULD ALSO BE MAKING COMPARATIVE JUDGMENTS, SO IMAGINE YOU HAVE THIS PROTOCOL AND YOU SAY, YEAH, THIS IS FINE, BUT IF THEY JUST DID THIS OTHER THING, IT WILL BE A MUCH MORE VALUABLE STUDY. IS THAT WITHIN THE PURVIEWS OF IRBs, SO DO THEY GET TO SAY TO INVESTIGATORS, YOUR STUDY IS ETHICAL BUT HERE'S A BETTER ONE, WE'RE GOING TO REQUIRE TO YOU DO THAT ONE, OR THAT VARIATION ON IT INSTEAD. ANOTHER ONE IS, WHAT IF YOU SAY, YEAH, THAT'S A FINE STUDY, BUT THERE'S THIS OTHER DISEASE THAT WE SHOULD BE STUDYING INSTEAD. IT'S A LOT MORE IMPORTANT. IS THERE SOMEBODY, AN IRB MEMBER OR SOMEBODY ELSE IN THE SYSTEM WHO'S SUPPOSED TO BE SAYING, NO, WHAT WE NEED TO DO IS WE NEED TO MAKE COMPARATIVE JUDGMENTS ABOUT WHICH DISEASES AND WHICH TREATMENTS WE SHOULD BE FOCUSIG ON, AND WHO DOES THAT. THIS IS JUST A QUOTE FROM A GROUP IN WEST AFRICA DURING THE RECENT EBOLA CRISIS, AND THEY WERE SAYING, LOOK, IN THAT CONTEXT, MAKING THESE PRIORITIZATIONS SEEMS REALLY IMPORTANT. THERE WERE A LOT OF PEOPLE WHO HAD A LOT OF IDEAS FOR TREATMENTS, VACCINES, THINGS TO STUDY, BUT YOU HAD ONLY SO MANY PATIENTS, AND IF YOU DON'T CLEARLY PRIORITIZE WHICH ONES YOU'RE GOING TO FOCUS ON, YOU MAY END UP WITH NONE OF THE STUDIES BEING ABLE TO ENROLL A SUFFICIENT NUMBER OF SUBJECTS. SO SOMEBODY HAS GOT TO BE DOING SOME KIND OF PRIORITIZATION AT SOME POINT IN THE SYSTEM. SO LET'S IMAGINE YOU'VE DONE THAT, WE'RE GOING TO COME BACK TO THAT, IT'S REALLY HARD. SO EACH THE INTERVENTIONS IN THE STUDY, THE BLOOD DRAWS THE RESEARCH PET SCAN, THE EXPERIMENTAL TREATMENT, THEY ALL HAVE SUFFICIENT SOCIAL VALUE TO JUSTIFY THE RISKS THAT THEY POSE, SO NOW WHAT YOU WANT DO IS YOU WANT TO LOOK AT WHAT ARE THE RISKS OF EACH OF THOSE INTERVENTIONS, IDENTIFY THEM, AND THEN SEE WHETHER YOU CAN MAKE THEM AS SMALL AS POSSIBLE. SO FOR INSTANCE, INSTEAD OF REPEATING A BLOOD DRAW OR A SCAN THAT SOMEBODY HAD IN CLINICAL CARE LAST WEEK OR LAST MONTH, CAN YOU JUST USE THE RESULTS FROM THAT SCAN RATHER THAN HAVING TO REPEAT IT. AND THIS IS THE MANTRA IN RESEARCH ETHICS IS, WHEN YOU THINK ABOUT RISKS, YOU SHOULD THINK ABOUT ALL THE RISKS, SO WHAT PEOPLE WILL SAY IS, WE'RE INCLINED IN CLINICAL RESEARCH TO FOCUS ON THE PHYSICAL PHYSIOLOGICAL RISKS, LIKE IT REDUCES YOUR KIDNEY FUNCTION OR IT CAUSES PAIN BUT THERE ARE OTHER RISKS THAT THEY MIGHT FACE LIKE IT MIGHT COST THEM MONEY TO GET TO THE CLINIC, THEY MAY HAVE TO STAY OVERNIGHT IN A HOTEL, THAT MIGHT MEAN THEM LOSING SOME MONEY, THEY MIGHT END UP STIGMATIZED, ANXIOUS, STRESSED OUT AS A RESULT OF YOUR STUDY, PSYCHOLOGICAL, SO THERE'S ALL RISKS, YOU'RE SUPPOSED TO CONSIDER ALL OF THEM. KEEP THAT IN MIND USE BAWS WE'RE GOING TO COME BACK TO THAT BUT THAT'S THE STANDARD LINE WITH RESPECT TO RISKS. SO HERE'S ONE OF THE OBVIOUS CHALLENGES, THE WAY YOU FIGURE OUT WHAT THE RISKS ARE OF A PARTICULAR INTERVENTION IS YOU GIVE IT TO 100,000 PEOPLE, YOU SEE WHAT HAPPENS AND THEN YOU KNOW WHAT THE RISKS ARE. WELL, THAT'S THE RIGHT WAY TO DO IT, OF COURSE THE PROBLEM IS IN CLINICAL RESEARCH, THE WHOLE POINT OF DOING THE RESEARCH IN THE FIRST PLACE, PARTICULARLY LIKE A PHASE 1 OR PHASE 2 TRIAL, IS TO FIND OUT WHAT THE RISKS OF INTERVENTION, IN FACT, ARE, SO HOW DO YOU ASSESS ETHICALLY WHETHER OR NOT THIS IS AN ACCEPTABLE STUDY TO DO WHEN YOU NEED TO KNOW THE RISKS AND THE POINT OF THE STUDY IS TO FIGURE OUT WHAT THE RISKS ARE, SO THIS IS, I THINK, ONE OF THE BIGGEST CHALLENGES THAT IRBs FACE AND SO THERE'S A COUPLE TRICKS. OR YOU TRY TO LOOK AT HAS THIS DRUG BEEN USED FOR A DIFFERENT DISEASE, HAS IT BEEN USED IN A DIFFERENT PATIENT POPULATION. IF NOT, ARE THERE DRUGS OF THE SAME CLASS THAT WORKED IN THE SAME WAY THAT HAVE BEEN USED BEFORE, WHAT ARE THE SIDE EFFECTS OF THOSE, HOW SIMILAR DO WE THINK THEY'LL BE OF THIS. ANOTHER ONE JUST TO DO IS YOU HAVE A PHASE 1 STUDY, IT'S NEVER BEEN USED IN HUMANS BEFORE, YOU CAN JUST LOOK AT, WELL, WHAT HAPPENS IF PHASE 1 STUDIES OVERALL, WHAT ARE THE RISKS OF THEM, IT GIVES YOU AT LEAST A LITTLE BIT OF INFORMATION WITH RESPECT TO THIS STUDY. ANOTHER CHALLENGE, WE'RE GOING TO TALK ABOUT THIS A LITTLE MORE AS, IN A LOT OF CASES WHAT THE RISKS ARE OF A PARTICULAR INTERVENTION, SO WHAT THE RISKS ARE OF AN MRI DEPENDS UPON WHO UNDERGOES IT. IF YOU'RE SOMEBODY WHO HAS A METAL PLATE IN YOUR HEAD, UNDERGOING AN MRI CAN BE A REALLY, REALLY BAD IDEA. IF YOU HAVE SEVERE CLAUSTROPHOBIA A, UNDERGOING AN MRI CAN BE A REALLY BAD IDEA. ON THE OTHER HAND FOR OTHER PEOPLE I KNOW, THEY THINK BEING IN AN MRI SCANNER IS KIND OF FUN, IT'S KIND OF HIGH-TECH AND KIND OF INTERESTING, SO WHAT THE RISKS AND BENEFITS ARE OF A PARTICULAR PROCEDURE IS GOING TO DEPEND A LOT ON WHO ENROLLS. SO WHAT PEOPLE NEED TO DO FOR THIS IS TO ASK QUESTIONS WITH RESPECT TO INCLUSION/EXCLUSION CRITERIA, WHO'S GOING TO GET INTO THE STUDY AND WHO CAN'T GET INTO THE STUDY, AND CAN WE MODIFY THE INCLUSION/EXCLUSION CRITERIA TO TRY TO MINIMIZE THE RISKS THAT THE STUDY POSES, SO THIS IS A STANDARD ONE, IF YOU HAVE A DRUG THAT'S EXCRETED BY THE KIDNEYS, THEN IRBs WILL STANDARDLY EXCLUDE PEOPLE WHO DON'T HAVE SUFFICIENT KIDNEY FUNCTION OUT OF WORRY THAT THE DRUG IS GOING TO BUILD UP IN THEIR SYSTEM AND THEY'RE GOING TO HAVE TOXIC SIDE EFFECTS. SO TRY TO FIGURE OUT WHO'S GOING TO DO IT, WHO'S GOING TO BE IN YOUR STUDY BASED ON RISKS. ANOTHER THING TO DO IS, IRBs ARE VERY GOOD AT LOOKING AT PROTOCOLS AT THE BEGINNING, BEFORE THEY'RE STARTED, AND ONE THING THAT'S IMPORTANT TO BE AWARE OF IS THE IMPORTANCE OF LOOKING AT WHAT HAPPENS TO SUBJECTS AS THE STUDY GOES ON. SO HERE'S ONE OF THE TRICTS THAT TRICKS TH AT IRBs CAN USE, IF IT'S A NEW AGENT, YOU SAY TO THE INVESTIGATOR, OKAY, YOU CAN GIVE IT TO TWO PEOPLE, THEN YOU HAVE TO STOP, YOU HAVE TO MONITOR THOSE TWO PEOPLE FOR A WEEM THEN COME BACK TO US AND TELL US WHAT HAPPENED, AND THAT'S GOING TO GIVE US INFORMATION ON WHETHER OR NOT WE THINK IT'S ACCEPTABLE FOR YOU TO CONTINUE. SO MONITORING OVER TIME DURING THE STUDY CAN BE AN IMPORTANT WAY TO MAKE SURE THE RISKS CONTINUE TO BE ACCEPTABLE. SO HERE'S ONE OF THE -- NOW WE'RE GOING TO GO BEYOND PHILOSOPHY 101 FOR A SECOND. SO IN MOST CASES IT SEEMS PRETTY OBVIOUS, IF I SAY WHAT ARE THE RISKS OF A DRUG, IT SEEMS LIKE YOU DON'T HAVE TO THINK VERY HARD. WELL, IT'S THE CHANCE THAT IT'S GOING TO HURT THE PERSON'S KIDNEYS, THAT IT'S GOING TO CAUSE PERIPHERAL NEUROPATHY. THOSE ARE THE RISKS OF THAT DRUG, BUT WHAT WE DON'T REALIZE IS THAT WHEN WE'RE DOING THAT, WE'RE ACTUALLY APPEALING TO SOME BASELINE AND COMPARING WHAT HAPPENS IF YOU GET THE DRUG AGAINST WHATEVER WE THINK THE APPROPRIATE BASELINE IS, SO WHY THAT'S IMPORTANT IS IT CAN RAISE DIFFICULT QUESTIONS ABOUT HOW YOU DECIDE WHAT IS THE APPROPRIATE BASELINE FOR DOING I.R.S. I.R.S. BEING/BENEFIT JUDGMENTS IN CLINICAL RESEARCH. SO I'M THE INVESTIGATOR, YOU GUYS ARE THE IRB, I COME TO YOU WITH A PHASE 2 STUDY, THIS IS A DRUG, IT'S BEEN GIVEN TO HUNDREDS OF THOUSANDS OF PEOPLE, IT'S BEEN SHOWN VERY SAFE, AND I THINK THERE'S A SMALL CHANCE THAT IT'S GOING TO BENEFIT PEOPLE WHO HAVE THIS OTHER CONDITION FOR WHICH IT HASN'T BEEN USED. SO THAT'S WHAT MY STUDY IS. VERY SAFE DRUG, MIGHT OFFER SOME CHANCE OF BENEFIT TO PEOPLE WHO HAVE A CONDITION FOR WHICH IT'S NEVER BEEN USED. SO YOU GUYS ARE ASSESSING THE RISK/BENEFITS OF THAT STUDY. IS THAT A POTENTIAL BENEFIT STUDY? IS IT A RISKY STUDY OR IS IT NEITHER OF THOSE? WHO THINKS IT'S A POTENTIAL BENEFIT STUDY? WHO THINKS IT'S A RISKY STUDY OVERALL? OKAY, NOBODY. SO THE POINT IS, WE TEND TO MAKE QUICK JUDGMENTS ABOUT THESE THINGS, BUT NOTICE IT CAN DEPEND UPON THE FACTS. IMAGINE THAT OUTSIDE OF THE RESEARCH, THE PEOPLE WHO HAVE THIS CONDITION GET THIS TREATMENT THAT IS PERFECTLY SAFE AND CURES THEM EVERY TIME. AND INSTEAD, I'M ASKING THEM TO BE IN MY STUDY RATHER THAN GET THAT DRUG. WELL, IF THAT'S THE FACTS, THEN THIS ACTALLY LOOKS LIKE A REALLY RISKY STUDY, RIGHT, BECAUSE WHAT IT MEANS IS, YOU'RE NOT GOING TO GET CURED. INSTEAD WHAT YOU'RE GOING TO GET IS SOME SMALL CHANCE OF SOME SMALL BENEFIT, THAT LOOKS LIKE EX-ANTE FROM THE BEGINNING OF THE TRIAL, IT LOOKS LIKE MAYBE IT'S A BAD IDEA CLINICALLY FOR PEOPLE TO BE IN THE TRIAL. SO IT DEPENDS A LOT ON WHAT THE BASELINE IS, OR MAYBE A DIFFERENT WAY TO SAY IT IS, WHAT'S THE ALTERNATIVE? IF THEY WEREN'T GOING T BE IN YOUR STUDY, WHAT WOULD HAPPEN TO THESE PEOPLE OTHERWISE, AND THAT OFFERS THE COMPARATOR FOR LOOKING AT RISKS AND BENEFITS. AND THIS IS IMPORTANT BECAUSE WHAT IT SUGGESTS IS, IT SUGGESTS THAT A STU CAN DI STUDY MIGHT BE REALLY RISKY IN ONE PLACE, FOR INSTANCE, WHERE THAT CURE TREATMENT IS AVAILABLE IN THE PREVIOUS EXAMPLE, BUT IT MIGHT BE POTENTIALLY BENEFICIAL IN ANOTHER PLACE, FOR INSTANCE, IN A PLACE WHERE THAT TREATMENT ISN'T AVAILABLE IN PEOPLE. SO THERE'S BEEN A LOT OF DEBATE NOW PARTICULARLY IN RESEARCH IN LOW AND MIDDLE INCOME COUNTRIES ABOUT HOW YOU DO RISK BENEFIT ASSESSMENT WHEN THE STANDARD TREATMENTS FOR A CONDITION AREN'T AVAILABLE. SO HERE'S THE CHALLENGE. I'LL JUST GIVE ONE EXAMPLE OF THIS. I THINK THE CHALLENGE THIS RAISES PHILOSOPHICALLY IS, WHAT'S THE RIGHT BASELINE FOR EVALUATING THE RISKS AND BENEFITS OF A STUDY. SHOULD THE IRB LOOK AT WHAT YOU'D EXPECT THE PEOPLE TO GET IF THEY WEREN'T IN YOUR TRIAL OR SHOULD THE IRB LOOK AT WHAT YOU THINK THE PEOPLE SHOULD GET IF THEY WEREN'T IN YOUR TRIAL. I DON'T KNOW IF ALLEN IS GOING TO TALK ABOUT THIS ONE A LITTLE BIT, THIS IS A STUDY THAT WAS DONE IN BALTIMORE ABOUT 20 YEARS AGO NOW. IT WAS DONE BY KENNEDY KRUEGER, WHICH IS AN INSTITUTION ASSOCIATED WITH JOHNS HOPKINS. THESE WERE INVESTIGATORS WHO WERE PEDIATRIC NEUROLOGISTS, AND THEY LEARNED A LOT ABOUT THE ADVERSE EFFECTS THAT EXPOSURE TO LEAD PAINT EARLY IN LIFE HAS ON OUR BRAINS. SO BEING EXPOSED TO LEAD PAINT WHEN YOU'RE SIX MONTHS OLD, WHEN YOU'RE A YEAR OLD, IS A REALLY BAD IDEA FOR THE DEVELOPMENT OF YOUR BRAIN. UNFORTUNATELY, THERE WERE A LOT OF PEOPLE IN AT THE TIME, PARTICULARLY IN EAST BALTIMORE, RAISING LITTLE KIDS IN HOUSES THAT HAD LEAD PAINT IN THEM AND THE QUESTION IS, WHAT COULD THEY DO ABOUT THAT? AT LEAST SOME PEOPLE CLAIM THAT GETTING OUT ALL THE LEAD PAINT, WHAT'S CALLED LEAD PAINT ABATEMENT, IT'S REALLY EXPENSIVE. IN SOME CASES MAYBE MORE EXPENSIVE THAN THE HOUSE, THE LANDLORDS WEREN'T GOING TO DO THAT, SO WHAT THESE GUYS TRIED TO DO WAS COME UP WITH A STUDY TO SAY, OKAY, IF WE CAN'T GET RID OF ALL THE LEAD PAINT, CAN WE GET RID OF SOME OF IT, AND IF WE GET RID OF SOME OF IT, DOES THAT PROTECT THE KIDS, IS THAT THE CHILDREN IF WE DO PARTIAL LEAD PAINT ABATEMENT. SO THEY DID A STUDY LIKE THAT, WHERE THEY PUT -- HAD KIDS IN HOUSES THAT HAD SOME LEAD PAINT BUT NOT COMPLETE LEAD PAINT. AND THE QUESTION HERE IS, WAS THAT A POTENTIAL BENEFIT STUDY OR IS THAT A RISKY STUDY? AND THIS IS -- SO THIS IS JUST ONE SITE THIS IS A PEDIATRICIAN AT THE UNIVERSITY OF CHICAGO. A LOT OF PEOPLE DEBATED THIS. THIS WENT TO THE HIGHEST COURT IN THE STATE OF MARYLAND THAT HAD A LOT TO SAY ABOUT IT, AND I THINK THE QUESTION IS, HERE, IT DEPENDS. IF YOU THINK THAT THE WAY YOU DO RISK/BENEFIT ASSESSMENT YOU SAY WHAT WOULD HAPPEN TO THESE KIDS OTHERWISE, THE CLAIM IS IF THEY WEREN'T IN A PARTIALLY ABATED HOUSE, THEY'D BE IN A HOUSE WITH FULL LEAD PAINT SO THIS IS ACTUALLY A BENEFICIAL STUDY.& OTHERS SAID NO, THAT'S RIDICULOUS, WE KNOW ANY LEAD PAINT IS A BAD IDEA FOR YOUR KID, GET RID OF ALL THE LEAD PAINT SO PUTTING A KID IN A HOUSE KNOWINGLY THAT HAS SOME LEAD PAINT IS REALLY RISKY TO THEIR BRAIN. AND THIS IS A REALLY RISKY STUDY. SO IT'S A GREAT EXAMPLE, I THINK, OF TRYING TO FIGURE OUT WHAT THE APPROPRIATE BASELINE IS, IS IMPORTANT TO DOING THIS RIGHT. SO YOU'VE FIGURED OUT THE RISKS, YOU WANT TO MINIMIZE THEM AS I SAID, DO RESEARCH BLOODS, TAKE THEM WHEN YOU ALREADY DID A CLINICAL STICK, DON'T DO EXTRA STICKS IF YOU CAN AVOID THEM. I HATE NEEDLE STICKS SO THIS RESONATES TO ME. THIS IS THE MOST IMPORTANT ONE. ANOTHER THING IS, WE'LL TALK ABOUT MORE IS, QUESTION OF FAIRNESS. AS I SAID, YOU CAN USE INCLUSION/EXCLUSION CRITERIA TO KEEP OUT, MINIMIZE RISK, SO YOU TAKE THE PERSON WHO DOESN'T HAVE GOOD KIDNEY FUNCTION, THEY'RE NOT IN THE STUDY, THAT REDUCES THE RISK, BUT NOW YOU WORRY, IS THAT SOMEHOW BAD FOR PEOPLE WHO HAVE REDUCED KIDNEY FUNCTION? THEY'RE ALREADY SICK. IF THEY NEED A TREATMENT, THE ONLY WAY TO GET A TREATMENT IS TO BE IN YOUR STUDY, IS IT FAIR FOR YOU TO EXCLUDE THEM FROM THAT STUDY IF IT'S STILL IN THEIR INTEREST TO BE IN THE STUDY. SO THAT'S ONE OF THE CHALLENGES. WE'LL COME BACK TO THAT. SO YOU'VE DONE RISK, YOU'VE IDENTIFIED THEM, YOU'VE MINIMIZED THEM, THEM BASICALLY YOU WANT TO DO THE ANALOGOUS -- IDENTIFY THEM RATHER THAN MINIMIZE THEM, PEOPLE TALK ABOUT ENHANCING THEM, TRY TO INCREASE THE BENEFITS OF BEING IN THE STUDY TO THE EXTENT THAT YOU CAN CAN. WHAT COUNTS AS A BENEFIT? SO REMEMBER BEFORE I SAID WHEN YOU LOOK AT RISKS, YOU'RE SUPPOSED TO TAKE ALL THE RISKS, SOCIAL, ECONOMIC, PSYCHOLOGICAL. YOU MIGHT THINK THAT THEN THE CORRESPONDING CLAIM WOULD BE LOOK AT ALL THE BEN THE FIT. THAT'S NOT WHAT PEOPLE DO IN RESEARCH ETHICS. WHAT THEY SAY IS YOU'RE ONLY SUPPOSED TO COUNT CERTAIN POTENTIAL BENEFITS. SO FOR INSTANCE, WHAT ABOUT PAYMENT, AND MOST RESEARCH ETHICISTS SAY PAYMENT, LOTS OF STUDIES PAY, CHRISTINE IS AN EXPERT ON PAYMENT IN CLINICAL RESEARCH. MOST RESEARCH ETHICS SAY YEAH, IT'S NICE FOR PEOPLE TO GET PAID BUT IT DOESN'T COUNT AS A BENEFIT, IT SHOULDN'T BE CONSIDERED A BENEFIT OF BEING IN THE STUDY. INSTEAD YOU SHOULD ONLY COUNT -- PEOPLE HAVE DIFFERENT WORDS FOR THIS. DIRECT BENEFITS IS SOMETHING THAT COMES OUT OF THE U.S. PEDIATRIC REGULATIONS, YOU SHOULD COUNT DIRECT BENEFITS, NOT INCLUSION BENEFITS. PEOPLE HAVE DIFFERENT WORDS FOR WHAT TO DO. SOME RATIONALE FOR WHY YOU SHOULD CONSIDER ALL THE RISKS BUT ONLY CERTAIN OF THE BENEFITS. SO HERE'S MY PHILOSOPHER'S EXAMPLE. IMAGINE I HAVE A STUDY AND IT INVOLVES ONE BIOPSY, AND IF YOU'RE IN MY STUDY, I'M GOING TO GIVE YOU $100. AND THE ONLY RISK, REMEMBER, THIS IS PHILOSOPHY, NOT MEDICINE, THE ONLY RISKS OF BEING IN THIS STUDY IS THE CHANCE OF GETTING AN INFECTION AND IF YOU GET AN INFECTION, YOU NEED AN ANTIBIOTIC AND THAT ANTIBIOTIC COSTS YOU $100. SO THERE'S THE POTENTIAL OF BEING IN THE BENEFIT , ECONOMIC RISK OF $100, YOU MIGHT THINK THOSE BALANCE EACH OTHER OUT. NO, ACCORDING TO RESEARCH ETHICS RS THIS IS A RISKY STUDY. THE $100 YOU GET DOESN'T COUNT AS A BENEFIT TO THE SUBJECTS, BUT THE $100 YOU MAY LOSE IF YOU HAVE TO PAY FOR THE ANTIBIOTIC COUNTS AS A RISK. SO ONE OF THE CHALLENGES NOW IS, IT SEEMS TO MAKE SENSE IN A WAY NOT TO COUNT ECONOMIC BENEFITS BUT THEN HOW COME WE COUNT ECONOMIC RISKS AND IS THERE WAY TO EXPLAIN THAT. IMPORTANT QUESTION. OKAY, YOU FIGURED OUT THE BENEFITS, WHAT YOU'RE GOING TO COUNT AS A BENEFIT, YOU TRY TO ENHANCE THEM, MAKE THEM AS HAY HIGH AS YOU HIGH AS YOU CAN. NOW YOU'VE GOT THE RISKS, THE BENEFITS, SO WHAT YOU'RE SUPPOSED TO DO IS JUST COMPARE THEM. FOR EACH INDIVIDUAL INTERVENTION AND THEN FOR THE STUDY AS A WHOLE, DO THE POTENTIAL BENEFITS TO THE SUBJECTS JUSTIFY THE RISKS THAT THEY FACE AND IF THE ANSWER TO THAT IS YES, FOR AN INDIVIDUAL INTERVENTION, OR FOR THE WHOLE STUDY, THEN THAT COUNTS AS AN ACCEPTABLE STUDY OR INTERVENTION AT LEAST WITH RESPECT TO RISKS AND BENEFITS. THERE MIGHT BE OTHER WORRIES ABOUT IT BUT WITH RESPECT TO RISKS AND BENEFITS, IT'S ETHICALLY ACCEPTABLE. HOW DO YOU DO THIS? SO PEOPLE WORRY A LOT, OH, WHAT DO YOU MEAN, YOU WEIGH THE RISKS AND BENEFITS, YOU BALANCE THE RISKS AND BENEFITS, YOU COMPARE THE RISKS AND BENEFITS, WHAT DOES THAT ALL MEAN IN PRACTICE, HOW ARE WE SUPPOSED TO DO IT, AND THE THING I TELL PEOPLE IS TO TRY TO USE WHAT I CALL THE INFORMED CLINICIAN TEST. WHAT YOU IMAGINE IS, SO YOU'RE ASSESSING A PARTICULAR INTERVENTION IN A STUDY, OR THE INTERVENTION AS A WHOLE. ASK YOURSELF THIS QUESTION. IF YOU HAD A REALLY SMART EXPERT CLINICIAN WHO KNEW EVERYTHING ABOUT THIS PATIENT'S CONDITION AND AVAILABILITY AND THE AVAILABILITY TREATMENTS FOR IT, WHAT WOULD THEY RECOMMEND WITH RESPECT TO THE INTERVENTION OR THE STUDY IN QUESTION? IF THEY WOULD SAY I THINK IT'S A GOOD IDEA FOR YOU TO GET THIS INTERVENTION, THEN IT'S A PROSPECT OF BENEFIT INTERVENTION. IF THEY'D SAY NO, IT'S AGAINST YOUR CLINICAL INTERESTS TO GET THIS INTERVENTION TO UNDERGO THIS M RI., THEN MRI THEN IT DOESN'T OFFER A PROSPECTIVE BENEFIT, THEY DON'T JUSTIFY THE RISKS TO THE SUBJECT. SO IT'S AT LEAST ONE PRAGMATIC WAY TO TRY TO ANSWER THE QUESTION. TRY TO FIGURE OUT WHETHER OR NOT THE POTENTIAL BENEFITS JUSTIFY THE RISKS. IF THE CLINICIAN SAYS NO, YOU SHOULDN'T UNDERGO THAT CONSIDERING JUST YOUR CLINICAL INTERESTS, THEN THE I WA I THINK ABOUT THAT IS THAT MEANS THE RISKS OUTWEIGH THE BENEFITS OR ANOTHER WAY TO PUT IT IS THAT THAT INTERVENTION OR STUDY POSES WHAT I CALL NET RISKS. THE RISKS ARE GREATER BY SOME DEGREE THAN THE POAT TENSION POTENTIAL BENEFITS. THE NEXT QUESTION FOR IRBs IS GOING TO BE, HOW DO WE FIGURE OUT WHAT LEVEL OF NET RISKS IS ACCEPTABLE, HOW BIG OF A NET RISK ARE WE GOING TO ALLOW IN CLINICAL RESEARCH. ONE MORE COMPLICATION TO THIS, SO WHAT I JUST SAID IS, WE'VE GOT TO FIGURE OUT HOW MUCH NET RISKS WE'RE GOING TO THINK ARE ETHICALLY ACCEPTABLE. THERE ARE SOME VERY INFLUENTIAL WRITERS IN RESEARCH ETHICS WHO SAY THAT DEPENDS. IT DEPENDS ON THE KIND OF INTERVENTION THAT YOU'RE TALKIN ABOUT. THERE'S TWO KINDS OF INTERVENTIONS FOR THIS. THERE'S DIFFERENT WAYS TO TRY DO THE EVALUATION OF WHETHER THE POTENTIAL BENEFITS JUSTIFY THE RISKS. I JUST SAID THE POTENTIAL BENEFITS JUSTIFY THE RISKS. THE POTENTIAL BENEFITS OF THE SPARE MENTAL TREATMENT CAN JUSTIFY WHICH RISKS IN THE STUDY? THERE'S A NUMBER OF POSSIBILITIES. ONE IS THEY CAN ONLY JUSTIFY THE RISKS OF THAT INTERVENTION, ANOTHER THING IS THEY COULD JUSTIFY THEIR RISKS OF INTERVENTIONS IN THE SAME ARM OF THE TRIAL, OR MAYBE THEY COULD JUSTIFY THE RISKS IN THE TRIAL AS A WHOLE. SO THERE'S A COMMON CLAIM IN RESEARCH ETHICS WHICH IS CALLED THE FALLACY OF THE PACKAGE DEAL. THIS TRACES TO BOB LEVINE, WHO'S IN SOME WAYS THE GODFATHER OF RESEARCH ETHICS, AT LEAST IN THE U.S., AND THE VIEW IS BASICALLY THAT THE POTENTIAL BENEFITS OF AN INTERVENTION CAN ONLY JUSTIFY THE RISKS OF THAT SPECIFIC INTERVENTION AND THEY CAN'T JUSTIFY THE RISKS OF ANY OTHER INTERVENTION IN THE TRIAL. SO IF I'M GOING TO GIVE SOMEBODY SPAIRM TALL TREATMENT AND BIOPSY, THEY CAN'T JUSTIFY THE RISKS OF THE BIOPSY. THAT'S A STANDARD VIEW AND THING I'VE BEEN THINKING ABOUT LATELY IS WHETHER OR NOT THAT VIEW IS JUSTIFIED, WHETHER OR NOT IT MAKES SENSE AND I'VE COME TO BELIEVE IT DOESN'T MAKE SENSE, THAT IT'S NOT JUSTIFIED. HERE'S THE JUSTIFICATION THAT'S OFFERED. THE REASON WHY WE WANT TO DO THIS IS HERE'S THE WORRY, THE WORRY IS THAT WE HAVE SOME POTENTIALLY LIFE SAVING BLOCKBUSTER EXPERIMENTAL TREATMENT. IF THE POTENTIAL BENEFITS OF RECEIVING THAT TREATMENT CAN JUSTIFY OTHER RISKS, THEN WHAT IT MIGHT ALLOW IS IT MIGHT ALLOW INVESTIGATORS TO PACK IN ALL SORTS OF EXTRA BIOPSIES. HEY, WE GOT THIS GREAT BLOCKBUSTER DRUG THAT MIGHT SAVE THESE PEOPLE'S LIVES, LET'S GET LIKE 10 EXTRA BIOPSIES FROM THEM FOR TISSUE WE CAN USE IN THE LAB. THAT SEEMS OR IT FEELS AT LEAST LIKE MAYBE IT'S EXPLOITING THESE PEOPLE IN A CERTAIN WAY. MOST PEOPLE WANT TO BLOCK THAT. THE WAY THEY BLOCK IT IS BY SAYING THAT THE POTENTIAL BENEFITS OF THE EXPERIMENT CAN ONLY JUSTIFY ITS OWN RISKS. THE PROBLEM, I THINK, IS THAT THAT NOT ONLY BLOCKS THE POTENTIAL BENEFITS OF THE EXPERIMENTAL TREATMENT JUSTIFYING THE RISKS OF UNNECESSARY UNRELATED PROCEDURES, IT ALSO BLOCKS THE POTENTIAL FOR THE BENEFITS OF THE EXPERIMENTAL TREATMENT TO JUSTIFY OTHER INTERVENTIONS THAT YOU NEED IN THE STUDY. AND THE QUESTION IS WHETHER OR NOT THAT'S JUSTIFIED OR NOT, AND THAT'S WHAT I THINK IS NOT JUSTIFIED. HERE'S A WAY JUST TO THINK ABOUT IT IN CLINICAL CARE, WE ACCEPT THIS ALL THE TIME. THERE ARE LOTS OF INTERVENTIONS THAT YOU NEED IN ORDER TO GET SOMETHING ELSE. FOR INSTANCE, IN ORDER TO ADMINISTER A LOT OF EXPERIMENTAL KRUTION, SOMEBODY'S GOT TO STICK YOU WITH A NEEDLE. YOU MIGHT SAY HOW DO YOU JUSTIFY THE RISKS OF STICKING A PERSON WITH A NEEDLE? THE OBVIOUS ANSWER IS THAT'S THE ONLY WAY WE CAN GET THE DRUG INTO THEM, AND THE DRUG OFFERS THEM BENEFITS. SO IT SEEMS LIKE IN CLINICAL CARE, WE ALLOW THE POTENTIAL BENEFITS OF A DRUG TO JUSTIFY THE RISKS OF OTHER PROCEDURES THAT ARE NECESSARY FOR ADMINISTERING IT. AND SO MY QUESTION IS, IS THERE A SIMILAR ARGUMENT YOU CAN USE TO SAY THAT THE POTENTIAL BENEFITS OF THE EXPERIMENTAL TREATMENTS SHOULD BE ABLE TO JUSTIFY THE RISKS OF OTHER PROCEDURES THAT YOU HAVE TO HAVE IN THE TRIAL IN ORDER TO ASSESS THE EXPERIMENTAL TREATMENT. LIKE LET'S SAY THE ONLY WAY I CAN SEE WHETHER OR NOT THIS EXPERIMENTAL TREATMENT WORKS IS BY DOING A BIOPSY. MY THOUGHT IS, IN THAT CASE, IT FEELS LIKE THE POTENTIAL BENEFITS OF THE EXPERIMENTAL TREATMENT SHOULD BE ABLE TO JUSTIFY THE RISKS OF THE BIOPSY, EVEN THOUGH THERE'S A WAY IN WHICH THEY'RE INDEPENDENT, YOU NEED THE BIOPSY TO ASSESS THE EXPERIMENTAL TREATMENT. SO WE CAN TALK ABOUT THAT IF PEOPLE ARE INTERESTED. A LOT OF PEOPLE THINK THAT'S WRONG, JUST -- SO IF YOU DISAGREE WITH ME, YOU'RE IN VERY, VERY GOOD COMPANY. SO NOW WE'VE FIGURED OUT WHICH POTENTIAL BENEFITS CAN JUSTIFY WHICH RISKS, WE'VE FIGURED OUT WHETHER INTERVENTIONS POSE NET RISKS. THE ONES THAT DON'T ARE OK. NOW WHAT WE HAVE LEFT IS A COUPLE PROCEDURES IN THE PROTOCOL THAT POSE NET RISKS. THE RISKS EXCEED THE POTENTIAL BENEFITS TO THE SUBJECTS. SO WE HAVE TO FIGURE OUT WHETHER OR NOT THOSE NET RISKS ARE ACCEPTABLE. HERE'S A QUESTION AT THE BOTTOM FOR PEOPLE WHO ARE STILL AWAKE, ANYBODY -- SOMEBODY STILL AWAKE? SEE IF YOU CAN MAKE SENSE OF THAT LAST QUESTION AND THEN WE CAN TALK ABOUT IT FOR ANYBODY WHO IS INTERESTED WHEN WE GET TO IT. SO WE'RE LOOKING AT WHETHER OR NOT NET RISKS ARE ACCEPTABLE OR EXCESSIVE. HERE'S A COMMON VIEW IN THE RESEARCH ETHICS LITERATURE. IT DEPENDS ON WHETHER IT'S THE WHAT'S CALLED A THERAPEUTIC OR NON-THERAPEUTIC INTERVENTION. IF IT'S A THERAPEUTIC INTERVENTION, THEN NO NET RISKS ARE ALLOWED. IF IT'S A NON-THERAPEUTIC INTERVENTION, THEN YOU CAN ALLOW SOME NET RISKS. THAT'S THE BASIC VIEW. HERE'S A DESCRIPTION, ONE OF THE PRIMARY PROPONENTS OF THIS VIEW IS A CANADIAN BIOETHICIST, CHARLES VEER. THIS IS BASICALLY HIS DESCRIPTION. BASICALLY WHAT HE'S SAYING IS, IF IT'S A THERAPEUTIC INTERVENTION, ONE THAT YOU'RE GIVING WITH THE IDEA OF HELPING OR BENEFITING THE PARTICIPANT THEMSELVES, THEN THE POTENTIAL BENEFITS HAVE TO JUSTIFY THE RISKS. THERE CAN'T BE ANY NET RISKS IN THAT CASE. ON THE OTHER HAND, IF IT'S JUST A RESEARCH BIOPSY, IT'S OKAY TO HAVE SOME NET RISKS AS LONG AS THEY'RE NOT TOO GREAT. THAT'S THE STANDARD VIEW, QUESTION IS DOES IT MAKE SENSE, SO HERE'S WHAT IT IS WHAT I WAS JUST SAYING, THERAPEUTIC INTERVENTIONS, NO NET RISKS, NON-THERAPEUTIC INTERVENTIONS, SOME NET RISKS. HERE'S THE REALLY IMPORTANT PART OF THIS IS THAT IF THAT'S RIGHT RIGHT, WHAT IF SUGGESTS IS THAT CLINICAL WE ECK WHICH -- YOU'RE TESTING AN INTERVENTION AND DON'T HAVE ANY REASON TO THINK IT'S ANY WORSE THAN ANY OTHER TREATMENT IN THE TRIAL SO THAT ALL THE TREATMENTS IN THE TRIAL ARE EQUAL WITH RESPECT TO RISKS AND BENEFITS AND ALL OF THOSE TREATMENTS ARE EQUAL IN COMPARISON TO ANYTHING ELSE THAT THE PEOPLE IN THE TRIAL COULD GET OUTSIDE OF THE STUDY. SO IT HAS TO BE AT LEAST AS GOOD. WHATEVER YOU'RE GIVING THEM HAS TO BE AT LEAST AS GOOD AS ANYTHING ELSE THAT THEY COULD GET. THAT'S BASICALLY THE IDEA OF CLINICAL EQUIPOISE. IF YOU'RE GIVING -- THAT THING POSES NET RISKS, THE COMPARATOR IS WHAT THEY COULD GET OTHERWISE, THAT THING COULD BE BETTER THAN THEM, THIS THING POSES NET RISKS. PEOPLE SAY THAT'S UNETHICAL RESEARCH. YOU'RE DEPRIVING RESEARCH PARTICIPANTS OF THE BEST CARE THAT'S AVAILABLE TO THEM, DOING THAT IS UNETHICAL. MY BASIC RESPONSE TO THAT IS, IT SEEMS ODD TO SAY WE HAVE THAT STANDARD WITH RESPECT TO THERAPEUTIC INTERVENTIONS BUT WE DON'T HAVE THE SAME STANDARD WITH RESPECT TO NON-THERAPEUTIC INTERVENTIONS. IF IT'S OKAY FOR RESEARCHERS TO DO RESEARCH BIOPSIES THAT HAVE NO CLINICAL BENEFIT TO THE PARTICIPANTS, THEN WHY MIGHT IT NOT BE ACCEPTABLE AT LEAST IN SOME CASES WHERE IT'S JUSTIFIED, WE COULD TALK ABOUT WHY IT MIGHT BE JUSTIFIED, TO GIVE A THERAPEUTIC INTERVENTION THAT MIGHT BE A LITTLE BIT WORSE THAN SOMETHING THEY COULD GET OTHERWISE. SO THIS IS THE EXAMPLE BASICALLY I'M SAYING HERE, IT SEEMS LIKE THERE'S WHAT TO ME SEEMS LIKE AN INCONSISTENCY, WHY SHOULD WE HAVE DIFFERENT ETHICAL STANDARDS DEPENDING UPON WHETHER IT'S A THERAPEUTIC OR NON-THERAPEUTIC INTERVENTION. I DON'T THINK THAT'S THE RIGHT APPROACH, I THINK INSTEPPED STED WE HAVE TO LOOK AT NET RISKS. THAT'S WHAT I CALL THE NET RISK TEST, DO THE COMPARISON I TALKED ABOUT, SEE WHICH INTERVENTIONS HAVE NET RISKS AND THEN ASK WHETHER OR NOT THOSE NET RISKS ARE ACCEPTABLE OR NOT. SO THEN THE QUESTION OBVIOUSLY IS HOW YOU FIGURE OUT WHETHER SOME GIVEN NET RISKS ARE ACCEPTABLE OR TOO MUCH, ARE THEY EXCESSIVE. HERE'S THE STANDARD THAT MOST PEOPLE GIVE AND I THINK ALAN IS PROBABLY GOING TO TALK ABOUT THIS A LOT MORE, THIS IS REALLY IMPORTANT WITH RESPECT TO PEDIATRIC RESEARCH. WHAT MOST PEOPLE SAY IS THAT NET RISKS ARE ACCEPTABLE AS LONG AS THEY'RE MINIMAL. SO THEY HAVE TO BE REALLY LOW, ESPECIALLY WHEN YOU'RE TALKING ABOUT RESEARCH WITH INDIVIDUALS WHO CAN'T CON SENT LIKE CHILDREN OR ADULTS WITH SEVERE DEMENTIA. WHAT ARE MINIMAL RISKS? MOST PEOPLE DEFINE THIS IN COMPARISON TO EVERYDAY LIFE, IF THE RISKS ARE NO GREATER THAN RISKS PEOPLE FACE IN DAILY LIFE, THAT COUNTS AS MINIMAL, IF THEY EXCEED THEM, THAT'S MORE THAN MINIMAL RISK AND THEN THEY'RE AT LEAST ETICALLY ETHICALLY PROBLEMATIC. ONE CAVEAT THAT I'VE BEEN ARGUING FOR IS, THAT COMPARISON TO ME IN GENERAL MAKES SENSE. THE WORRY I HAVE ABOUT IT IS THAT THERE'S CERTAIN RISKS THAT PEOPLE ORDINARILY FACE IN DAILY LIFE THAT ARE PRETTY HIGH, LIKE THE RISKS, FOR INSTANCE, OF SNOW SKIING. SNOW SKIING ACTUALLY IS A FAIRLY DANGEROUS ACTIVITY. WHY DO WE LET PEOPLE DO IT? BECAUSE WE THINK THE POTENTIAL BENEFITS JUSTIFY THOSE RISKS. IF THAT'S RIGHT, THEN IT SEEMS LIKE THE RISKS OF SNOW SKIING DON'T PROVIDE AN APPROPRIATE COMPARATOR FOR A RESEARCH INTERVENTION THAT OFFERS NO POTENTIAL FOR BEN FI. WE WANT TO KNOW WHEN IT'S ACCEPTABLE IN RESEARCH TO POSE RISKS TO PEOPLE FOR NO PERSONAL BENEFIT, IT SEEMS LIKE THE RIGHT COMPARATOR CAN'T BE RISKS THAT ARE JUSTIFIED BY THE PERSONAL BENEFIT, LIKE THE RISKS OF SNOW SKIING. IF THAT'S RIGHT, WE NEED A DIFFERENT STANDARD OR TO LOOK AT ONLY SOME OF THE RISKS THAT PEOPLE ORDINARILY FACE IN DAILY LIFE. MY THOUGHT IS IT'S SOMETHING LIKE THE RISKS THAT PEOPLE, FOR INSTANCE, CHILDREN FACE IN APPROPRIATE CHARITABLE ACTIVITIES. WE CAN TALK MORE ABOUT THAT TOO IF PEOPLE HAVE QUESTIONS. SO WHAT IF I HAVE A PERFECTLY COMPETENT SMART BRILLIANT INFORM INFORMED ADULT, AND I HAVE A STUDY THAT POSES REALLY HIGH RISKS TO THEM BUT HAS THE POTENTIAL TO GATHER SOME INFORMATION TO BE REALLY, REALLY IMPORTANT. IS THAT AN ETHICAL STUDY OR IS THAT AN UNETHICAL STUDY? DOES THAT -- REALLY HIGH RISKS, SO A CHALLENGE STUDY FOR HIV, I'M GOING TO INJECT A COUPLE PEOPLE WITH ZIKA OR EBOLA OR HIV AND I'M GOING TO LEARN SOMELY& IMPORTANT THINGS THAT COULD HELP MILLIONS OF PEOPLE. THAT'S AN ACCEPTABLE -- DOES ANYBODY THINK THAT'S AN ETHICALLY ACCEPTABLE STUDY? SO WE ALL THINK THERE'S SOME LIMIT, THERE'S SOME CAP, EVEN IF YOU'RE A COMPETENT CONSULT SCENTING ADULT, THERE'S A CAP. OBVIOUSLY THE DEBATE SOME PEOPLE ARE HAVING IS IF THERE'S SOME CAP, YOU PEOPLE ARE REALLY SMART. WHAT'S THE CAP ON HOW MUCH NET RISK I CAN EXPOSE A COMPETENT UNDERSTANDING CONSENTING ADULT IN ORDER TO TRY TO LEARN THINGS THAT ARE REALLY IMPORTANT. HERE ARE SOME OPTIONS. SOME PEOPLE THINK WE HAVE -- I THINK ONE OF OUR FELLOWS THINKS THERE SHOULDN'T BE ANY LIMITS AT ALL. IF IT'S REALLY, REALLY IMPORTANT AND THEY'RE COMPETENT, THEY GET TO DECIDE. WHO ARE WE TO SAY THEY CAN'T BE PART OF THAT STUDY? ANOTHER ONE THAT GOT PROPOSED BY ONE OF OUR -- STEVE JAFI, I DON'T KNOW IF HE'S COMING TO -- LAST WEEK, STEVE WAS HERE LAST WEEK. OKAY. SO ONE OF OUR EX-COLLEAGUES, FRANK MILLER, AT LEAST DISCUSSED THE POSSIBILITY OF -- THERE SEEMED LIKE THESE COMPARISONS BETWEEN NET RISK RESEARCH, RISKS TO THESE PEOPLE FOR THE BENEFITS OF OTHERS AND CERTAIN KINDS OF ORGAN DONATION. SO MAYBE THE RIGHT STANDARD FOR THE ACCEPTABLE RISK LEVEL SHOULD BE THE RISKS OF ORGAN DONATION. THEY CONSIDER THAT, THEY ACTUALLY SORT OF KIND OF REJECT IT IN THE END BUT AT LEAST THAT'S ANOTHER POBILITYD. A DIFFERENT ONE THAT ALEX LONDON SUGGESTS IS MAYBE WE SHOULD DO AS A KIND OF PUBLIC SERVICE TO BE IN THIS RESEARCH, SO MAYBE WE SHOULD LOOK AT THE RISKS OF OTHER PUBLIC SERVICE ACTIVITIES LIKE BEING A FIREFIGHTER OR SOMETHING LIKE THAT. ANOTHER ONE IS VERY STRICT, I HAVE A COLLEAGUE WHO SAYS THIS, LOOK, DAVE, YOU JUST STARTED OUT YOUR WHOLE TALK WITH THE IMPORTANCE OF SOCIAL VALUE AND YOU HAD A BULLET THAT SAID MAKING SOCIAL VALUE DETERMINATIONS IS REALLY, REALLY, REALLY HARD. THE MOST ACCURATE THING YOU SAID IN THAT ENTIRE TALK -- HE ACTUALLY SAID THIS WHEN I GAVE THIS TALK RECENTLY IN HIGH THAI THAILAND, WAS THAT THOSE JUDGMENTS ARE REALLY HARD. IN FACT, THEY'RE SO HARD THAT THEY'RE ESSENTIALLY IMPOSSIBLE. AND IF THAT'S RIGHT, THEN THOSE JUDGMENTS CAN'T JUSTIFY EXPOSING PEOPLE TO HARDLY ANY RISKS AT ALL. AND IF THAT'S RIGHT, THEN THIS CAP ON THE NET RISKS TO WHICH WE COULD EXPOSE PEOPLE IN RESEARCH SHOULD BE REALLY, REALLY, REALLY LOW. THAT'S THE ONLY WAY TO MAKE SURE THAT WE'RE DOING ETHICAL RESEARCH. SO THAT'S -- OBVIOUSLY WE'VE GOT THE WHOLE -- AND THAT'S NOT JUST IN OUR DEPARTMENT, WE'VE GOT BASICALLY ALL OF THE EXTREMES REPRESENTED. SO OKAY. THE SUMMARY OF THIS IS I STILL THINK THAT RISK/BENEFIT EVALUATION IS CENTRAL TO DOING ETHICAL RESEARCH, I THINK HAVING A SYSTEMATIC FRAMEWORK LIKE THIS CAN HELP IRBs TO DO IT RIGHT, HELP INVESTIGATORS TO DO IT RIGHT, AND HOPEFULLY IF I HAVEN'T CONFUSED YOU TOO MUCH, I'VE ALSO CONVINCED YOU I THINK THERE ARE A LOT OF REALLY INTERESTING, IMPORTANT QUESTIONS THAT WE STILL HAVE TO FIGURE OUT IN THIS REGARD. OKAY. THANK YOU. [APPLAUSE] SO WE HAVE TIME FOR QUESTIONS IF I HAVEN'T COMPLETELY KNOCKED EVERYBODY OUT. AND YOU SEE THAT I DO HAVE QUESTIONS, SO IF YOU GUYS DON'T ASK ME QUESTIONS, I'M GOING TO ASK YOU QUESTIONS. AND MAYBE WHAT I'LL EVEN DO IS I'LL I'LL STARE AT A PARTICULAR PERSON AND I'LL PICK ON THEM. DO YOU WANT THE PERSON NEXT TO YOU TO FEEL UNCOMFORTABLE LIKE THAT? NO, YOU DON'T WANT THAT! [LAUGHTER] PROTECT YOUR NEIGHBORS. EVERYBODY GETS A MINUTE THE. COULD YOU COME TO THE MIEX? I THINK MICS? >> HOW DOES TISSUE BANKING FALL UNDER THESE CATEGORIES? LIKE YOU SAID IN RESEARCH WHEN YOU WANT TO GET, FOR EXAMPLE, BIOPSIES AND YOU'RE LOOKING AT GETTING MULTIPLE BIOPSIES FOR ARCHIVING FOR LOOKING IN TO THE FUTURE. HOW DOES THIS FALL INTO THE RISKS BENEFITS AND THE ETHICS? >> WELL, YOU HEARD THE LECTURE, RIGHT? YOU'RE AN EXPERT ON RISK/BENEFIT ASSESSMENT. DO YOU HAVE A GUESS ON HOW IT WOULD GO? >> I DON'T KNOW. [LAUGHTER] >> TO BE HONEST. HUMAN SUBJECTS, I WORK WITH SAMPLES -- >> HERE'S A BASIC WAY, TELL ME IF I MISSED THE IMPORTANT PART OF YOUR QUESTION. SO SAMPLE RESEARCH IS HUGE NOW. EVERY PROTOCOL I'VE REVIEWED FOR THE LAST FIVE YEARS TAKES SOME SAMPLES, STORES THEM TO TRY TO DO SOME FUTURE RESEARCH ON THEM. SO HOW DO YOU DO THAT RISK/BENEFIT WISE? THERE'S A COUPLE THINGS YOU NEED TO DO. OBVIOUSLY THERE'S JUST THE RISK OF THE COLLECTION OF THE SAMPLE. USUALLY THAT'S PRETTY MINIMAL. MIGHT BE A SINGLE BLOOD DRAW, MIGHT BE A BUCCAL SWAB, SO USUALLY THE RISKS OF THE INTERVENTION ITSELF ARE PRETTY MINIMAL. USUALLY THE RISKS PEOPLE WORRY ABOUT ARE THE RISKS OF INFORMATION FLOW THAT MY HAPPEN AFTER YOU GET THE SAMPLE. SO I GET THE SAMPLE AND I LEARN THAT THIS PERSON HAS A CERTAIN MUTATION. FOR A BAD DISEASE. IS THERE A POTENTIAL FOR STIGMA IF OTHER PEOPLE FIND OUT ABOUT THAT? POSSIBILITY? THAT'S ONE. ANOTHER ONE IS, DO I TELL THEM? SHOULD I GO BACK AND TELL THEM? AND IF I DO, IS THAT A POTENTIAL BENEFIT FOR LEARNING THAT INFORMATION OR IS THAT ACTUALLY A RISK BECAUSE THEY MIGHT END UP HAVING SOME SURGERY THAT THEY DON'T NEED? SO THOSE ARE THE KINDS OF RISKS AND BENEFITS THAT PEOPLE REALLY NEED TO FOCUS ON. I CAN TELL YOU WHAT IRBs MOSTLY FOCUS ON IN MY EXPERIENCE THEY WORRY ABOUT PRIVACY AND CONFIDENTIALITY, MAKE SURE NO ONE ELSE CAN GET THE INFORMATION. I THINK THAT'S IMPORTANT BUT I THINK THE RISKS OF THAT ARE JUST EXTRAORDINARILY LOW, SO I HAVE COLLEAGUES IN NHGRI THAT ESTIMATE THIS RESEARCH HAS BEEN DONE WITH HUNDREDS AND HUNDREDS OF MILLIONS OF SAMPLES AND WE STILL HAVE TROUBLE FINDING EVEN ONE EXAMPLE OF A CASE IN WHICH SOMEBODY GOT IN, BROKE INTO A LAB, GOT INTO THE COMPUTER, GOT SOMEBODY'S IDENTITY, DENIED THEM INSURANCE, A JOB OR STIGMATIZED. IF IT HAPPENS, IT ALMOST NEVER HAPPENS, SO THAT RISK I THINK IS REALLY LOW. I THINK THE REAL QUESTION IS FIGURING OUT WHAT INFORMATION WE'RE GOING TO GIVE BACK AND WHAT'S THE IMPACT OF GIVING THAT INFORMATION BACK. I THINK WHAT WE STILL DON'T KNOW IS WE STILL DON'T KNOW WHAT INFORMATION IS GOOD FOR PEOPLE TO GET AND WHAT INFORMATION JUST MAKES THEM NERVOUS, WHAT INFORMATION THEY DON'T UNDERSTAND AND WHAT INFORMATION LEADS THEM TO HAVING UNNECESSARY CLINICAL PROCEDURES. I THINK THAT'S THE REAL CHALLENGE. >> ALSO NEXT WEEK -- [INAUDIBLE] >> PERFECT. SO EVERYBODY'S GOT TO SHOW UP NEXT WEEK. >> HI. MY QUESTION IS, WHY DO YOU THINK WE'RE SO OBSESSED ABOUT RISK AND BASICALLY DISCARD SOME BENEFITS, LIKE SAY WE'RE NOT GOING TO KRL THE SECOND CONSIDER THE SECOND WAVE BENEFITS OR OTHER BENEFITS? >> I DO THINK THERE'S THIS KIND OF DISPROPORTIONATE ASSESSMENT, RIGHT? RISK/BENEFIT ASSESSMENT IS SUPPOSED TO BE DO THE POTENTIAL BENEFITS JUSTIFY THE RISKS. AND SAID IN THAT WAY, IT SEEMS LIKE THEY'RE BOTH EQUALLY IMPORTANT, BUT I DO THINK THERE'S WAY IN WHICH THERE'S A LOT MORE FOCUS IN RESEARCH ETHICS ON THE RISKS THAN THERE IS ON THE POTENTIAL BENEFITS, EITHER SOCIAL VALUE THAT I TALKED ABOUT OR THE POTENTIAL BENEFITS TO EVEN THE SUBJECTS. SO A LOT OF IRBss, FOR INSTANCE, ARE REALLY RELUCTANT TO EVEN SAY THAT BEING IN RESEARCH OFFERS POTENTIAL BENEFITS TO SUBJECTS BUT THEY'RE HAPPY TO TALK ABOUT THE RISKS. SO I THINK THERE IS THIS DISCREPANCY. I THINK SOME OF IT HAS TO DO WITH JUST OUR ATTITUDE TOWARDS RISKS. I THINK THERE'S A WAY -- I THINK THERE'S A DEEP FACT ABOUT ETHICAL THEORY WE COULD TALK ABOUT WHERE I THINK THE PEOPLE ARE JUST MORE WORRIED AND MAYBE IT'S MORE PROBLEMATIC TO DO SOMETHING THAT HURTS SOMEBODY THAN TO HELP SOMEBODY. LIKE IF I HURT A LITTLE KID, THAT'S TERRIBLE, RIGHT? IF I GIVE A LITTLE KID SOMEBODY THAT HELPS THEM A LITTLE BIT EU, YOU'RE LIKE, YEAH, WHATEVER, THAT'S NICE. I THINK THERE'S THIS DEEP DISCREPANCY BETWEEN THE TWO OF THEM. THE OTHER IS I THINK PEOPLE ARE JUST WORRIED IN THE RESEARCH CONTEXT, WE THINK ABOUT RESEARCH AS REALLY RISKY, AS UNCERTAIN, SO WE FOCUS MORE ON THE RISKS. I THINK THAT'S CHANGING, THOUGH, THERE'S A CLAIM THAT USED TO BE REALLY THE FOCUS, BUT THINGS LIKE RESEARCH ON AIDS, RESEARCH ON BREAST CANCER WHERE YOU START SEEING PEOPLE REALLY GETTING SERIOUS BENEFITS, MAYBE THERE'S MORE OF AN EMPHASIS OR RECOGNITION THAT THEY COULD BE BENEFICIAL AS WELL. WE HAVE TIME FOR MAYBE TWO MORE QUESTIONS. YES. INTO URBAN >> I WAS INTRIGUED A LITTLE BY YOUR COMMENT ABOUT THE PRIORITIZATION ISSUES. MOSTLY BECAUSE I NEVER REALLY THOUGHT ABOUT THAT BEING PART OF THE IRB,I WAS THINKING THAT OF OCCURRING MORE OFTEN ON THE DECISION OF WHICH THINGS TO FUND. >> YEP. >> SO I'M KIND OF WONDERING WHAT KIND OF RISK-BENEFIT ANALYSIS GOES INTO FUNDING DECISION AND HOW OFTEN THAT ACTUALLY COMES ALONG FURTHER IN THE PROCESS AND GETS TO THE IRB. >> YEP. I HAVE A REALLY CLEAR ANSWER FOR YOU, I DON'T KNOW. CHRISTINE MIGHT HAVE MORE TO SAY ABOUT THIS. I THINK THAT -- SO THERE'S TWO PROBLEMS. ONE IS, I THINK THERE IS EVEN THIS DEBATE ABOUT WHETHER OR NOT YOU SHOULD DO PRIORITIZATION AT ALL. SOME PEOPLE THINK THAT TRYING TO PRIORITIZE IS, A, REALLY HARD, AND B, YOU'RE MORE LIKELY TO MESS IT UP THAN GET IT RIGHT, SO MAYBE WHAT WE SHOULD DO INSTEAD IS, THE PHRASE IS, LET SCIENTISTS BE SCIENTIST, LET THEM FOCUS ON WHAT IF THEY WANT TO FOCUS ON WITH THE THOUGHT THAT THAT'S MAYBE HOW WE'RE GOING TO GET THE BIGGEST SORT OF BANG IN THE BUCK FOR THE END. SO THAT'S A PROBLEM. BUT DO YOU THINK WE SHOULD DO SOME PRIORITIZATION, I THINK WE SHOULD. IT'S A QUESTION OF WHO SHOULD DO IT. ON OUR IRB, YOU MIGHT THINK AND A LOT OF PEOPLE THINK IRBs SHOULDN'T BE DOING THIS. BUT I CAN TELL YOU, WE'RE SITTING ON THE IRB AND WE'RE TALKING AMONGST OURSELVES AND WE'RE LIKE, YEAH, WHY DOESN'T THIS GUY JUST ADD ONE MORE BLOOD DRAW? HE COULD FIGURE OUT THIS QUESTION THAT'S REALLY BEEN BOTHERING A LOT OF PEOPLE. YOU MIGHT SAY, I DON'T KNOW, TO ME IT JUST FEELS LIKE THAT'S PART OF WHAT IRBs SHOULD BE DOING, BUT IF THEY'RE DOING THAT, NOW IT LOOKS LIKE THEY'RE IN THE BUSINESS OF MAKING THESE COMPARATIVE JUDGMENTS AND THEN DOES THE WHOLE THING JUST GET TO BE TOO COMPLICATED, IRBs ARE ALREADY DOING THINGS THAT ARE COMPLICATED. SO I THINK WHAT WE NEED IS WE NEED SOMEBODY TO CHART OUT THE WHOLE SYSTEM AND MAKE SURE THAT ALL THESE DECISIONS ARE GETTING MADE BY SOMEBODY SOMEWHERE AND I WORRY THAT BECAUSE IT'S SUCH A COMPLICATED SYSTEM, THERE'S THIS DIFFUSION OF RESPONSIBILITY AND SOME OF THESE QUESTIONS AREN'T GETTING ASKED IN THE WAY THEY SHOULD AND WE NEED DO A BETTER JOB OF IT. >> THAT'S PROBABLY TRUE. THANKS. >> HI. MY QUESTION IS, DO YOU EVER ASK YOURSELF WHETHER YOU WOULD ACTUALLY GO IN A CLINICAL TRIAL BEFORE YOU -- TO UNDERSTAND THE RISK AND BENEFIT ANALYSIS THIS ACTUALLY POINTS OUT TO THE QUESTION THAT THE OTHER GENTLEMAN JUST ASKED, AND ALSO AT WHAT POINT DO YOU THINK SOCIAL VALUES WOULD JUSTIFY INDIVIDUAL RISKS? >> YEAH, GOOD QUESTION. SO TO WHAT EXTENT DOES SOCIAL VALUE JUSTIFY THE RISKS, I DON'T KNOW IF YOU REMEMBER WHEN I HAD THE SLIDE WHERE IT SAID, THE SOCIAL VALUE OF THE STUDY, AND WHETHER THE NET RISKS ARE ACCEPTABLE OR EXCESSIVE, THEN I HAD A LITTLE ARROW THAT SAID SHOULD THE ORDER OF THESE BULLETS BE REVERSED. SO I THINK BASICALLY THE QUESTION THERE IS A QUESTION OF, DO YOU THINK THAT THE LIMIT ON THE RISKS YOU WOULD EXPOSE SUBJECTS TO, IS THAT SORT OF FIXED INDEPENDENT OF THE VALUE OF THE STUDY? NO MATTER HOW VALUABLE THE STUDY IS, WE CAN ONLY EXPOSE PEOPLE TO 10 BLOOD DRAWS OR SOMETHING. OR DO YOU SAY YEAH, THAT'S USUALLY TRUE, BUT IF YOU GET THIS REALLY, REALLY VALUABLE STUDY, THAT'S GOING TO ALLOW YOU TO SAY, MAYBE A COUPLE BIOPSIES IS JUSTIFIED BECAUSE THIS STUDY SO VALUABLE. NOT FOR THE SUBJECTS BUT FOR SOCIETY. >> THOSE EXAMPLES IN WHICH THE NET DIFFERENCE OF RISK AND BENEFIT ARE LARGE. >> RIGHT. >> SO THERE ARE ACTUALLY SOME POINTS IN THEY'RE [INAUDIBLE] SHO HOW WOULD >> SO YOU WANT AN EXAMPLE WHERE THE BENEFIT OF THE STUDY SORT OF IS REALLY SIMILAR TO THE RISKS TO THE SUBJECTS, LIKE DOES IT JUSTIFY THE RISKS? IT'S A CLOSE CALL. SOMETHING LIKE THAT? >> YEAH. >> OKAY. SO I WOULD SAY FOR ME, THAT DEPENDS UPON HOW RISKY THE STUDY IS. SO WE SEE THESE STUDIES WHERE THEY BASICALLY JUST ASK PEOPLE A COUPLE OF QUESTIONS. THERE'S A SMALL CHANCE THEY MIGHT MAKE THE PEOPLE ANXIOUS. WE'RE NOT REALLY SURE HOW VALUABLE THESE QUESTIONS ARE. IN A CASE LIKE THAT, WE'RE LIKE, YEAH, GO AHEAD. BUT IF THEY WANT TO DO MORE INVASIVE THINGS LIKE BIOPSIES, THEN IT'S THE A CLOSE CALL, I'M GOING TO SAY, NO, YOU CAN'T DO THAT. I'VE GOT TO BE CONVINCED THAT THE SOCIAL VALUE OF DOING THIS REALLY JUSTIFIES THOSE RISKS. MY COLLEAGUE IS LIKE, HOW CAN YOU TELL THAT THE SOCIAL VALUE -- THE VALUE OF THIS INFORMATION IN 20 YEARS IS GOING TO JUSTIN FALCONER THESE RISKS JUSTIFY THE SE RISKS TO THESE PEOPLE, SOMETIMES THAT'S HARD BUT SOMETIMES YOU CAN FIGURE IT OUT. >> THANK YOU, DAVE. [APPLAUSE] HOPEFULLY EVERYBODY'S GOT A LOT TO THINK ABOUT. PLEASE TAKE A BREAK AND IF YOU CAN COME BACK AT 9:40, THAT WE'RE VERY LUCKY TO HAVE WITH US TODAY DR. ALAN FLEISCHMAN, PROFESSOR OF PEDIATRICS AND PROFESSOR IN THE DEPARTMENT OF EPIDEMIOLOGY AND POPULATION HEALTH AT ALBERT EINSTEIN COLLEGE OF MEDICINE IN NEW YORK. ALAN IS A WELL-KNOWN, WELL WRITTEN GREAT REPUTATION PEDIATRICIAN WHO IS ALSO A BIOETHICIST AND HAS DONE A LOT OF REALLY IMPORTANT WORK ON THE ETHICS OF RESEARCH WITH CHILDREN. SO THANK YOU FOR COMING, ALAN. >> THANK YOU VERY MUCH. IT'S MY PLEASURE TO BE BACK AT THE NIH. I WAS FIRST HERE IN 1972, WHICH IS PROBABLY BEFORE MANY OF YOU WERE BORN. AND OVER MY EDUCATION AND MY TRAINING, I'VE LEARNED THAT SOME OF MY BEST PHILOSOPHERS ARE FRIENDS. AND I ENJOY WORKING WITH PHILOSOPHERS, I WRITE WITH THEM QUITE A BIT, BUT I'M MUCH MORE DOWN TO EARTH. NOT QUITE A COUNTRY DOC, BUT TRY TO DO RESEARCH ETHICS FROM THE PERSPECTIVE OF PROTECTING THE SUBJECTS AND THINKING ABOUT SOME OF THE ISSUES THAT DAVID SHARED WITH YOU IN A MORE PRACTICAL MANNER. LET ME JUST TELL YOU ONE STORY. I LEFT THE NIH IN 1975. I ACTUALLY CAME BACK FOR A SEND ITERATION IN THE 2000s, BUT I WAS AT THE NIH FROM '72 TO '75, AND CAME BACK TO THE ALBERT EINSTEIN COLLEGE OF COLLEGE OF MEDICINE AN D MY CHAIR ASKED ME IN THE DEPARTMENT OF PEDIATRICS IF I WOULD BE ON THE IRB. A NEW VENTURE IN 1975. THEY HAD ALREADY CALLED WHAT THEY CALLED A RESEARCH COMMITTEE, NOW IT WAS CALLED AN INSTITUTIONAL REVIEW BOARD OH. THEY WERE ALL A BUNCH OF MEN AND THEY WERE ALL CHAIRS OF DEPARTMENTS, AND I WAS THE KID WHO JUST CAME FROM THE NIH WHO WAS INTERESTED IN ETHICS AND VIRGINIA BEACH. SO THE FIRST DAY I READ ALL THE PROTOCOLS. I HAD A BIG PAPER TRAIL OF PROTOCOLS, AND I DIDN'T KNOW THAT NOBODY ELSE IN THE ROOM HAD READ ALL THE PROTOCOLS. BUT I READ ALL THE PROTOCOLS. AND THE FIRST PROTOCOL WAS A STUDY -- THEY WERE WELL-KNOWN FOR SEMINOLE WORK IN ELECTROPHYSIOLOGY OF THE HEART. SO ONE OF THE FIRST PROTOCOLS, IT WAS JULY, AND THEY WERE GOING TO TAKE NORMAL VOLUNTEERS, MOSTLY COLLEGE STUDENTS BACK IN NEW YORK FOR THE SUMMER WHO WOULD VOLUNTEER, AND THEY'D GET $100, A LOT OF MONEY IN 1975, AND THEY'D COME TO THE CATH LAB AND THEY'D FLOAT SOME CATHETERS UP INTO THEIR HEARTS, THEY'D DO WHAT IS CALLED CAUSE FIBRILLATION. THEY WOULD CAUSE THE HEART TO STOP FUNCTIONING. AND THEN THEY WOULD GIVE SOME DRUGS TO SEE IF THEY COULD CHANGE THAT, AND IF THEY COULDN'T, THEY WOULD JUST ELECTRICALLY RESTART THE HEART. $100, AND IT SAID IN THE INFORMED CONSENT, YOU MAY DIE. [LAUGHTER] IT TOOK THEM NINE MINUTES TO GO THROUGH THAT PROTOCOL AND APPROVE IT. THE PHILOSOPHER THEN, A VERY, VERY FAMOUS PHILOSOPHER WHOSE NAME I WILL NOT TELL YOU, WHO WAS NEVER ON THE FACULTY AT EINSTEIN BUT WAS ON THE FACULTY AT A VERY IMPORTANT ETHICS CENTER IN HASTINGS, THE NAME OF WHICH IS THE HASTINGS CENTER. HE'S NO LONGER THERE. HE'S STILL VERY ACTIVE IN THE FIELD. HE SAID, WELL, YOU KNOW, AUTONOMY TRUMPS. THAT'S IT. THEY KNOW. THEY'VE BEEN TOLD. THEY'RE GOING TO DO THIS. HMMM. APROPOS TO THE COMMENT ON WHO CHECKS THE LEVEL OF RISK FOR SUBJECTS. THAT STUDY MADE ME START MY THEORY OF YOU'VE GOT TO BE OUT OF YOUR -- MIND IF YOU DO THE STUDY. THE SAME IRB, THIS IS NOT -- THIS IS ABSOLUTELY TRUE, ON THE SAME DAY, I WAS THE PEDIATRIC REPRESENTATIVE. THERE WAS AN ADOLESCENT STUDY, A CLASSIC QUESTIONNAIRE TO KIDS WHO WERE 15 AND 16 ABOUT SEX, DRUGS AND ROCK AND ROLL. THOSE ARE CLASSIC STUDIES IN THOSE DAYS OF LEARNING WHAT KIDS THINK ABOUT DRUGS, SEXUAL ACTIVITY, WASN'T SO MUCH INTO PRESCRIPTION DRUGS AS IT WOULD BE NOW. IT TOOK THEM 40 MINUTES TO ARGUE ABOUT WHETHER WE SHOULD ALLOW ADOLESCENTS TO BE ASKED IF THEY'RE SEXUALLY ACTIVE OR THEY WERE OUT TO PROTECT THE CHILDREN BECAUSE IF WE ASKED THEM QUESTIONS, THE CHILDREN MIGHT THINK THAT WE THINK THESE ARE ACTIVITIES THEY SHOULD BE DOING. SO I RAISED MY HAND FOR THE VERY FIRST TIME AT THE IRB AND I SAID YOU KNOW, I'M CLOSER TO AN ADOLESCENT THAN ANY OF YOU GUYS BUT I U. MAY HAVE SOME ADOLESCENTS AT HOME OR MAYBE THEY ALREADY LEFT, BUT DO YOU THINK THINK ADOLESCENTS AREN'T THINKING ABOUT THIS EVERY DAY? DO YOU THINK THIS ISN'T WHAT THEY THINK ABOUT OR DO, AND DO YOU THINK IT'S NOT GOOD FOR US TO LEARN ABOUT HOW THEY'RE THINKING ABOUT IT SO WE CAN UNDERSTAND HOW ADOLESCENTS ARE THINKING AND FEEL SO WE CAN ACTUALLY DEVELOP BETTER WAYS OF HELPING ADOLESCENTS? NOW, YOU MAY THINK THAT'S, YOU KNOW, LIKE TRIVIAL, EASY STUFF, BUT IN 1975, THAT WAS LIKE NEW AND CUTTING EDGE. THE WHOLE FIELD OF ADOLESCENT MEDICINE WAS JUST BEGINNING, AND I TELL YOU THAT STORY TO UNDERSTAND THAT IRBs ARE COMPLEX, THEY'RE POLITICAL, THEY'RE VERY INDIVIDUAL AND IF YOU'VE BEEN ON ONE IRB, YOU'VE SEEN ONE IRB. THEY'RE ALL DIFFERENT. BUT THEY'RE NOT THE ONLY WAYS WE PROTECT HUMAN SUBJECTS OF RESEARCH. THEY'RE NOT THE ONLY WAYS THAT WE PRIORITIZE RESEARCH, ONE OF THE QUESTIONS BEFORE. AND WE DO THAT NOT ONLY THROUGH FUNDING, BUT I CHAIR NOW, FOR MY SINS, THE PEDIATRIC RESEARCH COMMITTEE AT THAT CHILDREN'S HOSPITAL AT THE ALBERT EINSTEIN COLLEGE OF MEDICINE WHO MUST REVIEW EVERY RESEARCH PROPOSAL BEFORE IT'S SUBMITTED TO THE IRB. AND WE'RE NOT LOOKING NECESSARILY AT PROTECTION OF RESEARCH SUBJECTS AS MUCH AS IRBs DO. WE'RE LOOKING MORE AT THE QUALITY OF THE SCIENCE. AND THAT'S WHAT YOUR DEPARTMENTS DO, THAT'S WHAT YOUR CHIEFS DO, OR SHOULD, AS YOU DEVELOP YOUR RESEARCH. SO THERE OUGHT TO BE SOME PROTECTIVE MECHANISMS FOR PRIORITIZATION, AND EVEN RISK ASSESSMENT, LONG BEFORE YOU GET TO THE IRB. HOW MANY OF YOU ARE ON IRBs? ONE? HOW MANY OH OF YOU OF YOU DO WORK WITH CHILDREN OR WISH TO DO WORK WITH CHILDREN? SO IT'S A SMALL NUMBER. I'LL PICK ON YOU LATER. BUT LET'S GET STARTED HERE. SO I DISCLOSE THERE ARE NO FINANCIAL CONFLICTS BUT IF YOU THINK THIS IS AN UNBIASED TALK, YOU'RE WRONG. MY VIEWS ARE SOLELY MINE. BUT LIKE DAVID, I'LL TELL YOU WHEN PEOPLE GENERALLY DISAGREE WITH ME, AND THEY'RE NOT THE POSITION OF ANY ORGANIZATION OR PERSON WITH WHOM THE SPEAKER IS OR HAS BEEN AFFILIATED INCLUDING THE NIH. SO THE FIRST QUESTION, OF COURSE, IS ALWAYS, HOW CAN WE JUSTIFY RESEARCH WITH CHILDREN? THEY CAN'T GIVE US INFORMED CONSENT IN THE GENERAL MANNER, ALTHOUGH WE HAVE EVOLVING AUTONOMY IN ADOLESCENTS, WE RESPECT THEIR INVOLVEMENT, WE ASK FOR THEIR CONSENT, SOME CALL IT ASSENT IN ADOLESCENTS, WE ASK FOR ASSENT IN YOUNGER CHILDREN. BUT HOW DO WE JUSTIFY RESEARCH WITH CHILDREN? THEY ARE VERY VULNERABLE SUBJECTS. NOW SOME OF US WHO HAVE BEEN DOING RESEARCH WITH CHILDREN FOR A LONG TIME, AND IN A PLACE LIKE THIS, THE LARGEST RESEARCH INSTITUTION IN THE WORLD, WE -- IT'S KIND OF A SILLY QUESTION. YOU DO RESEARCH BECAUSE YOU NEED TO FIND OUT NEW THINGS. WELL, PARTICULARLY WITH CHILDREN, THEIR DISEASES ARE UNIQUE. I TOOK CARE OF PREEMIES FOR 25 YEARS. I CALL MYSELF A FORMER NEONATOLOGIST AND THAT MAKES THE FELLOWS FEEL BETTER. THEIR DEVELOPMENT IS INCREDIBLY INTERESTING. FROM 400-GRAM PREEMIES TO 350-POUND ADOLESCENTS. OR MORE. THERE'S NO REASON IN THE WORLD TO BELIEVE THAT THAT DEVELOPMENT DOESN'T NEED ASSESSING. THEIR GROWTH, THEIR METABOLISM AND THEIR TOX TOXICITY, AND NOW WE KNOW THAT THINGS THAT IMPACT ON FETUSES AND INFANTS ARE PREDETERMINE NANTS OF ADULT DISEASE, SO HOW CAN WE NOT STUDY CHILDREN? BUT ARE WE WILLING TO PLACE CHILDREN AT RISK TODAY FOR THE SAKE OF OTHER CHILDREN WHO MIGHT BENEFIT IN THE FUTURE OR ADULTS WHO MIGHT BENEFIT IN THE FUTURE? THAT'S THE KEY QUESTION WE ASK IN RESERCH ETHICS CONCERNING KIDS. AND IF WE ARE, HOW DO WE PROTECT THE CHILDREN TO ASSURE THEY'RE NOT PLACED AT UNDUE RISK? THAT 22-YEAR-OLD IN THAT CATH LAB WHOSE HEART WAS FIB LATED WAS PLACED IN UNDUE RISK. WE WOULD NEVER ALLOW CHILDREN TO HAVE THAT LEVEL OF RISK REGARDLESS OF THEIR ASSENT OR THEIR PARENTS' CONSENT. SO HERE'S A QUICK LISTING. WITH THE NAZI EXPERIMENTS ON THE BOTTOM OF THE SLIDE, EVERYONE THINKS RESEARCH ATROCITIES BEGAN IN WORLD WAR II. BEFORE WORLD WAR II IN THE UNITED STATES OF AMERICA, PEDIATRICIANS WELL-INTENTIONED PEDIATRICIANS WHO WERE CLINICAL SCIENTISTS DID SPINAL TAPS ON HEALTHY CHILDREN TO DEFINE NORMAL VALUES. THEY DIDN'T KNOW WHAT WAS ABNORMAL, BUT THEY KNEW THAT YOU COULD GET MENINGITIS AND YOU NEEDED TO DO SPINAL TAPS ON KIDS WHO WERE SICK, SO WHAT SHOULD THE NORMAL BE THAT YOU COMPARED THE SIC TO? SO THEY TOOK SOME NORMAL KIDS AND DID SPINAL TAPS. WHO WERE THOSE CHILDREN? THEY WERE GENERALLY IN ORPHANAGES, THEY WERE GENERALLY ABANDONED IN SOME KIND OF FOSTER SITUATION. THEY DID X-RAYS AND FLUOROSCOPY TO DETERMINE NORMAL STOMACH EMPTYING TIME AS PART OF METABOLIC -- AND THEY WERE -- TO COLLECT STOOL FOR METABOLIC BALANCE STUDIES THE. WERE HEROS IN PEDIATRICS, THEY WERE PUBLISHING IN THE JOURNALS. SO THERE WERE THINGS THAT PEDIATRICIANS WERE PROUD OF HAVING DONE THAT SOME OF US WOULD FROWN UPON NOW AS INAPPROPRIATE FOR KIDS. THAT WAS PF THE BEFORE THE NAZI EXPERIMENTS. I'M NOT GOING TO TALK ABOUT THE TWIN STUDIES VERY MUCH BUT JUST TO SAY THAT THESE WERE EVIL, NOT WELL INTENDED BUT THEY HAD RESEARCH QUESTIONS SOMEWHERE BEHIND THEM. AND ONE OF THE INTERESTING ETHICAL QUESTIONS HAS ALWAYS BEEN, DO YOU USE ANY OF THE DATA THAT ARE OBTAINED FROM EVIL? AND WE'RE NOT GOING TO TALK ABOUT IT BUT WE COULD LATER IF YOU'D LIKE. SO AFTER THE NAZI EXPERIMENTS CAME THE NUREMBERG TRIALS, THE DOCTORS' TRIALS, AND THE NUREMBERG CODE. THE FIRST STATEMENT OF THE NUREMBERG CODE WAS THE VOLUNTARY CONSENT OF HUMAN SUBJECTS IS ABSOLUTELY ESSENTIAL. SO EVERYBODY IN THE U.S. SAT THERE IN THE PEDIATRIC COMMUNITY AND SAID, WHOA, WE DON'T GET THE CONSENT FROM THE KIDS. SO WE GOT TO MAKE SURE THEY UNDERSTAND THAT THIS CODE MEANT TO PLEA PREE CLEUD PRECLUDE CONSENT FROM IT WAS PART OF THEIR REACTION TO THE DOCTORS' TRIALS. OF COURSE THIS WAS TOTALLY IGNORED IN THE UNITED STATES BECAUSE WE WEREN'T THOSE EVIL PEOPLE LIKE THOSE PEOPLE IN NAZI GERMANY, SO WE WERE GOING TO DO OUR RESEARCH HERE, WE WERE GOING TO CREATE THE NIH AND WE WERE GOING TO ACTUALLY FOSTER RESEARCH WITH ADULTS AND THEN QUICKLY CHILDREN, AND WE WERE GOING TO DO THAT WORK BECAUSE IT WAS IMPORTANT FOR THE HEALTH OF AMERICANS AND OTHERS IN THE WORLD. BUT THE NUREMBERG CODE SAID WE COULD NOT. SO AT SOME POINT WE WERE GOING TO NEED TO JUSTIFY RESEARCH IN CHILDREN IF WE WERE STUDYING OUR PAST. NOW POST WORLD WAR II, THERE ARE A WHOLE HOST OF PEDIATRIC-RELATED CONCERNS, AND I'M GOING TO GO THROUGH EACH OF THESE VERY QUICKLY, BUT JUST TO SAY TO YOU THAT THE REASON THAT WE WORRY ABOUT RESEARCH WITH CHILDREN IS BECAUSE CHILDREN HAVE BEEN HURT IN RESEARCH. IT'S NOT JUST AN IMPEDIMENT TO GOOD WORK. IT'S NOT JUST A HURDLE TO GET BY BY. LAST WEEK IF YOU READ "THE NEW YORK TIMES," IT PROBABLY WAS ALSO IN THE "WASHINGTON POST," THERE WAS AN ADULT STUDY THAT WAS PROUT UP AND BROUGHT UP AND QUESTIONED . THAT DOESN'T MEAN THE ADULT STUDY IS EVIL BECAUSE SOMEBODY QUESTIONED IT, BUT ALL OF THESE PEDIATRIC STUDIES HAVE BEEN QUESTIONED AND I WANT TO GO THROUGH THEM VERY QUICKLY, BUT TO SHOW YOU THAT WE NEED TO WORRY ABOUT HOW WELL-INTENTIONED DOCTORS DO RESEARCH. WILLOW BROOK STATE SCHOOL IN STATEN ISLAND IN NEW YORK, YOU KNOW, THAT'S THE OTHER BURROUGH, THERE WAS A VERY FINE, WELL-KNOWN STATE SCHOOL, IT WAS REALLY FOR THOSE CHILDREN WHO HAD BEEN ABANDONED AND THOSE WHO WERE DEVELOPMENTALLY SEVERELY DISABLED, AND THERE WAS A BIG PROBLEM WITH HEPATITIS A. WITH INFECTIOUS HEPATITIS IN THAT SCHOOL, BECAUSE MANY OF THE INFANTS WERE NOT HANDLED PERFECTLY, LET'S SAY, HEPATITIS SPREAD FROM STOOL TO MOUTH, AND THEY NEEDED TO UNDERSTAND BETTER ABOUT THE NATURAL HISTORY OF THAT DISEASE, THEY WERE CONCERNED THAT MAYBE GAMMA GLOBULIN MIGHT PREVENT TRANS MISSION OF THAT DISEASE OR AMELIORATE DISEASE, AND SOME OF THE FINEST SCIENTISTS IN NEW YORK WERE WORKING ON AN IMMUNIZATION, A VACCINE FOR HEPATITIS, AND THAT WAS ULTIMATELY WHERE THEY WERE GOING TO DO THE FIRST TESTING, AND THEY HAD JUST BUILT AN ABSOLUTELY BEAUTIFUL NEW WING TO THE HOSPITAL. SO THEY CREATED A STUDY. BUT IF YOU WANTED TO BE ADMITTED INTO THE NEW WING OF THE HOSPITAL FOR A NEW PATIENT, YOU HAD TO CONSENT TO BE IN THE STUDY. AND WHAT WAS THE STUDY? IT WAS QUITE SIMPLE. CHILDREN WERE DELIBERATELY INFECTED WITH HEPATITIS BY FEEDING EXTRACTS OF INFECTED PATIENT STOOL. AND THEY STUDIED THE NATURAL HISTORY OF THE DEVELOPMENT OF HEPATITIS. THEY JUSTIFIED IT BECAUSE THEY SAID WELL, MOST CHILDREN HERE GET HEPATITIS AT SOME POINT OR ANOTHER, SO WE'LL JUST GIVE IT TO THEM. SO WE CAN STUDY IT. THE PERSON WHO DID THAT STUDY, 25 YEARS LATER, WON THE MOST PRESTIGIOUS PEDIATRIC AWARD IN THE UNITED STATES. HMMM. THEN WE HAVE A BRITISH STUDY. ANDREW WAKEFIELD, YOU MAY KNOW THIS GENTLEMAN PHYSICIAN, HE STUDIED MUMPS, RUBELLA AND MEASLES VACCINE, WHEN IT WAS FIRST CREATED INTO A TRIPLE. IF ANY OF YOU HAVE CHILDREN, YOU KNOW THAT WE GIVE MMR. HE WAS STUDYING WHETHER THIS NEW TRIPLE VACCINE WAS EFFECTIVE AS COMPARED TO THE SINGLE VACCINES THAT REQUIRED THREE DIFFERENT SHOTS. HE CONCLUDED THERE SEEMS TO BE AN OWE ASSOCIATION BETWEEN MMR VACCINATION AT ABOUT 14 MONTHS, WE DO GIVE IT, AND THE DEVELOPMENT OF BOWEL DISEASE IN A PERVASIVE DEVELOPMENTAL DISORDER RESEMBLING AUTISM. NOW, YOU MAY KNOW THAT IN THE UNITED STATES TODAY, THERE'S AN EXTREME CONCERN ABOUT THE LACK OF ADEQUATE IMMUNIZATION AND IMMUNIZATION REFUSAL OF CHILDREN. IT'S A CLINICAL PEDIATRIC ISSUE. SERIOUS ISSUE. WELL, LOTS OF PARENTS BELIEVE THAT IMMUNIZATIONS ARE RELATED OR CAUSATIVE TO AUTISM. THERE ARE NO SCIENTIFIC DATA TO SUPPORT THAT CLAIM. BUT WAKEFIELD'S FIRST, FIRST ARTICLE, PUBLISHED IN LANCET IN 1998, CLAIMED THAT CAUSED THIS DROP, DRAMATIC DROP IN THE IMMUNIZATION RATE WITH MMR IN ENGLAND, AND THERE WERE SIMILAR AND CONTINUED DROPS IN THE U.S. BUT SON OF A GUN, BY 2004, LANCET PARTIALLY RETRACTED THE ARTICLE AND BY 2010, IT COMPLETELY RETRACTED THE ARTICLE BECAUSE ALL OF THE DATA THAT WAKEFIELD PUBLISHED WAS FRAUDULENT. HE WAS BEING PAID BY THE COMPANIES THIS MADE THE SINGLE VACCINES TO TRY TO FIND SOME REASON THAT THE TRIPLE WAS NOT EFFECTIVE OR WAS TOXIC. HE LOST HIS MEDICA LICENSE, HE WAS CONVICTED OF A CRIME, BUT HE HAD A DRAMATIC IMPACT BASED ON HIS RESEARCH "RESEARCH." THEN THERE WAS THE LEAD BASED PAINT STUDY THAT DR. WENDLER DID TELL YOU A LITTLE BIT ABOUT, ABATEMENT REPAIR. I ACTUALLY WAS A HOPKINS INTERN IN 1970, WAS AMAZED AT THE AMOUNT OF LEAD POISONING IN BALTIMORE, WAS ABSOLUTELY BLOWN AWAY THAT WHEN IN THE 1990s, IT WAS STILL JUST AS BAD AS IT HAD BEEN IN THE 1970s, AND SOME OF MY BEST FRIENDS LIVE IN BALTIMORE. IN THE 1990s, ABOUT 95% OF CHILDREN LIVING IN LOW INCOME HOUSING IN BALTIMORE WERE AT RISK FOR TOXIC LEAD LEVELS. ZERO IS NOT THE LEVEL OF TOXICITY, ZERO IS WHAT YOU AIM FOR, BUT TOXIC LEVELS. THEY'RE ACTUALLY LOWER NOW, BY THE CDC'S RECOMMENDATIONS. 40 TO 50% OF CHILDREN IN LOW INCOME AREAS HAD ELEVATED BLOOD LEAD LEVELS. INTO URBAN SO THIS WAS AN EXTRAORDINARY SERIOUS PUBLIC HEALTH PROBLEM. LEAD ABATEMENT OF AN INDIVIDUAL APARTMENT COST UP TO $10,000. AND THE OWNERS, AS DAVID SAID, WERE LIKELY TO LEAVE THE DAMN BUILDINGS EMPTY THAN ABATE THE APARTMENTS, AND THE CITY WAS NOT PREPARED TO SPEND $10,000 PER APARTMENT. THEY BLAMED THE LANDLORDS, MADE IT THEIR RESPONSIBILITY. THAT'S A POLITICAL DECISION. SO THE SCHOOL OF PUBLIC HEALTH DECIDED THAT LIKE OUR HIGHLY ACTIVE RETROVIRAL TREATMENT OF AIDS TODAY, AND OUR INTERNATIONAL STUDIES TO FIGURE OUT IS THE EXPENSIVE AMERICAN APPROACH THE BEST OR ONLY ADEQUATE APPROACH TO TREATMENT OR PREVENTION, THIS PUBLIC HEALTH GROUP DECIDED TO LOOK AT LESS ABATEMENT BUT SUFFICIENT ABATEMENT TO KEEP THE LEAD LEVELS BELOW TOXIC IN 50% OF THE STOCK -- OR 50% OF THE CHILDREN IN 95% OF THE HOUSING STOCK IN BALTIMORE. SO CAN PARTIAL LESS COSTLY LEAD ABAIMENT ACTUALLY ABATEMENT ACTUALLY WORK. THIS STUDY WAS REVIEWED BY AN IRB AT HOPKINS, AND IT'S A COMPLICATED STUDY, IT HAD THREE GROUPS, THE LOW ABAIMENT, MIDDLE ABATEMENT, THE LITTLE BETTER ABATEMENT AND THE FULL COURT PRESS ABATEMENT. SO FOUR DIFFERENT LEVELS. SOME CHILDREN WERE PLACED INTO HOUSING THAT WEREN'T IN, BUT THEY WERE LOOKING FOR HOMES, THEY WERE HOMELESS IN THIS LEVEL AND SOME WERE ALREADY IN THOSE KINDS OF HOMES SO THAT'S WHY YOU HAVE THIS SPLIT. THIS GOT A LOT OF CRITICISM. WHY WOULD YOU PUT HOMELESS KIDS INTO HOMES THAT WEREN'T FULLY THERE WERE TWO CONTROL GROUPS, FULLY ABATED AND A MODERN APARTMENT, THERE ACTUALLY WERE SOME IN BALTIMORE, WHICH SHOULD NOT HAVE HAD ANY LEAD AND DID NOT HAVE ANY LEAD. SO IT'S A COMPLICATED STUDY, AND IT WAS SEVERELY CRITICIZED. SEVERELY CRITICIZED, PRIMARILY FOR PUTTING KIDS INTO PLACES WHERE THEY WEREN'T DOING FULL ABATEMENTS. AND IT DIDN'T PASS WHAT WE'D CALL THE BALTIMORE NEWSPAPER TEST, WE WORRY ABOUT "THE WASHINGTON POST" TEST HERE AT THE NIH, WE WORRY ABOUT "THE NEW YORK TIMES" TEST IN NEW YORK, OR MAYBE THE "NEW YORK TIMES" POST-TEST. AND THERE WAS A LOT OF CRITICISM OF THIS STUDY WHEN TWO YOUNG GIRLS WERE FOUND TO HAVE HIGH LEAD LEVELS. NOW THESE CHILDREN WERE BEING STUDIED, FOLLOWED CAREFULLY FOR LEAD LEVELS. THEIR HOMES WERE BEING TESTED FOR LEAD, BUT TWO CHILDREN WERE FOUND TO HAVE HIGH LEAD LEVELS THAT REQUIRED TREAT:. MENT. WHAT ISN'T WELL STUDIED OR KNOWN IS THAT THOSE TWO CHILDREN WERE ACTUALLY IN THESE HOUSES. HUH! MAYBE THEY SPENT TIME AT THEIR GRANDMA'S HOUSE AFTER SCHOOL. MAYBE THEY WENT TO THEIR AUNT'S ON THE WEEKEND. I DON'T KNOW. BUT THE TWO CHILDREN WHO WERE LEAD-TOXIC WERE NOT IN ANY OF THOSE GROUPS. JUST -- YOU NEED TO KNOW THAT. YET, THE WORLD OF MARYLAND WENT NUTS OVER THIS STUDY. SEVERE LEA CRITICIZED JOHNS HOPKINS AND THE KRUEGER KENNEDY CENTER. NOW HERE'S ANOTHER ONE. THE EPA, AN ORGANIZATION THAT I RESPECT, HAVE WORKED FOR, THE STUDY CONDUCTED BY THE EPA IN FLORIDA IN 2004, THE EPA NEVER HAD AN IRB BEFORE THIS STUDY. IT USED LOCAL IRBs AS ITS COLLABORATIVE IRB. SO IT WAS DESIGNED TO UNDERSTAND HOW DO YOUNG INFANTS WHO CRAWL ON THE FLOOR A LOT, YOU KNOW THOSE LITTLE 9 MONTH OLD, 12 MONTH OLD, 15 MONTH OLDs OR 9 TO 12 MONTH OLDS, HOW DO THEY ACTUALLY GET PESTICIDES INTO THEIR SYSTEMS? BECAUSE THEY DO. SO THEY WENT TO FLORIDA, OUTSIDE OF TAMPA, AND THEY WANTED TO DO AN OBSERVATION THEY CALL MINIMAL RISK STUDY. NOW PETE PEDIATRICIANS ACROSS THE COUNTRY WERE ALREADY RECOMMENDING TO PARENTS NOT TO USE PESTICIDES WHEN YOUNG INFANTS ARE CRAWLING ON THE FLOORS. EXCEPT THEY WENT TO TAMPA BECAUSE MOST OF THE PARENTS THERE WERE USING THEM ANYWAY BECAUSE THE GREMLINS THAT THEY WERE TRYING TO STOP WERE MORE TROUBLING TO THEM THAN THEIR FIERCE OF PESTICIDES FEARS OF PESTICIDE IN THEIR CHILDREN, BECAUSE THEY WERE VERY, VERY HUMID, HOT HOUSES. SO HOMES HAD TO HAVE PARENTS WHERE THEY WERE ROUTINELY SPRAYING PESTICIDES ANYWAY. BUT THERE WERE TWO INTERESTING THINGS ABOUT THIS STUDY THAT WERE CRITICIZED. ONE IS THEY NEVER TOLD THE PARENTS THAT PEDIATRICIANS DON'T RECOMMEND SPRAYING PESTICIDES. THEY JUST ASKED, DO YOU ROUTINELY SPRAY PESTICIDES? THEY WEREN'T THE DOCTORS, THEY WERE JUST THE EPA. SO THEY WERE DOING WHAT THEY CALLED A NATURAL HISTORY STUDY. AND THE STUDY REQUIRED THAT YOU VIDEOTAPE YOUR CHILD, THAT WE GIVE YOU ACTUAL CLOTHING THAT THE CHILD IS GOING TO WEAR DURING THAT TIME SO WE CAN COLLECT THE CLOTHING, AND WILL THERE'S A WHOLE HOST OF THINGS WE'RE GOING TO DO FOR YOU. COMPENSATION WAS INTERESTING IN THIS STUDY. YOU WILL RECEIVE COMPENSATION FOR EACH PHASE OF THE STUDY. UP TO $970 OVER A TWO-YEAR PERIOD. AND BESIDES YOUR CERTIFICATE OF APPRECIATION, A CHEERS BIB AND A T-SHIRT AND A STUDY NEUTS NEUS LETTER, NEWSLETTER, YOU CAN KEEP THE VIDEO CAMCORDER. SO THE QUESTION WAS, WAS THIS UNDUE COMPENSATION? WELL, WHEN THEY FIGURED OUT THE NUMBERS OF HOURS THE PARENTS WERE ACTUALLY BEING ASKED TO DO THIS WORK, IT ENDED UP BEING ABOUT 75 CENTS AN HOUR. BUT THERE WAS A LOT OF CRITICISM OF THIS STUDY. THE E PA CHANGEDPA CHANGED ITS WHOLE WAY O F PROTECTING HUMAN SUBJECTS AFTER THIS STUDY. THEN THERE'S THE STUDY OF JESSI GELSINGER. JESSI WAS A 17/18-YEAR-OLD YOUNG MAN. HE HAD A MILD FORM -- IT'S A VERY SERIOUS DISEASE IN INFANCY, CHILDREN OFTEN DIE IN THEIR FIRST MONTHS. IT'S A RAPID DETERIORATING RARE GENETIC DISEASE OF AMMONIA METABOLISM. IT'S GOT THIS LESS PENETRANT TYPE WHERE SOME CHILDREN DO EXTRAORDINARILY WELL, EVEN RARER THAN THE RARE DISEASE IN INFANCY. JESSE LIVED, I THINK, IN ARIZONA AND HE CAME TO THE CHILDREN'S HOSPITAL AT THE UNIVERSITY OF PENNSYLVANIA, AND HE WAS GOING TO VOLUNTEER. HIS FRIENDS THOUGHT HE WAS A HERO, HIS PARENTS WERE VERY PROUD OF HIM. HE WAS GOING TO VOLUNTEER FOR THIS STUDY, A PHASE 1 TRIAL TO DETERMINE IF NORMAL GENES FOR ORN THEEN -- PLACED INTO AN ADENOVIRUS COULD BE INJECTED DIRECTLY INTO THE ARTERIAL CIRCULATION OF THE LIVER, COULD THEN ENTER THE LIVER CELLS, AND RESULT IN ACTIVE PRODUCTION OF THE ENZYME. IT WAS ONE OF THE VERY FIRST GENE TRANSFER EXPERIMENTS. SHORTLY AFTER JESSE'S INJECTION, THEY WAITED UNTIL HE WAS 18, THEY WANTED HIS SIGNATURE AT 18, THEY DECIDED 17 WASN'T ENOUGH, JESSE AND HIS FATHER DIDN'T CARE. HE CAME IN, FLEW IN, HAD HIS BLOOD WORK, GOT EVERYTHING READY READY, GOT THE INJECTION. JESSE'S AMMONIA LEVEL ROSE DRAMATICALLY. HE WENT INTO COMA. HE HAD MULTI-ORGAN FAILURE AND HE DIED. THIS WAS TRAGIC, PEOPLE WERE TERRIBLY UPSET, THEY SAID THEY WERE SORRY. JESSE'S FAMILY GRIEVED HIS LOSS BUT TOOK IT AS AN UNFORTUNATE BUT UNFORESEEABLE CONSEQUENCE OF HIS ALTRUISTIC ATTEMPT TO HELP THOSE LITTLE INFANTS WHO DIED. THE PRINCIPAL INVESTIGATOR AT UNIVERSITY OF PENNSYLVANIA FLEW OUT TO ARIZONA FOR THE FUNERAL AND SAT ON THE PORCH WITH JESSE'S FATHER AND MOTHER AND TALKED WITH THEM ABOUT THIS TRAGIC, TRAGIC OCCURRENCE. WHAT JESSE'S FAMILY DIDN'T KNOW WAS DURING THE ANIMAL PHASE OF THESE STUDIES, TWO MONKEYS HAD DIED SUDDENLY. THIS FACT HAD APPEARED ON THE INFORMED CONSENT FORM APPROVED BY THE NIH RECOMBINANT DNA REVIEW COMMITTEE. WHICH HAD SEEN THIS STUDY. IT HAD SEEN THE INFORMED CONSENT BUT IT WASN'T ON THE UNIVERSITY OF PENNSYLVANIA FORM. DON'T KNOW WHY. JES SE.'S AMMONIA LEVEL ON THE DAY OF THE STUDY WAS ABOVE THE ACCEPTABLE LEVEL FOR ELIGIBILITY IN THE TRIAL. THERE WERE ELIGIBILITY CRITERIA. THE P.I. SAID, AH, IT'S OKAY, JUST A LITTLE BIT HIGHER. THE P.I., THE DIRECTOR OF THE GENETICS PROGRAM AT THE UNIVERSITY OF PENNSYLVANIA EACH HAD AN EQUITY STAKE IN THE COMPANY THAT WAS FUNDING THE TRIAL. THIS COMPANY KNEW, AS DID THE GENETICS DIRECTOR, THAT THIS COULD BE A TREMENDOUS WINDFALL. NOT THAT THERE ARE JUST THESE CHILDREN BUT USING THE ADENOVIRUS AS A VECTOR TO PUT GENES INTO YOUNG PATIENTS WAS GOING TO BE AN EXTRAORDINARILY IMPORTANT PART OF GENE TRANSFER. THEY BOTH, INCLUDING THE UNIVERSITY, HAD A CONFLICT OF INTEREST. AND THEN WE LEARNED THAT THE DIRECTOR OF THE BIOETHICS CENTER AT THE UNIVERSITY OF PENNSYLVANIA WAS BEING PAID BY THE STUDY FUNNER TO CONSULT ON THE ETHICAL ASPECTS OF THE RESEARCH STUDIES FOR THE GENETICS PROGRAM. NOT A SMALL AMOUNT OF INCOME. THEN THERE'S THE SUPPORT STUDY, IT'S FROM THE NICHD NEONATAL NETWORK WHICH IS THE MOST PRESTIGIOUS ACADEMIC NEONATAL UNITS IN THE COUNTRY. ELIGIBLE CHILDREN WERE VERY PREMATURE, 24 TO 27 WEEKS. THOSE ARE THE LITTLE GUYS. OF COURSE WE TAKE CARE OF SOME EVEN LITTLER. BUT THESE -- THERE WERE SOME STANDARD PRACTICES IN NEONATOLOGY IN THE 2000s. THAT IS THAT OXYGEN ADMINISTERED TO THESE PREEMIES WOULD KEEP THE SATURATION ABOUT 85 TO 95%. THAT WAS REASONABLE, SEEMED ADEQUATE. THAT'S WHAT WE WERE DOING. AND THAT WAS TO TRY TO PREVENT WHAT WAS CALLED RETINOPATHY OF PREMATURITY, AND MANY OF THESE PREEMIES WILL GO ON TO DEVELOP CHRONIC LUNG PROBLEMS CALLED BRONCO PULMONARY DYSPLASIA. SO THE RESEARCH QUESTION WAS IN THE STANDARD RANGE, CAN YOU DECREASE THE INCIDENCE OF RETINOPATHY, AND BRONCO PULMONARY DYSPLASIA IF YOU DECREASE THE LEVEL OF OXYGEN WIN THE RANGE BUT TRY TO KEEP IT 85 TO 90 RATHER THAN HIGHER? RANDOMIZED CLINICAL TRIAL. SOUNDED LIKE AN IMPORTANT QUESTION. HERE'S WHAT THEY LEARNED. FAR MORE CHILDREN DIED IN THE LOWER LEVEL OXYGEN. NO ONE HAD PREDICTED THAT. THIS WAS STANDARD TREATMENT. BUT ACTUALLY RETINOPATHY WAS FAR LESS. THE STUDY OUT OHCOME OUT COME WAS DEATH OR RETINOPATHY, AND THAT ACTUALLY WAS ABOUT THE SAME IN THE TWO GROUPS. THIS CREATED A TREMENDOUS SCREAMING AND YELLING ABOUT SHOULD THIS HAVE BEEN DONE, SHOULD NOT IT HAVE BEEN DONE, HOW MUCH SHOULD WE HAVE TOLD THE PARENTS OF THESE PREMATURE BABIES ABOUT THE LIKELIHOOD OF DEATH IN THE LOWER OXYGEN GROUP, SINCE NO NEONATOLOGIST THAT I KNEW IN THOSE TIMES THOUGHT ANY OF THESE CHILDREN WERE GOING TO HAVE AN INCREASED DEATH. ALTHOUGH WE KNEW THAT IF YOU DIDN'T GIVE OXYGEN OR THEY GOT HYPOXIC, THEY COULD GET APNEAC AND DIE, BUT NOBODY THOUGHT THAT PERCENTAGE WOULD HAVE AN INCREASED INCIDENCE OF DEATH, BUT THEY DID. AND AN EDITORIAL IN THE "NEW YORK TIMES," ONE OF THE GREAT JOURNALS, SAID LEADING MEDICAL CENTERS FAIL TO INFORM PARENTS OF A STUDY'S REAL RISK, AUTHORIZING RESEARCH PROJECTS THAT FAIL TO MEET THE MOST BASIC STANDARD PROVIDING AN INFORMED CONSENT DOCUMENT TO PARENTS THAT ACCURATELY DESCRIBED RISKS AND BENEFITS. THIS WAS STARTLING AND DEPLORABLE. THAT'S PRETTY HEAVY. THE NIH TOOK A BIG HIT ON THIS, AS DID EVERY ONE OF THOSE ACADEMIC CENTERS. I GOT THOSE INITIAL INFORMED CONSENT FORMS BEFORE THEY WERE TAKEN OFF ALL THOSE WEBS AND OUT OF THE NIH'S CLINICAL.GOV, CLINICALTRIALS.GOV. I GOT THEM BECAUSE I KNEW THIS WAS GOING TO BE A HOT PEDIATRIC ISSUE. THEY WERE LOUSY INFORMED CONSENT FORMS, THEY WEREN'T VERY GOOD. A LOT OF PLACES THOUGHT THEY WERE QUITE ADEQUATE. THEY WERE VERY CONFUSING. THEY COULD HAVE BEEN BETTER. SO GOING BACK TO THE NEW ENGLAND JOURNAL IN 1966, HENRY BEECHER DID A CLASSIC STUDY THAT FOCUSED OUR ATTENTION ON THESE KINDS OF PROBLEMS, 22 EXAMPLES OF PUBLISHED CLINICAL RESEARCH, MANY INVOLVING CHILDREN, AND HE FOUND THAT MANY OF THE PATIENTS OR PARENTS EVER HAD THOSE RISKS EXPLAINED TO THEM IN THOSE STUDIES, HUNDREDS NEVER EVEN KNEW THEY WERE SUBJECTS OF RESEARCH. THAT WAS A BIG DEAL IN 1966, WHEN IN THE 1970 TIME, THEE LOGES WERE ARGUING, SHOULD WE EVER DO RESEARCH ON CHILDREN THAT ISN'T THERAPEUTICALLY INTENDED? RAMSEY SAID ONLY IF RESEARCH FURTHERS THE MEDICAL INTERESTS OF THE CHILDREN. MCCORMICK SAID, PARENTS MAY CONSENT EVEN IF THERE'S NO THERAPEUTIC BENEFIT. WE ALLOW ALTRUISM, WE WANT TO TEACH CHILDREN, BUT THE QUESTION IS HOW RISKY SHOULD THE RESEARCH BE, NOT WHETHER IT'S ONLY THERAPEUTIC. THEN THERE WAS THE TUS TUSKEGEE STUDY PUBLISHED IN '72. YOU'VE ALL LEARNED ABOUT THAT. THEIR RESEARCH QUESTION WAS THE NATURAL HISTORY OF UNTREATED SYPHILIS AND THIS STUDY HAS BEEN RIVETTING SINCE THEN, WHEN "THE NEW YORK TIMES" AND "WASHINGTON POST" PUBLISHED IN '72. THIS STUDY, WHICH HAD BEEN REVIEWED BY THE U.S. PUBLIC HEALTH SERVICE SERIALLY HAD BEEN PUBLISHED IN THE LITERATURE, WAS REFUNDED SERVE TIMES, WAS A NATIONALLY FUNDED STUDY THAT HAD OPINION BEEN REVIEWED AND IT WAS FELT TO BE COMPLETELY UNETHICAL TO CONTINUE TO STUDY THE NATURAL HISTORY OF A DISEASE AFTER THERE WAS A TREATMENT WITHOUT OFFERING THE TREATMENT. THIS WAS VERY SERIOUS. IT GENERATED THE NATIONAL COMMISSION FOR THE PROTECTION OF HUMAN SUBJECTS OF BIOMEDICAL AND BEHAVIORAL RESEARCH, THAT'S THE NATIONAL COMMISSION, THE FIRST NATIONAL COMMISSION IN BIOETHICS THAT GAVE YOU THE BELMONT REPORT AND RESEARCH INVOLVING CHILDREN. AN EXTRAORDINARILY IMPORTANT REPORT, WHICH IS THE BASIS OF THE FEDERAL REGULATIONS TODAY. NOW, DAVID WENDLER TALKED ABOUT THE BELMONT REPORT, YOU'VE ALL READ THE BELMONT REPORT, YOU'VE ACTUALLY BEEN TESTED ON THE BELMONT REPORT. IT HAD ITS THREE MAGIC PRINCIPLES. IT'S PROBABLY THE MOST READ AND MOST IMPORTANT BIOETHICS DOCUMENT EVER. IT'S ONLY FIVE PAGES, AND YOU SHOULD READ IT EVERY ONCE IN A WHILE BECAUSE IT'S REALLY QUITE POWERFUL. IN THE BENEFICENCE AREA, IT JUSTIFIES RESEARCH IN CHILDREN. THIS COMMISSION KNEW IT NEEDED TO DO THIS BECAUSE OF THE NUREMBERG CODE. IT WAS THE FIRST TIME THAT A U.S. COMMISSION WOULD OPINE AND IT SAID EFFECTIVE WAYS OF TREATING CHILDHOOD DISEASES ARE BENEFITS THAT JUSTIFY RESEARCH IN CHILDREN. THIS WAS THE AMERICAN COMMENT ABOUT THAT. RESEARCH ALSO MAKES IT POSSIBLE TO AVOID THE HARM THAT MAY RESULT FROM THE APPLICATION OF PREVIOUSLY ACCEPTED ROUTINE PRACTICES THAT MAY TURN OUT TO BE DANGEROUS. IN 1975, I BECAME A NEONATOLOGIST IN NEW YORK. IN 1975, AND IF I WERE IN A PEDIATRIC AUDIENCE, I WOULD ASK THE RESIDENTS OR THE FELLOW,S, BECAUSE YOU NEVER ASK THE ATTENDINGS, I WOULD ASK THEM, WOULD YOU GIVE A BOLUS OF BICARBONATE, WHICH IS BASE, TO A VERY ACIDOTIC INFANT RIGHT AFTER DELIVERY IF THE BABY WAS SERIOUSLY ILL? AND NO ONE OF THE RESIDENTS OR FELLOWS WOULD SAY THEY WOULD DO THAT. IN 2018. I WAS DOING IT ALL THE TIME IN 1975. IT HAD NEVER BEEN STUDIED. BUT IT MADE SENSE TO MOST OF US. MY TEACHERS HAD TAUGHT ME TO DO IT. IT MADE SENSE. BABY IS VERY ACIDOTIC, YOU WANT TO GIVE THEM A LITTLE BUFFER. WELL, WHAT WE DIDN'T KNOW IS THAT WAS VERY HYPERTONIC AND WAS BLOWING OUT BLOOD VESSELS IN THOSE BRAINS OF THOSE LITTLE PREEMIES, CALLED INTRAVENTRICULAR HEMORRHAGE. WE WERE KNOCKING OFF A LOT OF THE BABIES WE WE WERE TRYING TO SAVE. IT HAD NEVER BEEN RESEARCHED. THE OTHER THING WE DID WAS WE HAD THIS NEW DRUG CALLED CORE AM 15 KOL. A VERY POTENT ANTIBIOTIC. WELL, PREEMIES ARE THE SICKEST CHILDREN IN THE HOSPITAL. I KNOW THE INTERNISTS DON'T THINK SO BUT WE KNOW IT. PREEMIES ARE THE SICKEST CHILDREN IN THE HOSPITAL. THEY OFTEN DIE OF SEPSIS. OF INFECTION. SO NEW DRUG, WE GAVE IT TO PREEMIES. THEY GOT SOMETHING CALLED A GRAY BABY SYNDROME. THEIR LIVER GOT SHOT TO HELL. WE KILLED A LOT OF BABIES WITH THE NEW DRUG. IT HAD NEVER BEEN STUDIED. THESE COMMISSION MEMBERS KNEW THAT. THAT'S WHAT THEY WERE TALKING ABOUT. DON'T AVOID STUDIES IN CHILDREN, STUDY THINGS IN CHILDREN, FEWER CHILDREN WILL BE HURT IF THINGS ARE STUDIED AND WE UNDERSTAND. WE ALSO HAD THIS RESPECT FOR PERSONS PRINCIPLE. IT HAD TWO PARTS. INDIVIDUALS WITH CAPACITY, IE,, SHOULD BE TREATED THE AS AUTONOMOUS AGENTS AND WE NEED TO ASK THEIR PERMISSION BEFORE WE DO SOMETHING TO THEM, BUT THEY CAN PUT THEMSELVES AT RISK. BUT PERSONS WITH DIMINISHED AUTONOMY WERE ENTITLED TO OUR PROTECTION AND WE OUGHT TO WORRY ABOUT HOW MUCH RISK WE ALLOW THEM TO BE IN. AND THEN THERE WAS THE JUSTICE PRINCIPLE. HISTORICALLY THE BURDENS OF SERVING AS RESEARCH SUBJECTS FELL LARGELY UPON THE POOR SO CALLED WARD PATIENTS OR IN THE PUBLIC HOSPITALS OR IN THOSE ORPHAN STATE FACILITIES. WHILE THE BENEFITS IMPROVE MEDICAL CARE, PRIMARILY TO PRIVATE PATIENTS. SO THEY KNEW THAT THERE WAS AN INEQUITY BETWEEN WHO THE SUBJECTS WERE AND WHO THE BENEFICIARIES WERE AND NOW WE ARGUE JUSTICE REQUIRES US FOR EVERYONE WHO CAN BENEFIT SHOULD BE PART OF THE RESEARCH AND ANYBODY WHO CAN BENEFIT CAN ALSO BE AT RISK IN THE STUDIES. INTO URBAN SO THEN THE FEDERAL POLICIES CAME, THEY WERE FINALIZED IN 1993, BUT THEY WERE DEVELOPED RIGHT AFT NATIONAL COMMISSION AND THE NATIONAL COMMISSION LAID OUT THE PRINCIPLES FOR THOSE FEDERAL REGULATIONS WHICH STILL EXIST FOR YOU TODAY. THERE WERE TWO PARTS THAT ARE RELEVANT TO CHILDREN, THE PREGNANT WOMEN, FETUS AND NEONATES PART BUT PRIMARILY WE'RE INTERESTED IN THE CHILDRENS' REGS BECAUSE THE PREGNANT WOMEN AND NEONATES PART WAS REALLY A MATTER OF MAKING SURE WE'RE NOT GOING TO DO EXPERIMENTS AND KILL FETUSES EXTRA UTERINE AND WE'RE NOT GOING TO KILL NEONATES AFTER THEY'RE BORN, WHICH I'VE NEVER SEEN A PROTOCOL TO DO EITHER OF THOSE THINGS. BUT THAT'S WHAT THE PREGNANT WOMEN FETUSES AND NEONATES SUBSET IS ABOUT. IT CAME IN THE SECOND BUSH ERA. BUT THE CHILDREN'S SUBPART D CAME IN THE EARLY 80s AND IS, WITH SOME TWEAKS BUT NOT VERY MANY, WHAT WE HAVE TODAY. SO I JUST WANTED TO SAY THERE'S A DISTINCTION BETWEEN ADULT AND CHILD STANDARDS. THAT ARE VERY MEANINGFUL. AND MISUNDERSTOOD BY MOST IRBs THAT AREN'T CHILDREN'S HOSPITAL IRBs. SO THE RESPECT FOR PERSONS PRINCIPLE SET THE TONE, IT SAID PERSONS WITH DIMINISHED AUTONOMY, I.E. CHILDREN, ARE ENTITLED TO PROTECTION. -- THAT WAS THE STANDARD THAT THEY HAD IN GENERAL WHICH WAS THE ADULT STANDARD. REASONABLE RISK. I DON'T THINK THEY MEANT THE RISK THAT THAT KID WHO WAS 22 IN NEW YORK GOT IN 1975, BUT THEY MEANT REASONABLE RISKS, DIDN'T HAVE TO HAVE A LOT OF COMPENSATING BENEFIT IF IT WAS REASONABLE. BUT THAT'S NOT ACCEPTABLE FOR CHILDREN. REASONABLE RISK WAS NOT THE STANDARD. IT WAS A MINIMAL RISK STANDARD UNLESS THERE WAS A PROSPECT OF DIRECT BENEFIT. EXCEPT IN VERY SPECIFIC CIRCUMSTANCES WHICH I'LL MENTION, AND IT REQUIRES PARENTAL PERMISSION. WE DON'T CALL IT PARENTAL CONSENT BECAUSE IT'S NOT FOR THEMSELVES, IT'S FOR SOMEONE ELSE, IT'S A SURROGATE PROCESS SO IT'S PERMISSION. AND WE GET INTO THE CHILD ASSENT ISSUE, SO WHICH KIDS SHOULD NEED TO SAY, YEAH, I'M INTERESTED. THE DEFINITION OF CHILDREN, VERY IMPORTANT, PARTICULARLY FOR THOSE INTERESTED IN ADOLESCENTS. CHILDREN ARE PERSONS WHO HAVE NOT ATTAINED THE LEGAL AGE FOR CONSENT TO TREATMENT OR PROCEDURES INVOLVED IN THE RESEARCH UNDER THE APPLICABLE LAW OF THE JURISDICTION UNDER WHICH THE RESEARCH WILL BE CONDUCTED. SO IN NEW YORK, AS IS TRUE IN MARYLAND, ADOLESCENTS WHO SEEK TREATMENT FOR SEXUALLY TRANSMITTED DEETZS, DISEASES, HIV, SYPHILIS, CHLAMYDIA, GONORRHEA, MENTAL ILLNESS, PREGNANCY AND ITS PREVENTION, ARE PERMITTED TO GET THAT TREATMENT WITHOUT PARENTAL INVOLVEMENT. AND IN OUR PROGRAM, WE DO THAT ALL THE TIME. IN FACT, WHEN WE HAVE ADOLESCENTS COMING TO THEIR FIRST VISITS TO OUR PROGRAM, WE MAKE IT CLEAR TO THE PARENTS THAT THERE ARE CERTAIN THINGS THAT WE INVITE THE CHILDREN WITHOUT THEIR PARENTS AND, IN FACT, WE ENCOURAGE THEM TO COME TO SEE US WHEN THEY HAVE THOSE PROBLEMS BECAUSE THE JUSTIFICATION IS CLEAR. THE LAW SAYS WE'RE ALLOWED TO DO IT, NOT BECAUSE THEY DON'T THINK PARENTS ARE IMPORTANT, BUT BECAUSE THEY DON'T THINK YOUNGSTERS WILL TELL THEIR PARENTS NOR SEEK HELP FOR THOSE VERY IMPORTANT THINGS AND THEN THEY'RE GOING TO GET VERY SICK AND NOT SEEK TREATMENT UNTIL TOO LATE. BUT THOSE LAWS ALLOW YOU AS A RESEARCHER, A CLINICAL RESEARCHER, TO RESEARCH ISSUES IN SEXUALLY TRANSMITTED DISEASES AND HIV WITHOUT PARENTAL INVOLVEMENT IN CERTAIN CIRCUMSTANCES BECAUSE THE LAW ALLOWS THE CHILDREN TO MAKE CLINICAL JUDGMENTS, IT ALSO PERMITS YOU TO INVOKE THIS DEFINITION OF CHILD AND THEY'RE OUT OF THE DEFINITION OF CHILD. NOW YOUR IRB MAY DISAGREE WITH YOU, THEY MAY HAVE A PROBLEM WITH THAT, BUT THAT'S WHAT YOU SHOULD KNOW AS AN ADOLESCENT CLINICAL INVESTIGATOR. AND THEN THERE ARE FOUR PERMISSIBLE LEVELS OF RISK. FOUR. SO IT'S MUCH MORE COMPLICATED TO BE AN IRB REVIEWING PEDIATRIC WORK. IT'S MUCH MORE COMPLICATED TO BE A PEDIATRICIAN THAN AN INTERNIST. HE SAYS, HOPING HE DOESN'T GET ANYTHING THROWN AT HIM. SO THERE ARE FOUR SEPARATE CATEGORIES OF RESEARCH IN THOSE REGULATIONS. THE FIRST IS MINIMAL RISK. AND DR. WENDLER HAS TALKED A LITTLE BIT ABOUT IT. WELL, THE DEFINITION IS HERE. IT'S GOT TWO VECTORS: THE RISK OF HARM OF THE PROPOSED RESEARCH ARE NOT GREATER CONSIDERING PROBABILITY AND MAGNITUDE. LIKELIHOOD AND SEVERITY. THOSE ARE TWO VERY DIFFERENT THINGS. SOMETIMES SOMETHING IS NOT VERY LIKELY BUT IS REAL BAD! SO YOU MIGHT SAY, WELL, YOU KNOW, ANYTHING IS POSSIBLE. NO, I'M NOT TALKING ABOUT THAT. IF THEY THOUGHT THE RISK OF DEATH WAS LIKELY, EVEN A LITTLE LIKELY IN THAT PEDIATRIC OXYGEN TRIAL, THAT REQUIRED THE IRB REVIEWING THAT AND REQUIRED AT LEAST INFORMING THE PARENTS. BUT IN IF THEY DIDN'T THINK THAT SERIOUS THING WAS AT ALL LIKELY THEN THEY DIDN'T NEED TO PUT IT IN. SO IT'S PROBABILITY AND MAGNITUDE. OF THOSE ORDINARILY ENCOUNTERED IN TWO DIFFERENT THINGS, WHAT IS DAILY LIFE, AND THE OTHER IS, WHAT I CALL WELL-BABY CHECKUPS. ROUTINE PHYSICAL VISITS TO THE DOCTOR WITH YOUR CHILD. SO A URINE ANALYSIS, NOT WITH A CATHETER OR NEEDLE, BUT INTO A CUP OR A BAG, THAT'S ROUTINE. ONE FINGER STICK OR 1I.V. OR ONE BLOOD TEST, THAT'S FAIRLY ROUTINE. IS A SPINAL TAP ROUTINE? WELL, I DON'T SEE THAT AT A WELL-BABY CHECKUP. IS AN X-RAY ROUTINE? WELL, I DON'T SEE THAT IN A WELL-BABY CHECKUP. SO YOU CAN TRY TO DO CORRELATES TO WELL-BABY CHECKUPS AS PART OF YOUR MINIMAL RISK IDEA. THE DAILY LIFE THING IS MUCH MORE COMPLICATED. I LIKE THAT DR. WENDLER TALKED ABOUT SNOW SKIING. I'M AN AVID SKIER. MY DAUGHTER IS WAY BETTER THAN I AM. MY GRANDCHILDREN ARE NOW WAY BETTER THAN I AM. THAT'S VERY UPSETTING. BUT I ADVOCATE FOR SKIING. I'M NOT SO CRAZY ABOUT FOOTBALL IN KIDS BECAUSE OF CONCUSSION RISK. BUT PARENTS ARE ALLOWED TO LET THEIR CHILDREN PLAY FOOTBALL. THEY'RE ALLOWED TO LET THEIR CHILDREN GO SKIING AND THEY'RE ALLOWED TO LET THEIR CHILDREN GO HORSEBACK RIDING. WHICH IS THE ONE I REALLY DON'T LIKE. BECAUSE THE HORSE THROWS YOU. YOU KNOW. SO THAT'S NOT WHAT WE MEAN BY MINIMAL RISK. SO YOU'RE NOT ALLOWED TO TAKE A 2 BY 4 AND SLAM A KID ACROSS THE HEAD LIKE HE WOULD GET HIT, YOU KNOW, IN FOOTBALL. YOU'RE NOT ALLOWED TO RUN A KID INTO A TREE LIKE MIGHT HAPPEN IN SKIING. THAT'S NOT MINIMAL RISK. BUT I THINK EVERY IRB KNEW THAT. OKAY? AND THAT'S IMPORTANT. SO WHEN PEOPLE ARGUE ABOUT THIS DEFINITION, AND DR. WENDLER HAS BEEN THE MOST VOCAL ARGUER ABOUT THIS DEFINITION, AS OTHERS HAVE AS WELL IN THE WORLD OF RESEARCH ETHICS, NO ONE HAS EVER COME UP WITH A BETTER ONE. SO I INVITE YOU TO -- HE'S GOT THE CHARITABLE IDEA, BUT NO ONE'S EVER COME UP WITH A BETTER ONE THAT'S ACTUALLY HAD ANY TRACTION. THAT IT MEANS IS THAT IRBs HAVE TO HAVE A LITTLE COMMON SENSE AS THEY LOOK AT THIS. AN INSTITUTE OF MEDICINE NATIONAL ACADEMY STUDY LOOKED AT THIS QUESTION. I HAD THE PLEASURE OF BEING ON THAT GROUP, AND WE OPINED -- I KNOW IT'S A LITTLE WHILE AGO BUT IT'S NOT A BAD REPORT IF YOU WANT TO READ IT. IT ACTUALLY WAS A HARD LOOK AT THE FEDERAL REGULATIONS, LOOKING AT INTERPRETING THEM SINCE THE OFFICE OF HUMAN RESEARCH PROTECTION SEEMED UNWILLING TO, EVEN THOUGH THE ADVISE RE COMMITTEE TO THEM, WHICH I ALSO SERVED ON, HAD ASKED THEM TO. SO THE IOM SAID INTERPRET MINIMAL RISK IN RELATION TO THE NORMAL EXPERIENCES OF AVERAGE HEALTHY NORMAL CHILDREN. AVERAGE HEALTHY NORMAL. YOU CAN CALL IT MONTGOMERY COUNTY OR SCARSDALEIAN IN WESTCHESTER. AVERAGE NORMAL HEALTHY. NOT CHILDREN IN WHICH GUNS ARE SHOOTING IN THEIR ENVIRONMENT EVERY DAY, NOT CHILDREN INTERNATIONALLY WHERE ANIMALS ARE WALKING INTO THEIR HUTS. AVERAGE HEALTHY NORMAL. MINIMAL RISK MAY VARY WITH AGE BUT NOT SOCIAL STATUS, ILLNESS OR CIRCUMSTANCES. SO BECAUSE YOU'RE SICK DOESN'T MEAN MINIMAL RISK IS ANY DIFFERENT THAN IF YOU'RE HEALTHY. IF YOU'RE ON A RESPIRATOR, IT DOESN'T MEAN THAT MINIMAL RISK FOR YOU IN DEFINITION IS HIGHER RISK. FOCUS ON EQUIVALENCE OF RISK IN DAILY LIVES OR EXPERIENCES IN ROUTINE PHYSICAL AND PSYCHOLOGICAL AND MINIMIZE RISKS WHENEVER POSSIBLE. THAT'S THE DEFINITION OF MINIMAL RISK WE WORK WITH. ALL MINIMAL RISK RESEARCH IS PERMISSIBLE. AND THAT'S AN IRB'S JOB. THEN THERE'S THIS GROUP SPECIFICALLY DEFINED OF GREATER THAN MINIMAL RISK WITH THE PROSPECT OF DIRECT BEN FI. WELL, THAT'S MOST OF THE CLINICAL TRIALS. ALL THE CANCER STUDIES OF CLINICAL TRIALS ARE -- WE HOPE THIS WILL BE BETTER. I MEAN, THE ONE PROBLEM I HAVE WITH SOME OF DR. WENDLER'S BLOCKBUSTER DRUGS IS THAT, YOU KNOW, 70 TO 80% OF CHILDREN'S ONCOLOGY GROUP STUDIES COME OUT NEGATIVE. EITHER TOO TOXIC OR NOT EFFECTIVE. YET WE FULLY SUPPORT RESEARCH ON CHILDREN WITH CANCER AND WE'VE DONE EXTRAORDINARILY WELL IN HELPING CHILDREN WITH CANCER. NOT ALL CANCERS, BUT MANY. BUT THESE ARE GREATER THAN MINIMAL RISKS, THE RISKS ARE QUITE SUBSTANTIAL. WE BEAT THE HELL OUT OF CHILDREN IN A LOT OF STUDIES. WE DO VERY AGGRESSIVE CARDIAC EXHIBIT VENGSES. WE INTERVENTIONS. WE DO TRANSPLANTATION OF KIDNEYS, HEARTS, LUNGS, RESEARCH, AND WE DO RESEARCH ON THOSE ACTIVITIES. THEY'RE REAL RISKY. BUT THEY HAVE THE PROSPECT OF DIRECT BENEFIT. THE PROBLEM COMES IF THEY'RE A PLACEBO-CONTROLLED TRIALS. ARE WE ENHANCING RISK WITHOUT THE POTENTIAL FOR BENEFIT, UNLESS WE FLIP AT THE END OF THE TRIAL. SO GREATER THAN MINIMAL RISK WITH DIRECT BENEFIT SHOULD BE TANGIBLE. THE BENEFIT SHOULDING TANGIBLE. THAT IS TO SAY CURE OF DISEASE, RELIEF OF PAIN OR INCREASED MOBILITY. WE SHOULD WORRY MORE ABOUT RISK THAN BENEFIT. IS OUR JOB IS PROTECTION OF CHILDREN. FROM UNDUE RISK. LEVEL OF RISK MAY BE GREATER THAN MINIMAL BUT BALANCED AGAINST COMPENSATING BENEFIT AND IF THERE IS RISK, WE SHOULD BELIEVE THAT THERE IS SOME POSSIBLE COMPENSATING BENEFIT. COLLATERAL AND INDIRECT BENEFITS ARE NOT CONSIDERED PROSPECT OF DIRECT BENEFIT. WHEN WE GO TO AN INTERNATIONAL COMMUNITY AND SET UP A NEW CLINIC, THAT'S NOT THE BENEFIT THAT WARRANTS RISKING CHILDREN. IF WE GIVE HEALTH INSURANCE TO CHILDREN IN THE U.S. WHO DON'T HAVE IT, IN ORDER TO GET THEM INTO A TRIAL, AND BY THE WAY, ALL OF THE AIDS RESEARCH IN CHILDREN WAS THE ONLY WAY YOU COULD GET PEDIATRIC DRUGS IN THE BEGINNING. IS THROUGH RESEARCH. NIH FUNDED RESEARCH. THE ONLY WAY. YOU COULDN'T BUY THEM. SO IT WAS IMPORTANT THAT WE DIDN'T INCLUDE BEING TREATED BY REALLY GOOD DOCTORS. FOR POOR KIDS WHO HAD HIV AS PART OF THE BENEFITS. GIFTS, PAYMENTS, COMPENSATION ARE NOT CONSIDERED PROSPECT OF DIRECT BEN AND SHOULD BENEFIT AND SHOULD N OT BE UNDUE. THEN WE HAVE THIS REALLY WONDERFUL -- IT COMES OUT OF THE COMMISSION, IT'S A SPECTACULARLY INTERESTING AREA. MINOR INCREASE OF MINIMAL RISK WITH NO PROS PROSPECT OF DIRECT BEN FI. WE WERE DOING LARGE NUMBERS IN THE 70s OF STUDIES WHICH WE'RE LEARNING ABOUT HORMONES, METABOLISM. GROWTH HORMONE WAS A CLASSIC. WE NEEDED TO DO LARGE AMOUNTS OF STUDIES ON PARATHYROID. THAT WAS MY SCIENCE WHEN I WAS HERE AS A FELLOW AT THE NIH. WE NEED TO DO A WHOLE HOST OF THINGS. BUT SOMETIMES WE NEEDED TO DO SOME METABOLIC BALANCE STUDIES OR WE NEEDED TO DO MULTIPLE BLOOD DRAWS. THEY DIDN'T FIT MINIMAL RISK, BUT THEY WERE IMPORTANT TO UNDERSTAND WHO HAD CERTAIN CONDITIONS OR DISORDERS. MINOR INCREASE OVER MINIMAL RISK WAS JUST A LITTLE BIT MORE. I LIKE TO SAY, AND CHRIS HAS SEEN ME DO THIS BEFORE, I LIKE TO SAY IF MINIMAL RISK IS OVER HERE, SIGNIFICANT RISK IS OVER HERE, MINOR INCREASE OVER MINIMAL RISK IS NOT AT MY NOSE. IT'S A LITTLE MORE. NOT A WHOLE HOST MORE. THAT'S FOR THE IRB, THOUGH, TO DECIDE. IT HAS TO BE REASONABLY COMMENSURATE WITH EXPERIENCES THAT CHILDREN WITH CONDITIONS AND DISORDERS THAT THEY'RE BEING STUDIED ABOUT WILL HAVE, SO MAYBE AN N G-TUBE IS OKAY IF THE CHILD HAS HAD AN NG TUBE. MAYBE THAT'S A MINOR INCREASE OVER MINIMAL RISK. BUT THERE'S SOME INTERESTING THINGS HERE. THE INTERVENTION OR PROCEDURE MUST BE LIKELY TO YIELD GENERAIZABLE KNOWLEDGE ABOUT THE SUBJECT'S DISORDER OR CONDITION. THAT'S WHERE WE GET THE DISORDER OR CONDITION ISSUE. WHICH IS OF VITAL IMPORTANCE. NOW YOU ASK ANY RESEARCHER, IS THEIR RESEARCH OF VITAL IMPORTANCE? THEY'RE GOING TO TELL YOU. ABSOLUTELY. BUT THEY HAVE TO ASSERT THAT. AND THEY HAVE TO PROVE THAT TO THE IRB. IF THEY'RE GOING TO DO MORE THAN MINIMAL RISK RESEARCH IN CHILDREN WITHOUT THE DIRECT BENEFIT. SO THAT'S A HIGH STANDARD. I THINK IT CAN BE MET. BUT IT'S A HIGH STANDARD. AND THEN, OF COURSE, SOLICITING ASSENT AND PARENTAL PERMISSION ACTUALLY FROM TWO PARENTS IN THESE STUDIES IF THEY'RE AVAILABLE. NOT JUST ONE. AND THEN THERE'S THIS WONDERFUL AREA OF SIGNIFICANT RISK TO CHILDREN FOR THE SAKE OF THE SOCIETY. WE CAN'T APPROVE THOSE AT A LOCAL IRB, BUT WE WISH WE COULD SH WE WANT TO, BUT IT DOESN'T FIT INTO THE RUBRIC, BUT IT MAY BE CRITICALLY IMPORTANT. LIKE UNDERSTANDING SMALLPOX VACCINATION AFTER MANY YEARS AFTER WE HAD ELIMINATED SMALLPOX IN THE WORLD, BUT WE KNEW THERE WAS SOME SMALLPOX AND SOME BAD GUYS MIGHT HAVE IT AFTER 9/11, AND THE QUESTION WAS, WAS SMALLPOX COMING BACK. HOW ABOUT ANTHRAX? ANTHRAX VACCINE HADN'T BEEN USED IN CHILDREN. SHOULD WE STUDY IT IN CHILDREN BEFORE WE HAVE TO GIVE IT TO CHILDREN, IF ANTHRAX GETS DISTRIBUTED ON THE METRO? OR ON THE SUBWAYS IN NEW YORK? WE WERE MODELING THOSE QUESTIONS. WE DIDN'T KNOW WHAT THE RISKS AND BENEFITS FOR CHILDREN WERE OF THOSE BIOTERRORIST ACTIVITIES, BUT WE HAD IN THE REGULATIONS THE POSSIBILITY TO DO THOSE STUDIES IF WE NEEDED TO, AN IRB COULD SAY I CAN'T APPROVE IT BUT I WISH I COULD AND SEND IT TO THE FEDERAL GOVERNMENT FOR THE SECRETARY OF HEALTH AND HUMAN SERVICES TO REVIEW, WITH A SPECIAL PANEL THAT WOULD BE CONVENED AND THAT STILL EXISTS AND IT STILL CAN BE USED IN VERY, VERY SERIOUS TIMES TIMES. SO LET ME CONCLUDE BY SAYING THERE ARE THREE LEVELS OF PROTECTION FOR OUR CHILDREN IN RESEARCH. THEY START WITH YOU. THEY START WITH ETHICAL RESEARCHERS WHO AREN'T SO ENGROSSED IN THEIR WORK THAT THEY CAN'T SEE THEIR OWN CONFLICTS. IT STARTS WITH PEOPLE WHO AREN'T CRIMINAL AND AREN'T SOCIOPATHS, AREN'T DR. ANDREW WAKEFIELD WHO DID THAT SO CALLED STUDY OF MEASLES, MUMPS AND RUBELLA. IT STARTS WITH GOOD ETHICS IN YOU. THEN THERE'S PEER REVIEW. THAT IS TO SAY, YOUR DEPARTMENT AND DIVISION SHOULD BE LOOKING AT THE WORK THAT YOU'RE CONSIDERING. AND COMMENTING ON IT. AND PRIORITIZING IT AND MAKING SURE IT MAKES SENSE. AND THEN THERE'S THE INSTITUTION REVIEW BOARD, WHOSE JOB IS TO PROTECT THE HUMAN SUBJECTS. ONLY THEN. AND FINALLY, THIS INFORMED CONSENT PROCESS. SO PARENTS ALWAYS HAVE THE OPTION OF NOT PLACING THEIR CHILDREN IN RESEARCH. THEY CAN'T COME HERE IF THEY DON'T WANT RESEARCH OR AT LEAST EVALUATION FOR RESEARCH, BUT THEY CAN BE TREATED ELSEWHERE. AND OF COURSE THE QUESTION OF CHILD ASSENT, AND WE'RE GOING TO GET INTO THAT A LITTLE WHEN WE REVIEW THIS PROTOCOL, BECOMES IMPORTANT. SO THESE THREE LEVELS ARE ALL CRITICAL. AND I'M HAPPY TO TAKE SOME COMMENTS AND QUESTIONS AND THEN WE'RE GOING TO RECONVENE TO TAKE A LOOK AT THAT REALLY COMPLEX STUDY. THANK YOU. [APPLAUSE] TWO BOYS AND A GIRL UP HERE. I WON'T TELL YOU WHO'S WHO. I MAINTAIN THEIR CON FI DEN SHA. CON FI DE N THEIR CONFIDENTIALITY. ANY QUESTIONS OR COMMENTS? RESEARCH WITH CHILDREN, ADOLESCENTS, PHILOSOPHY. YES. >> HI. IN CLINICAL PRACTICE, CHILDREN OFTEN EXPRESS THAT THEY DON'T WANT TO PARTICIPATE, I DON'T WANT THAT SHOT, I DON'T WANT THIS BLOOD DRAW. >> ABSOLUTELY. YOU'D BE NUTS IF YOU WEREN'T. >> IN RESEARCH PRACTICE, IF THE PARENTS HAVE GIVEN PERMISSION AND THE CHILDREN HAVE ASSENTED A GENERAL LEVEL, WHERE DO YOU DRAW THE LINE IN THE SPECIFIC RESEARCH PROTOCOL FOR THEM TO SAY, I DON'T WANT THAT BLOOD DRAW? >> SO CHILDREN ARE PERMITTED TO ASSENT TO RESEARCH WHEN THEY HAVETHE CAPACITY TO ASSENT. SO SOME PEOPLE THINK IT'S 6 OR 7 AND EVERY BODY'S IRB HAS A LITTLE DIFFERENT IDEA. BY THE WAY, THERE'S NOTHING IN THE REGULATIONS THAT SAY IT HAS TO BE WRITTEN AND THERE'S NOTHING IN THE REGULATIONS THAT SAY IT HAS TO BE SIGNED. HOWEVER, MOST OF YOUR INSTITUTIONS WANT IT WRITTEN AND MOST OF THEM WANT IT SIGNED. AND THAT HAS TO DO WITH PROTECTION AND LAWYERS AND THINGS OF THAT SORT. BUT WE ALSO ARE ALLOWED TO SAY THERE ARE CERTAIN STUDIES WHERE ASSENT IS NOT REQUIRED AND THAT IS IF, IN FACT, IT'S IN THE CLINICAL BEST INTERESTS OF CHILDREN TO GET THOSE STUDIES AND THEY CAN'T GET THOSE CLINICAL INTERVENTIONS WITHOUT THOSE STUDIES, SO WE DON'T ASK FOR ASSENT. I AM OPPOSED TO ASKING FOR I FOR ASSENT IF WE'RE NOT GOING TO ACCEPT DISSENT. IT IS DISRESPECTFUL OF CHILDREN TO SAY, YOU GOT THAT WRONG, YOU GOTTA BE IN THIS STUDY. I DIDN'T ASK YOUR PERMISSION, I EXPLAINED IT TO YOU, BUT YOUR PARENTS WISH YOU TO BE IN THIS STUDY, AND YOU'RE GOING TO BE IN THE STUDY. NOW, SO I'M NOT AN OGRE WITH CHILDREN BUT I'VE GOT TO TELL YOU THAT MANY 3-YEAR-OLDS NEED TO BE HELD WHEN YOU DRAW THEIR BLOOD. NOT EVERYBODY AT 3 BUT ALMOST EVERYBODY. AT 6, IT'S FEWER. AT 10, VERY FEW. AND THEN THERE ARE SOME, YOU KNOW, 72-YEAR-OLDS WHO NEED TO BE HELD, EXCEPT THEY WANT THEIR OTHER HANDHELD. BUT IT'S IMPORTANT THAT WE RESPECT CHILDREN. SO I HAVE OFTEN SAID TO A CHIEL, I'M GOING TO STICK YOU NOW, YOU CAN SCREAM AS LOUD AS YOU WANT, YOU CAN CALL ME A NAME, BUT PLEASE DON'T MOVE YOUR ARM BECAUSE I'D LIKE TO GET IT DONE AND YOU KNOW THAT I CAN GET IT DONE. SO I THINK IT'S A RELATIONSHIP, WE SHOULD BE HONEST, SOMETIMES IF YOU NEED TO DO A SPINAL TAP, A BONE MARROW AND A BLOOD DRAW, YOU CAN SAY WHICH ONE DO YOU WANT FIRST? YOU KNOW, AND KIDS IN CANCER STUDIES KNOW THEY'RE GOING TO GET THEM. SO I THINK IT'S HARD, IT'S UP TO THE CLINICIANS, THE IRB SHOULD NOT REQUIRE ASSENT IN STUDIES FOR WHICH WILL ASSENT SHOULDN'T BE DONE BECAUSE YOU'RE NOT GOING TO RESPECT DISSENT. THERE ARE SOME CLINICAL STUDIES THAT REQUIRE ASSENT AND THEN THE KIDS AREN'T INVOLVED IN THE STUDY BUT THEY CAN'T GET THE DRUG. BUT THE REGULATIONS ARE CLEAR, READ THEM, ABOUT ASSENT. THEN WHEN A KID IS IN A STUDY, YOU NEGOTIATE LIKE YOU NEGOTIATE WITH ALL KID, BUT AT SOME POINT, YOU GO FORWARD WITH THE STUDY BASED ON PARENTAL PERMISSION AND MAKING SURE THEY'RE STILL IN AGREEMENT. >> THANK YOU. SHALL WE JUST ROLL INTO THAT? OKAY. NOW, I SAID TO YOU WHEN I FIRST GOT TO BE AN IRB MEMBER, I WAS ON TO IRBs, I CREATED ONE, FOR MY SINS, I AM NO LONGER ON AN IRB BECAUSE I'VE REFUSED, BUT IT'S A LOT OF WORK. NOW I WANT HONESTY. IS THERE ANYONE IN THE ROOM WHO READ THE ENTIRE PROPOSAL? IR WAS GOING TO GIVE YOU EXTRA CREDIT, I WAS GOING TO ASK CHRIS TO -- YOU KNOW, TO PAY YOU A HIGHER INCENTIVE FOR COMING. MAYBE THERE'S SOMEONE AT ONE OF THE OUTSIGHTS WHO READ IT. IT IS A VERY COMPLICATED PROTOCOL. IT IS EXTRAORDINARILY WELL WRITTEN. I'M NOT SAYING IT DOESN'T HAVE SOME POTENTIAL FOR CRITICISM. BUT IT'S A VERY WELL WRITTEN, EXTRAORDINARILY COMPLICATED PRO PROAT KOL. PROTOCOL. DO YOU HAVE SOME SLIDES THAT YOU'RE GOING TO TELL US A LITTLE ABOUT THIS PROTOCOL BEFORE WE ATTACK IT. >> YES. >> OKAY. >> SO I'M PRETENDING TO BE THE P.I. FOR A FEW MINUTES. BECAUSE DR. FLEISCHMAN WHO'S THE IRB CHAIR INVITED ME TO COME AND TELL YOU A LITTLE BIT ABOUT MY STUDY, SO I KNOW THAT IT WAS LONG AND COMPLICATED SO I'M GOING TO JUST SUMMARIZE SOME OF THE DETAILS OF THE STUDY. SO THIS IS A RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED PHASE 3 TRIAL OF ZGN440 IN OBESE PATIENTS IN ORDER TO EVALUATE TOTAL BODY WEIGHT, FOOD RELATED BEHAVIOR AND SAFETY OVER SIX MONTHS. SO SOME OF YOU MAY KNOW, PRADER-WILLI SYNDROME IS A RARE AND COMPLEX NON-INHERITED GENETIC DISORDER RESULTING FROM AN ABNORMALITY ON THE 15TH CHROMOSOME AND IS THE MOST COMMON KNOWN GENETIC CAUSE OF LIFE-THREATENING OBESITY. THE BRAIN OF PATIENTS DOES NOT REGULATE METABOLISM AND APPETITE. PERSONS WITH PWS IS RAH CONSTANT PREOCCUPATION WITH FOOD AND UNRELENTING OVERWHELMING OVERRIDING PHYSIOLOGICAL DESIRE OR DRIVE TO EAT. THEY ALSO HAVE OTHER SYMPTOMS THAT ARE LESS RELEVANT TO THE STUDY AT HAND BUT I'LL JUST SAY THAT THEY FREQUENTLY HAVE HYPOGONADISM, DELAYED BEU PER DE, GROWTH DEFICIENCY AND LOW I.Q. THERE'S NO TREATMENT FOR PWS, THERE ARE SOME SYMPTOMATIC TREATMENTS BUT MANY OF THOSE CHALLENGING SYMPTOMS ARE VERY DIFFICULT TO TREAT. HUMAN GROWTH HORMONE WAS APPROVED FOR PWS BY THE FDA AND CAN IN MANY KAIZ CASES DECREASE BODY FAT, MUSCLE MASS, IMPROVE WEIGHT MANAGEMENT AND OTHER THINGS, IT DOESN'T WORK FOR EVERYBODY, BUT THERE ARE NO MEDICATIONS THAT ARE EFFECTIVE IN REGULATING APPETITE. THE INABILITY TO CONTROL FOOD INTAKE OFTEN PREVENTS THOSE WITH PWS FROM LIVING INDEPENDENTLY BECAUSE THEY THEIR EATING HABITS HAVE TO BE MONITORED. ADULT PATIENTS REQUIRE STRICT ENVIRONMENTAL CONTROL AND CONSTANT SUPERVISION TO PREVENT LIFE-THREATENING OVEREATING AND SUPERVISION, SOMETIMES INDIVIDUALS DIE PREMATURELY AS A RESULT OF CHOKING ON FOOD, FROM STOMACH RUPTURE FROM EATING TOO MUCH, FROM TISSUE NE GROW C.E.O. CYST OR FROM COMPLICATIONS CAUSE BID CAUSED BY MORBID OBESITY. THIS DRUG, BELARANIB IS AND IRREVERSIBLE INHIBITOR OF METH NIGH ON AM KNOW PEPIDASE. NOW I'M NOT THE P.I., ANYWAY -- MET AP2. AND IT'S BEEN -- IT WAS ORIGINALLY STUDIED IN PATIENTS WITH METASTATIC CANCER BECAUSE IT INHIBITS ENDOTHELIAL CELL GROWTH AND REDUCES AND YOE GENESIS AND TUMOR GROWTH UNDER CERTAIN CONDITIONS BUT IN THOSE EARLY STUDIES, IT WAS SHOWN THAT IT ALSO REDUCES FOOD INTAKE AND LOWERS BODY WEIGHT AND SELECTIVELY REDUCES ADIPOSE TISSUE. IT'S BEEN GIVEN IN HIGH DOSES TO PATIENTS WITH METASTATIC CANCER AND ALREADY IN SOME CLINICAL, EARLY CLINICAL TRIALS IN LOWER DOSES TO PERSONS WITH OBESITY. IT'S GENERALLY WELL TOLERATED IN BOTH THANK YOU MAN HUMAN STUDIES AND NON-H UMAN ANIMAL STUDIES AND DOES RESULT IN MANY CASES IN SIGNIFICANT WEIGHT LOSS. SO A PREVIOUS RANDOMIZED PHASE 2 RANDOMIZE D DOUBLE BLIND PARALLEL COMPARISON STUDY OF ADULTS WITH PWS HAD BEEN DONE AND DEMONSTRATED PROOF OF CONCEPT OF SAFETY AND EFFECTIVENESS OF BE RAH NAB, ON BODY COMPOSITION, FOOD RELATED BEHAVIORS AND CARDIOVASCULAR RISK MARKERS. SUPPORTING ADEQUATELY POWERED AND MONITORED PHASE 3 STUDY WI IS WHAT WE'RE PROPOSING TODAY. SO THE STUDY WILL BE RANDOMIZED DOUBLE BLIND AND PARALLEL COMPARISON OF TWO DOSE LEVELS OF BELL RAH ANYBODY, TWO FOR PURPOSES OF COMPARISON, THERE WILL BE 102 SUBJECTS ALL TOGETHER RANDOMIZED INTO ONE OF THE FOUR ARMS BUT IN A 1 TO 1 AND 2 TO 2 RATIO. SO EACH PERSON WILL HAVE ABOUT A THIRD CHANCE OF GETTING PLACEBO, BUT TWO THIRDS CHANCE OF GETTING THE LOWER OR HIGHER DOSE OF BELORANIB. PRIMARY OBJECTIVES OF OUR STUDY ARE TO ASSESS CHANGES IN TOTAL BODY WAIT WEIGHT AND CHANGES IN HYPERFASCIA RELATED BODY BEHAVIORS IN SIX MONTHS AND ALSO TO ASSESS SAFETY AND TOLERABILITY, AND SECOND TO ASSESS CHANGES IN TOTAL BODY FAT MASS AS MEASURED BY DEXA SCAN AND OTHER METABOLIC BIOMARKERS. THE SCHEMA IS COMPLICATED, EVERYONE WILL GET PLACEBO IN THE FIRST COUPLE OF WEEKS. THE DRUG IS ADMINISTERED SUBCUTANEOUSLY. AFTER WHICH -- AFTER TWO WEEKS, THEY WILL BE RANDOMIZED TO EITHER CONTINUE RECEIVE PLACEBO OR RECEIVE ONE OF THE TWO DOSES. THE PEOPLE RANDOMIZED TO THE HIGHER DOSE WILL START FOR FOUR WEEKS ON THE LOWER DOSE AND THEN GRADUALLY MOVE TO THE HIGHER DOSE. SO IT'S A COMPLICATED STRUCTURE. RANDOMIZATION WILL ALSO BE STRATIFIED BASED ON WHETHER OR WHETHER OR NOT THEY'VE HAD GROWTH HORMONE AND WHETHER OR NOT THEY'RE OLDER OR YOUNGER THAN 16 YEARS OF AGE. SUBJECTS WILL ALSO BE ASKED TO BE PART OF TWO PHARMACOKINETIC SAMPLING GROUPS AT TWO DIFFERENT TIMES IN THE STUDY. OUR PRIMARY END POINTS ARE CHANGE IN TOTAL BODY WEIGHT FROM BASELINE TO THE END OF THE RAN RNA DOMMIZED TREATMENT AND CHANGE IN HYPERFASCIA-RELATED BEHAVIOR BY QUESTIONNAIRE. AND THERE'S A NUMBER OF SECONDARY END POINTS WHICH I'M NOT GOING TO READ. 102 PARTICIPANTS IN THE STUDY ALL WITH PWS BETWEEN THE AGES OF 12 AND 65 YEARS OLD RANDOMIZED INTO FOUR GROUPS AND NOT JUST HERE AT THE CLINICAL CENTER BUT AT 10 TO 15 OTHER CENTERS AROUND THE COUNTRY. SO NOT JUST HERE. A BUNCH OF INCLUSION CRITERIA, THEY HAVE TO HAVE A CONFIRMED DIAGNOSIS OF PRADER-WILLI SYNDROME, BETWEEN THE AGES OF 12 AND 65, THEY HAVE TO HAVE OBESITY DEPENDING ON THEIR AGE, THE BODY MASS INDEX IS SLIGHTLY DIFFERENT. THEY HAVE TO AGREE TO USE AN APPROVED METHOD OF CONTRACEPTION THROUGHOUT THE ENTIRE STUDY, AND IF THEY'RE ON A NUMBER OF THESE DRUGS, THEY HAVE TO HAVE BEEN ON A STABLE DOSE OF THOSE DRUGS FOR AT LEAST THREE MONTHS PRIOR TO BEGINNING. YOU CAN SEE THE LIST OF DRUGS. THEY ALSO HAVE TO HAVE AT LEAST ONE CONSISTENT AND RELIABLE PRIMARY CAREGIVER WHO CAN ACCURATELY EVALUATE CHANGES IN THEIR MOOD, QUALITY OF LIFE, ADVERSE EVENTS, BEHAVIOR, AND DOCUMENT THOSE AND DOCUMENTARY SOURCE UTILIZATION AS WELL AND ACCOMPANY THEM TO VISITS AT THE NIH. THE CAREGIVER MUST HAVE BEEN CARING FOR THE SUBJECT FOR AT LEAST SIX MONTHS PRIOR TO THE STUDY, ANTICIPATED TO BE THE PRIMARY CAREGIVER FOR THE DURATION OF THE TRIAL, AND SPEND AT LEAST FOUR HOURS PER DAY WITH THE PERSON WHO'S BEING STUDIED. AND THEN THERE ARE A NUMBER OF EXCLUSION CRITERIA, THEY CAN'T LIVE MORE THAN HALF THEIR TIME IN A GROUP HOME, THEY CAN'T HAVE HAD RECENT WEIGHT LOSS OR USED RECENT WEIGHT LOSS AGENTS, THEY CAN'T HAVE POORLY CONTROLLED PSYCHIATRIC DISORDERS OR OTHER CLINICALLY SIGNIFICANT ILLNESSES AT OUR DISCRETION. THEY CAN'T HAVE A HISTORY OF ANY BLEEDINGS DISORDERS, DEEP VEIN THROMBOSIS OR THROMBOEMBOLIC DISEASE. THEY CAN'T HAVE ABNORMAL LIVER, KIDNEY OR PULMONARY OR CARDIAC TESTS. AND THEY CAN'T HAVE TYPE 1 DIABETES. THE STUDY WILL TAKE ABOUT SEVEN MONTHS, INCLUDES 9 NIH VISITS AND 51 HOME VISITS BY A HOME HEALTHCARE NURSE, THERE'S A SCREENING CYSTVIST IT WHICH IS A PHYSICAL EXAM AND HISTORY, VITAL SIGNS, EKG, BLOOD TESTS INCLUDING FOR HIV, HEPATITIS B AND HEPATITIS C, ALL OF WHICH WOULD PRECLUDE THE PERSON FROM PARTICIPATING, PREGNANCY TEST, DEXA SCAN AND A HYPERFASCIA QUESTIONNAIRE, AND THEN ON EACH OF THE CLINIC VISITS, MANY OF THESE THINGS WILL BE REPEATED, MOSTLY BLOOD TESTS AND VITAL SIGNS AND EKG. VITAL SIGNS, OF COURSE, INCLUDING WEIGHT. BIOMARKERS, PHOTOS, DEXA SCANS, HOSPITAL ANXIETY AND DEPRESSION SCALE, AND THEN A NUMBER OF DIFFERENT QUESTIONNAIRES THAT THE CAREGIVER WILL COMPLETE. AND THEN JUST IN TERMS OF RISKS SINCE TODAY WE'RE TALKING ABOUT RISKS, THERE ARE SOME RISKS TO BELORANIB FROM THE PREVIOUS STUDIES THAT HAVE BEEN DONE. IT'S CLEAR THAT WE HAVE NEVER GIVEN THIS DRUG TO PEOPLE FOR MORE THAN 12 WEEKS, SO THE RISKS OF LONG TERM TAKING THE DRUG ARE NOT KNOWN. IN TRIALS WITH -- PREVIOUS TRIALS WITH OBESE PATIENTS, THE RISKS WERE VERY MILD OR MODERATE: HEADACHE, NAUSEA, VOMITING, SLEEP DISTURBANCE AND REACTION AT THE SUBQ SITE OF THE INJECTION, ANOREXIA, WHICH IS WHAT WE'RE AIMING FOR IN A CERTAIN WAY, THE MOST COMMON IS SLEEP DISTURBANCE, AND IN TRIALS WITH CANCER PATIENTS, SOME OF WHO RECEIVED ALMOST 50 TIMES THE DOSE OF WHAT WE'RE USING IN THIS STUDY, THERE WERE SOME OTHER SERIOUS COMPLICATIONS, NEUTROPENIA, THROMBOCYTOPENIA, FATIGUE, LIVER FUNCTION CHANGES, AND YOU CAN SEE THE LIST. I PUT OTHER DOWN HERE BECAUSE IN THE PROTOCOL AND IN THE CONSENT FORMS, WE ALSO TALK ABOUT THE BHURD AND RISKS OF OTHER THINGS LIKE BLOOD DRAW, URINE SAMPLING, TAKING PHOTOS, ANSWERING QUESTIONNAIRES, THINGS LIKE THAT THAT. AND THAT'S IT. THOSE ASKING QUESTIONS, PLEASE USE THE MICS OR I'LL BRING YOU A MIC. >> SO I JUST WANT TO GET YOUR FIRST REACTION TO THIS STUDY. FIRST REACTIONS. WHAT ARE YOU THINKING? WHAT ARE YOU HEARING? SO PHASE # IN ADULTS, JUMPING STRAIGHT TO CHILDREN. WHAT OTHER FIRST REACTIONS? THE ARMS ARE CONVOLUTED, COMPLICATED TO FOLLOW. OKAY. WHAT ELSE? LONG TERM SAFETY. WE DON'T HAVE ANY IDEA, RIGHT. ANYBODY EVER STUDIED OR TAKEN CARE OF CHILDREN WITH PRAY PRADER-WILLI SYNDROME, OR ADULTS? VERY SERIOUS. WE HAVE A GOOD MARKER IN ORDER TO TELL US THE DIAGNOSIS. SO WE'RE NOT GOING TO GET A LOT OF PEOPLE IN THIS STUDY WHO, YOU KNOW, KIND OF HAVE SOME KIND OF SPECTRUM OR SYNDROME OR CLINICAL DIAGNOSIS. IT'S A GENETIC MARKER DIAGNOSIS. WHEN DOES THE PROBLEM START? IN INFANCY. INTO YOUNG CHILDHOOD. WHAT'S THE AGE RANGE FOR THIS STUDY? 12 AND UP. WHAT IF THEY ACTUALLY HAD STARTED THE STUDY AT 4? BY THE WAY, THERE ARE ONLY -- # IN 10,000, 1 IN 20,000 CHILDREN WITH GREATER WILLIE SYNDROME.& 4 MILLION BIRTHS A YEAR IN THE UNITED STATES, 1 IN 10,400. PER YEAR IN THE UNITED STATES. BUT THAT'S A LOT OF YEARS. BUT THAT'S WHY MAYBE THE SAMPLE IS SMALL, 102. WE GOT A LOT OF EXCLUSION INCLUSION CRITERIA, THE QUESTION OF DO WE HAVE POWER HERE. SO WE'LL ASK THOSE STUDIES OF THE BIOSTATISTICIANS, NOT OUR PART OF THE IRB. THERE'S USUALLY A BIOSTATISTICIAN ON THE IRB OR SOMEWHERE IN THE PROCESS TO MAKE SURE BECAUSE OBVIOUSLY NO RESEARCH IS ANY GOOD IF IT CAN'T ANSWER THE QUESTION. SO WE NEED TO MAKE SURE WE HAVE ENOUGH POWER. BUT THEY'RE GOING TO DO 102 OF WHICH A THIRD ARE GOING TO BE PLACEBO. I WANT TO TALK ABOUT THE PEDIATRIC SIDES OF THIS ONE. YOU KNOW, THE ADULTS, THIS IS A VERY SERIOUS DISEASE AS THE INVESTIGATOR HAS TOLD US. THE ADULTS MAY NOT BE COMPASS DECISIONS BUT THEY WILL HAVE HOPEFULLY A LEGAL GUARDIAN OR SOMEONE WHO IS MAKING CLINICAL DECISIONS FOR THEM WHO COULD CONSENT OR GIVE PERMISSION. AND WE NEED TO TAKE THAT INTO ACCOUNT. BUT LET'S TALK ABOUT THE KIDS WHO ARE BETWEEN 12 AND 18. AND WILL WE'LL THINK ABOUT THE ADULTS AS WE TALK ABOUT THE KIDS BUT SINCE THIS IS KIDS TODAY, LET'S TALK ABOUT KIDS BETWEEN WELL AND 18. THEY'RE ALREADY OBESE, THEY'VE ALREADY GOT SOME VERY SUBSTANTIAL PROBLEMS. SHOULD WE TELL THE INVESTIGATOR, LET'S DO THIS STUDY STARTING AT 4? WHAT IF HE CAME UP WITH THAT AS HIS PLANS? ALL THE GENETIC DISEASE GROUPS HAVE LISTSERVS AND INTERACT ALL THE TIME, IF YOU GO ON THE WEB TODAY FOR PRADER-WILLI, I DIDN'T, MAYBE I SHOULD HAVE, YOU'LL PROBABLY SEE A LISTSERV OF FAMILIES WHO SUPPORT ONE ANOTHER, TALK ABOUT CUTTING EDGE THINGS, THEY PROBABLY KNOW THIS DRUG IS GOING TO BE OUT THERE IN A STUDY AND THEY MAY BE SCREAM SCREAMING AT THEIR GENETICIST OR METABOLIC SPECIALIST OR ENDOCRINOLOGIST, I WANT IN FOR MY 4-YEAR-OLD, BECAUSE SHE'S ALREADY OBESE, SHE'S ALREADY AT RISK. HE ALREADY GAVE HER GROWTH HORMONE. BECAUSE SHE'S NOT GROWING. SHE'S GOT THYROID PROBLEMS. WA ABOUT THAT? WHAT IF HE SAID 4-YEAR-OLDS? WOULD IT FEEL ANY DIFFERENT THAN THE 12? HELP ME. YEAH. CAN WE MAKE THIS WORK? IT DOES WORK. OKAY. I'LL HOLD IT. >> I DON'T KNOW, AT FIRST PASS IT SEEMS LIKE IT MIGHT BE DIFFERENT BECAUSE A 12-YEAR-OLD MAY BE -- EVEN IF THEY DON'T HAVE CAPACITY, THEY MAY HAVE SOME DEGREE OF UNDERSTANDING. AND POTENTIALLY WOULD BE ABLE TO PROVIDE ASSENT WHEREAS A 4-YEAR-OLD WOULD NOT. >> SO THE CONCEPT OF ASSENT FOR YOU GIVES YOU THE FEELING OF DIFFERENCE HERE. THAT THIS 12-YEAR-OLD MIGHT GIVE US MORE AND MIGHT PARTICIPATE IN THIS RESEARCH EVEN THOUGH THERE'S PROSPECT OF DIRECT BENEFIT HERE, AT LEAST FOR THOSE GETTING THE ACTIVE AGENT. WHY IS IT DIFFERENT FOR YOU? >> IT'S DIFFERENT FOR ME BECAUSE IT'S A 4-YEAR-OLD VERSUS A 12-YEAR-OLD. I DON'T WORK WITH CHILDREN, BUT I THINK THAT BASICALLY THEY'RE DIFFERENT -- YOU CAN'T COMPARE THE TWO GROUPS. AND I DON'T THINK THEY SHOULD -- I THINK ASSENT SHOULD BE WAIVED BECAUSE IT'S POTENTIALLY A CATEGORY 2, APPROVABLE, BUT I THINK THAT THE CHILDREN THEMSELVES ARE DIFFERENT SO YOU CAN'T LUMP THEM ALL TOGETHER BECAUSE THEY'RE METABOLICALLY DIFFERENT THAN OLDER CHILDREN. >> SO YOU HAVE A GOOD SCIENCE REASON TO TRY TO KEEP THEM SEPARATE. >> RIGHT. >> BECAUSE THE SCIENCE AT 4 MAY BE DIFFERENT AT 12, ABSOLUTELY CORRECT. OTHER PEOPLE WHO WANT TO COMMENT? ANY COMMENT? >> NO, I THINK I AGREE THAT MAYBE THE DRUG WAS DEVELOPED FOR 12 AND OLDER, SO MAYBE IT'S TO THE SUITABLE FOR 4 YEARS OLD. >> OH, I THINK THEY'LL WANT TO GIVE IT TO 4-YEAR-OLDS IF IT'S OKAY IN 12-YEAR-OLDS. IN FACT, ONE OF THE PRINCIPLES IN PEDIATRIC RESEARCH ETHICS HAS ALWAYS BEEN, ANIMALS FIRST, THEN ADULTS, THEN CHILDREN. IF IT'S A DISEASE THAT SPANS THE ADULT AND CHILD. CAN'T DO THAT WITH SURFACTANT FOR PREEMIES WHO NEED LUNG MATURATION, BUT IF YOU ARE SEEING A DISEASE IN ADULTS, WE WOULD OH DO IT FIRST DO IT FIRST IN ADULTS SO WE COULD ASSESS THE RISKS AND FIGURE OUT. IT'S ALWAYS RISKIER IN KIDS AND WHAT PEOPLE OFTEN SAY IS LET'S DO IT IN THE BIG KIDS A, BECAUSE THEY CAN ASSENT, AND B, BECAUSE WE'LL GET A BETTER UNDERSTANDING IF IT'S DIFFERENT, AND ADD LE VENTS EVOLVING IN THEIR DEVELOPMENT. THEY'RE EVOLVING IN THEIR ENDOCRINE LOGIC CAPACITY, BUT IT'S OFTEN RISKIER IN THOSE LITTLE GUYS THAT CAUSE ALL OF BECAUSE ALL OF THEIR ORGANS ARE DEVELOPING. AND REMEMBER, ONE OF THOSE STUDIES IN THE CANCER PATIENTS AFFECTED A LOT OF OTHER ORGANS. AND RE FETUSES AND YOUNG INFANTS GOT A LOT OF ORGANS THAT ARE GROWING IN THERE AND DEVELOPING, INCLUDING THE BRAIN. BRAIN AIN'T DONE WHEN YOU'RE BORN. OKAY? IT MAY NOT BE DONE FOR A LONG TIME, BUT IT'S CERTAINLY ACTIVELY EVOLVING IN THE FIRST YEARS OF LIFE. SO THESE ARE IMPORTANT QUESTIONS. AND ONE OF THE RESEARCH ETHICS PRINCIPLES IN PEDIATRICS HAS BEEN DO THE OLD KIDS FIRST, SEE HOW THAT WORKS, AND STUDY THEM. YOU'VE GOT TO HAVE ENOUGH OF THEM. YOU SEE, OUR IRB AND OUR BIOSTATISTICIANS MIGHT HAVE SAID, YOU'RE GOING TO HAVE TO MAKE SURE YOU'VE GOT ENOUGH POWER IN THAT 12 TO 16 OR 12 TO 18 GROUP OR MAYBE EVEN MAKE IT 12 TO 20. SO THAT YOU CAN STUDY THAT GROUP SEPARATE FROM THE ADULTS IN TERMS OF YOUR STATISTICAL POWER. BECAUSE IF YOU LUMP THEM, YOU MAY NOT FIND THOSE PROBLEMS IN THOSE KIDS BECAUSE YOU DON'T HAVE ENOUGH IN THAT GROUP. SO THE FIRST QUESTION OF AGE IS AN IMPORTANT ONE. THE SECOND QUESTION WE REALLY NEED TO THINK ABOUT IS WHAT'S THE LEVEL OF RISK OF THIS STUDY? WHAT'S THE LEVEL OF RISK OF THIS STUDY? WHERE DOES IT FIT? REMEMBER THOSE FOUR CATEGORIES: MINIMAL, MORE THAN MINIMAL WITH PROSPECT TO DIRECT BENEFIT, MINOR INCREASE OVER MINIMAL WITH NO PROS PROS PECT NO PROSPECT OF DIRE CT BENEFIT, AND THEN SECRETARY'S ADVISE RE COMMITTEE. WHERE DOES THAT FIT IN MINIMAL, MINOR INCREASE, PROSPECT OF DIRECT BENEFIT RUBRIC? WHERE DOES IT FIT? WHERE DO YOU THINK? >> I THINK IT'S POTENTIALLY SLIGHTLY OVER MINIMAL WITH POTENTIAL OF BENEFIT, BUT I THINK THE WIDE AGE DISTRIBUTION CAUSES A NEED TO QUESTION THAT FOR DIFFERENT SUBPOPULATIONS OF THAT AGE. >> RIGHT. SO WERE YOU AFFECTED TO SAY THAT BY THOSE STUDIES IN THE OBESE PATIENTS THAT SEEM TO SHOW THAT IT WAS PRETTY SAFE? >> POSSIBLY. >> I'M JUST ASKING. >> RIGHT. >> OKAY. SO YOU'RE SAYING, WELL, YOU KNOW, WE DID THIS AND WE DIDN'T FIND ANYTHING REALLY TOO TERRIBLE. SO LET'S CALL IT MINIMAL. WOULD IT FIT THE DEFINITION WE SAID ABOUT DAILY LIFE, ACTIVITIES OF DAILY LIFE AND ROUTINE WELL-BABY VISITS? >> HMM. >> HMM. WHAT DO YOU THINK? WOULD IT FIT? >> NO, I DON'T THINK IT FITS THE WELL-BABY, BUT MAYBE BEING COMMENSURATE WITH INTERVENTIONS THAT YOU MIGHT EXPERIENCE AS SOMEONE WITH THIS CONDITION IS A REASONABLE APPROXIMATION. >> SO MAYBE MINOR INCREASE OVER MINIMAL RISK WITH POSSIBLE DIRECT BENEFIT, >> EXCEPT MAYBE IT'S MORE THAN A MINOR INCREASE OVER MINIMAL RISK. >> MAYBE IT IS. IT'S THE A NEW DRUG. IT'S A NEW DRUG. SO IT'S PRETTY TOUGH TO GIVE A NEW DRUG TO A KID AND CALL IT MINIMAL RISK. BUT YOU KNOW WHERE WE DO IT ALL THE TIME? IN VACCINE TRIALS. SO DO YOU WANT TO PLAY THIS OUT AS MINIMAL RISK? >> YOU KNOW, AS YOU KNOW, THIS STUDY HAS BEEN DOOND THE DONE, THE DATA HAS BEEN PUBLISHED AND YOU KNOW THE RESULTS. >> I DON'T KNOW THE RESULTS ACTUALLY. >> WELL, THE DRUG HAS BEEN -- THERE WERE TWO UNEXPECTED DEATHS. >> OH, I DO KNOW THAT. >> OKAY. SO AND FDA SHUT IT DOWN. SO IS THAT WHY WE'RE TALKING ABOUT THE POSSIBILITY OF UNEXPECTED RESULTS IN A DIFFERENT GROUP EVEN THOUGH AN EARLIER GROUP OF OBESE INDIVIDUALS HAD LITTLE TOXICITY? >> I HAVE TO SAY THAT PROFESSOR GRADY OVER THERE IS THE PERSON WHO CHOSE THIS. I HAD A CHANCE TO SEE IT, OF COURSE. AND SHE DID EXPLAIN TO ME THAT FACT. I WASN'T GOING TO REVEAL THAT UNTIL A LITTLE LATER. BUT IT SPEAKS TO THE POWER AND IMPORTANCE OF DATA AND SAFETY MONITORING BOARDS. IT DOES SPEAK TO THAT, AND IT SPEAKS TO THE IDEA THAT STUFF HAPPENS. THAT WE DON'T REALLY EXPECT. BUT I THINK AS WE CALLED THIS TRIAL, AS WE PLACE IT INTO THE MINIMAL RISK MINOR INCREASE OVER MINIMAL RISK, PROSPECT OF DIRECT BENEFIT, IT'S VERY HARD TO PUT THE THIS INTO A MINIMAL RISK TRIAL. IN FACT, I THINK IT WOULD BE IMPOSSIBLE FOR AN IRB TO DO THAT. YES. >> SO I WAS THINKING, I'M A PEDIATRICIAN AND ONE OF THE FIRST THINGS THAT WORRIES ME IS THINKING ABOUT THE MECHANISM OF ACTION OF THIS DRUG WITH PROTEIN MODIFICATION IN QHOIRN WERE GROWING AND DEVELOPING, NOT ONLY THE IMPACT ON ANGIOGENESIS IN GROWTH AND DEVELOPMENT, BUT ALSO ON PROTEINS, LONG TERM IN GROWTH AND DEVELOPMENT OF A CHILD AND THEY REALLY HAD NO PRELIMINARY DATA, IT'S BEEN USED IN CANCER PATIENTS IN THE PACK GROUND, AND THE OTHER IS THE PHASE TWO STUDY DONE IN ADULTS, SO FOR THE POTENTIAL IMPACT IN CHILDREN, IT WORRIES ME FROM A PEDIATRIC PERSPECTIVE THAT THERE MAY BE THINGS THAT YOU WOULD NOT EXPECT TO SEE IN AN ADULT THAT YOU WOULD SEE IN A CHILD UNDERGOING GROWTH AND DEVELOPMENT. >> I THINK THAT'S ABSOLUTELY CRITICAL AND WELL SAID. PEDIATRICIANS ARE CLASSICALLY PATERNALISTIC. WE COULD CALL THEM MATERNALISTIC SINCE THE VAST MAJORITY ARE NOW WOMEN, BUT THEY'RE CERTAINLILY PARENTALLISTIC, AND THEY SHOULD BE, WE SHOULD WORRY ABOUT CHILDREN. AND THAT'S PART OF THE IRB'S RESPONSIBILITY. SO LET'S THINK FOR A MINUTE, EVEN IF WE THINK THERE IS THE PROSPECT OF DIRECT BENEFIT, WE'VE NOW KIND OF UPSET YOU BY THE DEATHS AND STOPING OF THE STUDY, BUT ASSUMING THAT WE BEFORE THE STUDY -- ASSUMING BEFORE THE STUDY WE DIDN'T EXPECT THAT WE DON'T KNOW, WE NEVER KNOW. I HAVEN'T DONE ENOUGH WORK TO UNDERSTAND WHAT THOSE DEATHS WERE ALL ABOUT. BUT AS WE INIT TER INTO THIS, BEFORE THE STUDY IS DONE, SO THE QUESTION OF THE LEVEL OF RISK COMES UP, AND WE DO BELIEVE THIS PROSPECT OF DIRECT BENEFIT. NOW, I WANT TO STOP ONE MINUTE AND BE CYNICAL A LITTLE BIT, PRADER-WILLI DISEASE IS AN EXTRAORDINARILY IMPORTANT DISEASE TO THE VENTURE CAPITAL WORLD. WHY WOULD THAT BE? PARDON ME? OH, OBESITY. IT'S THE BIGGEST PUBLIC HEALTH PROBLEM IN AMERICA TODAY. IT'S WAY BIGGER THAN SMOKING NOW IS A PROBLEM. IT'S BIGGER THAN ALL THE DRUG PROBLEMS THAT WE'RE TALKING ABOUT WITH PRESCRIPTION DRUG ABUSE. IT IS AMONG THE LARGEST PUBLIC HEALTH PROBLEMS IN THE WORLD. AND THE REST OF THE WORLD IS CATCHING UP. OBESITY IS A PROBLEM. IF YOU CAN FIND A DRUG THAT WILL DECREASE APPETITE AND DECREASE OBESITY THE, IT'S A BIG, BIG BLOCKBUSTER. IT'S NOT A BLOCKBUSTER, IT'S A BLOCK AND A HALF BUSTER. OKAY? SO PRADER-WILLI BECOMES OF INTEREST TO DRUG COMPANIES AND THEY'RE WILLING TO SPEND AN EXTRAORDINARY AMOUNT OF MONEY TO PROVE A DRUG COULD CHANGE HYPERFASCIA AND DECREASE OBESITY. NOW I DON'T WANT TO BE A CYNIC ON THE IRB, BUT IN MY IRB, BEFORE IT WOULD GET TO ME, IT WOULD GO THROUGH A CONFLICT OF INTEREST REVIEW. RIGHT? NOW, THIS IS A FUNDED STUDY BY A DRUG COMPANY OR BIOTECH COMPANY. DOES THE INVESTIGATOR WHO'S WRITING THIS PROPOSAL HAVE AN INTEREST IN THIS COMPANY? WE HAVE VERY STRICT RULES HERE, I'M SURE, ABOUT FINANCIAL INTERESTS. WELL, WE HAD AN ISSUE IN MY INSTITUTION IN WHICH THERE WAS A PHYSICIAN TESTING NOT A MAJOR DRUG BUT A MAJOR DRUG, HE SAID HE HAD NO FINANCIAL INTEREST IN THE COMPANY, HE'D NEVER BEEN GIVEN ANY MONEY, BUT YES, THEY HAD GIVEN HIM 10% OF HIS FUTURE. HEBUT HE HADN'T MADE A NICKEL. BUT THAT IN OUR RULES AT A VERY IMPORTANT MEDICAL SCHOOL, IN OUR RULES, DIDN'T REQUIRE HIM TO BE RECUSED FROM THE STUDY BEFORE IT GOT TO THE CONFLICT OF INTEREST COMMITTEE THAT I WAS ON. AND WE SAID BUT -- IF THIS GOES, HE BECOMES A RICH MAN. I DON'T KNOW HOW RICH, BUT A RICH MAN. IF IT DOESN'T GO, SO DOES THAT CONFLICT HIM? EVEN THOUGH HE'S NEVER HAD $5,000, IS IT FIVE YEAR, OR 10? FIVE, I THINK. $5,000 IN MONEY FROM THEM. SO WE'RE VERY WELL REGULATED AT THE NIH IN TERMS OF MONEY ON THE OUTSIDE. THE ACADEMIC WORLD IS VERY POORLY REGULATED, CONCERNING MONEY ON THE OUTSIDE. AND THAT'S A BIG ETHICS QUESTION TODAY. SO IF I SAW THIS AS THE IRB CHAIR, I'D WANT TO CALL MY CHAIR OF THE CONFLICT OF INTEREST COMMITTEE AND MAKE SURE THAT WE WEREN'T GOING TO HAVE A JESSE GELSINGER STORY WHO DIED BECAUSE HE NEVER SHOULD HAVE GOTTEN THAT DRUG THAT DAY BECAUSE HIS AMMONIA LEVEL WAS TOO HIGH, AND HIS FAMILY SHOULD HAVE KNOWN THAT THERE WERE MONKEYS THAT DIED. AND MAYBE HE WOULDN'T HAVE BEEN IN THE STUDY. SO I THINK THAT'S A BIG PIECE FOR OUR PROTECTION PART. NOW, THERE ARE A COUPLE OF OTHER ISSUES. SO THIS HAS A PLACEBO ARM. NOW AT SOME POINT, THESE INVESTIGATORS ARE GOING TO FLIP AND GIVE THE DRUG TO THE PLACEBO SO THERE'S PROSPECT OF DIRECT BENEFIT DOWN THE ROAD FOR THE PLACEBO PATIENTS. BUT NOT IN THE FIRST PART OF THIS STUDY. SO HOW DOES THAT PLAY OUT IN OUR ASSESSMENT OF WHATEVER THESE RISKS ARE AND WHERE THIS FITS? NOW FOR THE PLA PLACEBO KIDS, THEIR PROSPECT OF DIRECT BENEFITS DOWN THE ROAD, IF EVERYTHING GOES WELL, THEY'LL HAVE AN OPPORTUNITY TO CONSENT TO GO INTO A FURTHER EXTENSION. BUT THE FIRST PART, THEY AIN'T GOT NO PROSPECT OF DIRECT BENEFIT EXCEPT THAT THEY'RE PARTICIPATING ALTRUISTICALLY IN THIS STUDY ABOUT THEIR CONDITION OR DISORDER WHICH MAY BRING A NEW DRUG TO REALITY FOR THEIR CONDITION OR DISORDER. ANYBODY WANT TO ARGUE WITH THAT? THE PLACEBO KIDS, UR KNOW, THEY'RE GETTING -- THEY'RE COMING TO VERY NICE DOCTORS AND VERY NICE PLACES, BUT THEY'RE NOT GETTING A PROSPECT OF DIRECT BENEFIT UNTIL LATER. AND THEN WE'RE GOING TO ASK THEM TO RECONSENT, AS I UNDERSTAND. WE'RE GOING TO ASK THEM TO RECONSENT TO MAKE SURE THEY WANT TO CONTINUE ON THE PART OF THE STUDY THAT'S THE EXTENSION. SO HOW DOES THAT PLAY OUT SO WHAT LEVEL OF RISK IS IT FOR THE PLACEBO IF THEY'RE NOT GETTING A PROSPECT OF DIRECT BENEFIT? >> COULD YOU REMIND US, IS THE PLA SEE GOA LIKE A SUGAR PILL OR SOMETHING COMPARABLE? >> IT'S A SHO. IT'S COMPARABLE IN TERMS OF HOW THE KID'S GOING TO FEEL, THE INJECTION, BUT IT'S GOT NO ACTIVE DRUG. I DON'T KNOW IF IT WAS SALINE OR, YOU KNOW, USUALLY. OR IT COULD BE SOMETIMES IT'S THE CARRIER FOR THE DRUG WITHOUT THE DRUG. BUT I DON'T KNOW EXACTLY WHAT IT WAS. >> I THOUGHT IT WAS INTERESTING WITH THE TWO PLACEBO ARMS, THINK IT WAS THE HIGH GROUP FIRST ON THE LOW AND THEN MOVED TO THE HIGH? I'M NOT REALLY SURE WHY THEY DID THAT. >> THAT'S ALSO A CLASSIC COMPLEX DRUG TRIAL, SO THE LOWER DOSE IS LESS LIKELY TO HAVE ANY PROBLEM PROBLEMS, SO YOU CHECK THAT. IF THEY'RE NOT HAVING PROBLEMS, YOU KICK THEM UP TO THE HIGHER DOSE, BUT THEY'RE REALLY IN THE HIGHER DOSE GROUP FROM THE BEGINNING, BUT THEY'RE GETTING THE LOWER DOSE JUST TO KIND OF SEE IF THEY'RE GOING TO HAVE BAD REACTION. BUT THE PLACEBO KIDS ARE GETTING NO DRUG THE WHOLE TIME. BUT SINCE MOST GET DILUTED AND IT'S A VOLUME THING, THEY'RE GIVING THEM THE SAME VOLUME. SO WHAT DO YOU THINK ABOUT THESE PLA SEE GOA BO KIDS? ARE THEY MINIMAL RISK, PROSPECT OF DIRECT BENEFIT, MINOR INCREASE OVER MINIMAL? BECAUSE AS AN IRB, WE'VE GOT TO TELL THE FETD FEDERAL GOVERNMENT OR AT LEAST OUR MINUTES HAVE TO SAY HOW ARE WE APPROACHING THIS THING? BECAUSE WE'RE SUPPOSED TO PROTECT CHILDREN. >> I WOULD SAY THEY'RE AMONG THE MINIMAL RISK GROUP WITH THE HIGH -- BOTH THE HIGH AND LOW PLACEBOS. >> SO PLACEBO IS MINIMAL RISK, THEY'RE GETTING SOME SHOTS, BUT THOSE SHOTS -- THEY'RE JUST SUBCUTANEOUS SHOTS, THEY'RE HAVING SOME BLOOD DRAWN. THEY'RE ALSO HAVING THIS THING CALLED A DEXA SCAN. DO YOU NO HE WHAT THAT IS? >> BODY COMPOSITION. >> BODY COMPOSITION. HOW DO YOU DO THAT? WHAT ARE THE RISKS? >> KIND OF LIKE AN MRI, I REMEMBER. YOU LAY ON IT AND IT KIND OF DOES A COMPLEX SCAN OF YOUR FAT AND YOUR BONE MASS AND MUSCLE MASS. >> IS THERE RADIATION INVOLVED? >> I THINK SO. >> YEAH, YEAH, THERE'S SOME RADIATION INVOLVED. THERE IS. I MEAN, IT'S NOT A TERRIBLE LOT, BUT THERE IS. DEXA SCANS ARE USED A LOT IN METABOLIC STUDIES. THEY'RE A GOOD OUTCOME STUDY FOR THESE KINDS OF THINGS. SO THE QUESTION OF IS THIS MINIMAL RISK RESEARCH GOING BACK TO THAT, DAILY LIVES AND THE ISSUES OF WELL-BABY VISITS. IT WOULD BE HARD TO SQUEEZE IN TO MINIMAL RISK. BUT THAT MINOR INCREASE OVER MINIMAL RISK CATEGORY FOR YOUR CONDITION OR DISORDER WOULD BE POTENTIALLY POSSIBLE TO JUSTIFY. SO WE MIGHT PUT THESE PLACEBO KIDS INTO THAT GROUP. ANYBODY GOT A PROBLEM WITH THAT? WHAT I LOVE ABOUT THE NIH IS THEY ACTUALLY LET YOU WALK THROUGH THE AISLES. >> SO THESE KIDS ARE ACTUALLY BEING TAKEN CARE OF BY CAREGIVERS, IS THAT CORRECT? >> WELL, MOST OF THEM BEM THEM BY PARENTS. >> SO THESE PARENTS WOULD HAVE TO GO THROUGH THE SAME TROUBLE OF GETTING THEIR KID TO THE CLINIC AND ALSO KEEP -- >> OH, YEAH. SURE. GIVING THEM THE DRUG. THE NURSE COMING TO THE HOME. >> SURE. AND THEN -- >> ALL THE INNOVATION OF PRIVACY. >> SO THEY'D HAVE TO MAKE SURE THEY'RE LAYING DOWN FOR THE DEXA AND GETTING THEIR BLOOD DRAWS. >> RIGHT. >> BUT THEY'D BE IN THE PLACEBO GROUP SO THEY MAY NOT HAVE THE BENEFIT. >> RIGHT. RIGHT. >> SO -- >> AND THE PARENTS WOULD KNOW THAT. IN THE INFORMED CONSENT, WE'D WANT IT TO LOOK VERY CAREFULLY TU INFORMED CONSENT, AND I DID, AND IT SAYS THERE MAY BE A PLACEBO, BUT AFTER THE FIRST PHASE, YOU'LL HAVE THE OPPORTUNITY -- >> AND THE PARENT WOULD THEN DECIDE WHETHER IT WAS WORTH THE BURDEN? >> THAT'S RIGHT. >> WELL, I WOULDN'T THINK THAT WOULD BE WORTH IF -- >> SO YOU WOULDN'T DO IT. >> NO. >> EXCEPT YOU HAVEN'T LIVED WITH CHILDREN WITH PRAY DER WILLIE PRADER-WILLI DISEASE, WHO ARE HARD TO TAKE CARE OF, THEY HAVE A LOT OF PSYCHIATRIC SYMPTOMATOLOGY, THEY WILL ATTACK A RETBRIJ RAY TORE. >> SURE, BUT THESE PARENTS IN THE PLACEBO GROUP WOULD HAVE TO DEAL WITH THAT -- >> ANYWAY. BUT THEY MIGHT BE QUITE HOPEFUL. >> OKAY. I SEE. >> AND THEY MIGHT UNDERSTAND AND BE ALTRUISTIC ENOUGH TO SAY WELL, IT WILL BE GOOD FOR ALL THOSE KIDS AND MY KID WILL BE THE FIRST ONE TO GET THE DRUG IN, YOU KNOW, 22 WEEKS OR WHATEVER, WHEN THE NEXT PHASE COMES. >> OKAY. >> SO I'LL ONLINE. >> OKAY. >> SO WE'RE GOING TO END THIS IN A FEW MINUTES. I WANT TO GET TO THE CONSENT AND YES.NT PROCESS.- >> WHY NOT REQUIRE FOR THE PLACEBO WITH SOME KIND OF VERY MINIMAL AND, YOU KNOW, BENEFIT SIMILAR DRUGS OR EVEN -- STUFF, AT LEAST -- WE KNOW THEY WILL TAKE CARE OF THE BABY FOR SOMEHOW DO WE KNOW IT'S A PLACEBO, THEN AT LEAST YOU HAVE A MINIMUM -- >> THAT WOULD MAKE YOU FEEL BETTER. MAKE YOU FEEL BETTER. >> NO, FOR THE BABY BETTER. >> YEAH, IT'S A 12-YEAR-OLD AT THIS POINT. >> STATISTICS ALSO COMPARE IN YOUR DRUG NOT BETTER THAN PLACEBO, WHY ARE YOU -- SO STATISTICALLY MAKE SENSE? >> WELL, WE HAVE THESE PLACEBO ARMS BECAUSE WE WANT TO COMPARE AND WE WANT TO HAVE ACTIVE DRUG AGAINST PLACEBO. IF WE COULD DO A DOSE TRIAL, THEY'RE STARTING AT A VERY LOW DOSE. THAT'S WHY THEY'RE DOING THE TWO LOW DOSES. SO THEY'RE STARTING CAREFULLY. SO GENERALLY IF YOU'RE GOING TO DO PLACEBO, IT OUGHT TO BE PLACEBO. AND THERE IS A LOT OF DATA ON HOW PLACEBOS ACTUALLY HAVE ACTIVITY, I MEAN, I DON'T MEAN THEY HAVE ACTIVITY AS KEM BUT THEY ACTUALLY DO SOME GOOD. I WANT TO TALK ABOUT THE CONSENT AND ASSENT PROCESS. DID ANYBODY READ THE ASSENT? I GOT ALL EXCITED. SO WHAT DID YOU THINK OF THIS ASSENT? >> THE PART THAT WAS REALLY HARD FOR ME, THIS IS BOTH -- MOSTLY AS A MOTHER, TO BE HONEST. >> OKAY. >> I'M PICTURING CHILDREN WITH PRADER-WILLI WHO ARE DESPERATE FOR FOOD AND WE ARE ASKING THEM, DO THEY UNDERSTAND THAT THEY'RE SIGNING UP FOR FASTING BLOOD WORK, DO THEY UNDERSTAND THAT THEY ARE -- AS IF THEIR LIFE IS NOT COMPLICATED ENOUGH WITH HOW MUCH THEY HAVE TO BE RESTRICTED, WE'RE RESTRICTING THEM FURTHER. AND DO YOU REALLY KNOW WHAT THAT MEANS, CAN YOU REALLY PROCESS THAT WE'RE GOING TO SAY NO FOOD UNTIL YOU'VE HAD YOUR EXAM AND YOUR BLOOD WORK. >> SO YOU WERE CONCERNED THAT HE THIS WOULDN'T UNDERSTAND THE ASSENT AND UNDERSTAND THE CONSEQUENCES TO THEM AND WE MIGHT GET THEM TO SAY YES, BUT WE'D BE REALLY DUPLICITOUS. >> YES. >> OKAY. ANY OTHER CONCERNS ABOUT THE ASSENT FROM ANYONE WHO MIGHT HAVE TAKEN A LOOK AT IT? I COULDN'T FIND MENTION OF THE PLACEBO ARM IN THE ASSENT. I READ IT TWICE, I COULD BE WRONG, BUT I COULD NOT FIND MENTION OF THE PLACEBO ARM IN THE ASSENT. NOW, ACCENTS HAVE TO BE SIMPLE, THEY HAVE TO BE CLEAR, THEY'RE NOT CONSENT-LIGHT. THEY REALLY HAVE TO FOCUS ON THE IMPACT OF THE CHILD, THAT'S THE GOAL OF AN ASSENT. HOW IS IT GOING TO IMPACT ON ME, DOCTOR, ON ME AS A KID? I MIGHT WANT TO KNOW IT BUT I DON'T HAVE KNOW THE SCIENCE. HOW MANY BLOOD DRAWS, DISCOMFORTS, THINGS YOU'RE GOING TO STAR STARVE ME, BUT ALSO WE HAVE SOME OBLIGATION TO TELL THE CHILDREN HONESTLY THAT SOME OF THE KIDS ARE GOING TO GET THE ACTIVE DRUG AND SOME AREN'T, BUT EVERYBODY IS GOING TO GET THE STICKS. THAT, I THINK WE'VE GOT TO TELL THEM. NOW, YOU DON'T REALLY WANT TO TELL THEM THAT BECAUSE IF THEY DON'T ASSENT, THEY DON'T IN THE TRIAL, RIGHT? SO IF YOU'RE THE INVESTIGATOR, YOU DON'T WANT TO TELL THEM ANYTHING THAT'S GOING TO STOP THEM FROM BEING IN THE TRIAL IF YOU'VE GOT THE PARENTS ON BOARD, RIGHT? AND, IN FACT, IN CANCER STUDIES, THERE'S A LOT DONE TO SHOW THAT KIDS USUALLY DO WHATEVER THEIR PARENTS WANT THEM TO DO IN TERMS OF ASSENT. THEY USUALLY ARE CONSISTENT WITH THEIR PARENTS' PERMISSION. BUT THESE ARE 12 TO 18-YEAR-OLD KIDS, AND THEY MIGHT NOT LIKE THE IDEA OF ALL THOSE STICKS UNLESS I'M GETTING SOMETHING IN THE RIGHT -- AND THEY MAY NOT BE HAPPY BECAUSE OF THEIR DISEASE THAT THEY'RE NOT GOING TO BE ALLOWED TO EAT. SO THE ASSENTS ARE A VERY POWERFUL AND IMPORTANT PART OF THIS PROCESS FOR THE IRB. IT SHOULDN'T BE CONSENT-LIGHT BUT IT SHOULD BE PUT YOURSELF IN THE SEAT OF THE KID WHO IS IN THIS CASE 12 BUT COULD BE 7, AND THEN ALSO DISCUSS WITH THE INVESTIGATOR, ARE YOU GOING TO DO A COGNITIVE CAPACITY ASSESSMENT WITH THE FAMILY ABOUT SHOULD THIS KID ASSENT OR SHOULD THEY GIVE PERMISSION WITHOUT THE CHILD'S ASSENT. BECAUSE THEY REALLY CAN'T UNDERSTAND THE COMPLEXITY OF THIS. THAT'S OKAY. SO DON'T ENTER INTO IT AGAIN IF YOU'RE NOT GOING TO ACCEPT THEIR DISSENT IF THEY DON'T HAVE THE CAPACITY TO INTERVENE. AND THE CONSENT IS VERY, VERY COMPLICATED BUT I THINK IT'S A GOOD ONE. THE NIH BOILERPLATE IS PRETTY GOOD. BUT IT'S LONG AND IT'S COMPLICATED AND THERE'S NO SIM SIMPLISTIC SUMMARY IN THE BEGINNING. NOW THIS IS AN OLD STUDY, SO MAYBE IT'S LESS LIKELY, BUT NOW HOPEFULLY THERE WOULD BE MORE WHICH WOULD HAVE A SIMPLISTIC, SIMPLE SUMMARY SO THAT YOU GET THAT INFORMATION ON ONE PAGE OR TWO PAGES WITHOUT ALL OF THE VERBIAGE THAT GOES INTO THE CONSENT, AND THEN YOU CAN READ THE REST OF IT AS YOU GO ALONG BECAUSE -- AND I'LL LEAVE YOU WITH THIS, WHEN WE WERE DOING OUR REVIEW OF THESE REGULATIONS, WE HAD A FATHER COME TO THE FEDERAL ADVISORY COMMITTEE, AND HE HAD HAD A YOUNG GIRL WHO HAD DIED OF BRAIN CANCER, AND HE LOVED HIS DOCTOR, AND HIS DOCTOR WAS ON THIS PANEL. AND HE SAID, YOU KNOW, I'M A LAWYER, I KEPT ALL THE RECORDS, I HAD THE INFORMED CONSENT FORM FOR THE STUDY, I WENT TO IT LAST NIGHT, I PULLED IT OUT, I SAW THAT MY SIGNATURE WAS ON IT. HE SAID, I NEVER REMEMBERED A WORE OF THE CONSENT. I READ IT AND I SAID I NEVER READ THIS, NEVER BEFORE. PAST MEMORY, WAS 15 OR 18 YEARS. BUT HE SAID I SIGNED IT. HE SAID, I CAN TELL YOU WHAT THE DOCTOR'S TIE WAS LIKE, BECAUSE HE ALWAYS WORE INTERESTING TIES. I CAN TELL YOU THE NURSE'S UNIFORM COLOR. I CAN'T TELL YOU A THING ABOUT THE CONVERSATION, BUT I TRUSTED DR. -- IT WAS FILP EE. ZO, WHO WAS HERE FOREVER AND THEN WENT OFF AND DID MORE IMPORTANT THINGS. I TRUSTED DR. PISO AND THEN I SIGNED THE FORM. SO REMEMBER THE POWER THAT YOU HAVE AS AN INVESTIGATOR, BUT ALSO REMEMBER THAT THE INFORMED CONSENT IS OFTEN LIKE YOU DEAL WITH WHEN YOU COME TO A NEW PLACE AND YOU WANT TO GET ON THE INTERNET AND THEY GIVE YOU THIS WHOLE THING, YOU'RE SUPPOSED TO SAY I ACCEPT THE TERMS, HAVE YOU EVER READ IT? THE PARENTS TEND NOT TO READ THE INFORMED CONSENT FORMS WELL EITHER. IF THEY DO, THIS HE SKIM THEM BECAUSE THEY TRUST YOU, WHICH MAKES IT EVEN MORE IMPORTANT THAT THE CONVERSATION BE THE CRITICAL PART, AND THE IRB AIN'T GOT NOTHING TO DO WITH THAT CONVERSATION. THANK YOU. [APPLAUSE] >> SO THANK YOU. I JUST WANT TO SAY WHY WE'VE USED THIS PROTOCOL, BECAUSE OF THE OUTCOME AS WAS POINTED OUT. THE P.I. ACTUALLY WANTED US TO TALK ABOUT IT, AND I THINK ONE OF THE REALLY IMPORTANT THINGS THAT WE WERE HOPING TO SORT OF IMPRESS UPON YOU IS THAT WHEN YOU'RE WRITING A PROTOCOL OR WHEN YOU'RE REVIEWING IT AS A MEMBER OF AN IRB, YOU DON'T KNOW WHAT THE OUTCOME IS GOING TO BE. YOU HAVE TO BE ABLE TO SAY TODAY, IS THIS JUSTIFIED, ARE THE RISKS OKAY, ARE THE CONSENT FORMS OKAY, ALL THE THINGS THAT ALAN WALKED YOU THROUGH. SO THOSE ARE THE KINDS OF THINGS YOU HAVE TO DECIDE BEFORE YOU KNOW THE OUTCOMES. IN THE PARTICULAR CASE, THE DRUG WAS EVENTUALLY PULLED. PRIOR TO WHEN IT WAS PULLED BY THE FDA, THE INVESTIGATORS HERE DROPPED OUT OF DOING THE STUDY BECAUSE THEY DIDN'T LIKE THE SIDE EFFECTS THAT WERE BEING SEEN IN OTHER PLACES BEFORE THEY EVEN HAD ANY DEATHS, THEY SAW LOTS OF DVTs AND A COUPLE OF PULMONARY EMBOLISMS, SO THE INVESTIGATOR HERE SAID I'M NOT GOING TO GIVE THIS TO ANY MORE PATIENTS UNDER THIS STUDY. AND EVENTUALLY, IT WAS CLOSED DOWN BUT NOT THE INITIALLY. BUT IT IS A VERY INTERESTING LESSON IN HOW YOU HAVE TO KNOW AHEAD OF TIME WHAT THE DECISION IS YOU'RE GOING TO MAKE. THE LAST THING I WANT TO REMIND EVERYBODY, I THINK I SAID LAST WEEK, WE DO HAVE ETHICS GRAND ROUNDS TODAY IF YOU HAVE THE TIME IN YOUR SCHEDULE, IT STARTS THE A NOON IN AT NOON IN THIS ROOM ON RESEARCH IN PREGNANT WOMEN.