>> GOOD MORNING EVERYONE. WELCOME TO THE THIRD SESSION OF THE REGULATORY ASPECTS OF CLINICAL RESEARCH. THIS MORNING WE ARE GOING TO TALK ABOUT RISKS AND BENEFITS, RESEARCH WITH CHILDREN AND RESEARCH WITH PREGNANT WOMEN. BEFORE WE GET THERE, I WANT TO REMIND EVERYBODY TO SIGN IN WHEN YOU COME AND FOR THOSE OF WHO YOU ARE WATCHING REMOTELY, WE DO HAVE A TWITTER OPTION FOR SENDING IN QUESTIONS THAT WE CAN ANSWER IN REALTIME. OUR -- TWEET US@NIH BIOETHICS AND WE'LL TRY TO GET THOSE QUESTIONS ANSWERED ON SITE. SO WITHOUT ANY FURTHER ADIEU, WE ARE GOING TO START WITH A DISCUSSION OF RISKS AND BENEFITS. THE MOST IMPORTANT THING TO THINK ABOUT IN THINKING ABOUT THE ETHICS OF CLINICAL RESEARCH, AND ONE THAT WE HAVE IN-HOUSE, ONE OF THE WORLD'S EXPERTS, I WOULD SAY, WHO HAS LOOKED VERY CAREFULLY AT THIS ISSUE OF RISKS AND BENEFITS IN EVALUATING CLINICAL RESEARCH AND TRYING TO DECIDE HOW TO IDENTIFY AND CATEGORIZE, I GUESS IS THE RIGHT WORD, RISKS. THIS IS DAVE WENDLER WHO IS A MEMBER OF OUR DEPARTMENT OF BIOETHICS AND HEAD OF THE SECTION ON RESEARCH ETHICS WHO YOU HEARD FROM LAST WEEK, I THINK, OR LAST TIME, ABOUT FAIR SUBJECT SELECTION. WELCOME BACK, DAVE. >> DAVE: SO THANK YOU. A COUPLE OF WARNINGS BEFORE WE START. A LITTLE BIT OF PHILOSOPHY MIXED IN HERE. I DON'T WANT ANYBODY TO HURT THEMSELVES THINKING THROUGH THESE THINGS TODAY SO IF YOU WANT TO TRY TO DO A COUPLE OF MENTAL GYMNASTICS BEFORE WE GET GOING. DOES EVERYBODY KNOW WHAT SERIAL 7S ARE AND HOW YOU DO THEM? SO THIS IS A VERY CLEVER TEST. YOU WANT TO COME UP WITH A TEST FOR HOW PEOPLE SHORT-TERM MEMORY IS. WHAT DO YOU DO? SO ONE IDEA IS YOU GET PEOPLE TO COUNT BACKWARDS FROM 100 BY 7. SO THE IDEA IS IF YOU TRY THAT, YOU GO 100, THEN GO 93. AND THEN TO GET TO THE NEXT ONE, YOU HAVE TO REMEMBER 93 IN YOUR HEAD AS YOU START SUBTRACTING 7 OR YOU LOSE IT. IF YOUR SHORT-TERM MEMORY IS BAD, YOU GET STUCK. SO IT'S A GOOD TEST FOR YOUR SHORT-TERM MEMORY TO SEE IF IT'S WORKING. IT'S LIKE MENTAL JUMPING JACKS. THAT'S ONE WAY TO WARMUP. THE OTHER WARNING IS THERE ARE LOTS OF QUESTIONS. MAYBE MORE THAN LAST TIME. SO I'M NOT GOING TO LET YOU GUYS SLEEP AND HOPE I GO AWAY. SO IN THE LIFT 10 MINUTES I'M GOING TO FORCE SOMEBODY TO ASK OR ANSWER MY QUESTIONS. SO AS YOU SEE, THIS IS RELATED TO FAIR SUBJECT SELECTION BECAUSE AS I MENTIONED IN FAIR SUBJECT SELECTION, ONE OF THE IMPORTANT QUESTIONS IN DECIDING WHO YOU WANT TO ALLOW INTO TRIALS AND WHO YOU WANT TO EXCLUDE FROM TRIALS IS BASED ON THE EXTENT TO WHICH THEY FACE POTENTIAL BENEFITS AND/OR RISKS FROM GOING INTO THE TRIAL. SO IT'S RELATED TO THAT AND I'LL TRY TO CONNECT IT UP. ALSO LATER TODAY, YOU'RE GOING TO HEAR FROM TWO EXPERTS, ONE ON PEDIATRIC RESEARCH ETHICS AND YOU CAN IMAGINE, ONE OF THE CENTRAL ISSUES THERE IS TO THE EXTENT TO WHICH YOU CAN EXPOSE CHILDREN TO RISKS IN CLINICAL RESEARCH. SO I'LL TRY TO SET THAT UP A LITTLE BIT AND THEN SOMEBODY ON -- TALKING ON RESEARCH WITH PREGNANT WOMEN AND FETUSES AND I'LL NOD TO THAT A LITTLE BIT, ALTHOUGH I DON'T KNOW WHAT THE RIGHT ANSWERS ARE. THAT IS A MORE DIFFICULT TOPIC. SO, THIS IS THE BELMONT REPORT THAT YOU HEARD ABOUT. SO THIS IS ONE OF THE GUIDING DOCUMENTS FOR CLINICAL REACH ETHICS AND BASICALLY WHAT THIS SAYS IS THAT GETTING RISK-BENEFIT JUDGMENTS RIGHT IS VERY IMPORTANT TO THE ETHICS OF CLINICAL RESEARCH AND WE SHOULD BE AS SYSTEMATIC ABOUT THAT AS WE CAN. WHAT IS INTERESTING WHEN I FIRST GAVE THIS LECTURE FOR CHRISTINE, I THOUGHT, WELL, THERE IS GOING TO BE SOME FRAMEWORK, SOMEONE IS GOING TO FIGURE THIS OUT HOW TO DO THIS IN A SYSTEMATIC WAY. I'LL STEEL WHATEVER FRAMEWORK THEY HAVE AND I'LL JUST PRESENT THAT. AND AS I STARTED GOING THROUGH LITERATURE, I COULDN'T FIND ANY SINGLE SYSTEMATIC APPROACH THAT ANYBODY HAD DEVELOPED SO I WAS TRYING TO FIGURE OUT WHAT SUCH SYSTEMATIC APPROACH WOULD BE. I'M GOING TO TRY TO PRESENT THAT TODAY. SO JUST A COUPLE OF BACKGROUND CAVEATS. I'M GOING TO FOCUS LARGELY, NOT ENTIRELY BUT LARGELY ON RISKS AND BENEFITS TO INDIVIDUAL SUBJECTS. A LOT OF OTHER QUESTIONS YOU COULD ASK. AND WE'LL TALK A LITTLE ABOUT THE SOCIAL VALUE OF THE RESEARCH, RISKS AND BENEFITS TO COMMUNITIES. I MENTIONED A LITTLE BIT TWO WEEKS AGO. I ALSO MENTIONED AGGREGATE, THE EXTENT TO WHICH RESEARCH ETHICS SHOULD CONSIDER AGGREGATE RISKS AND BENEFITS. I THINK THAT IS IMPORTANT HERE BUT I'M NOT GOING TO TALK ABOUT IT IN THIS PARTICULAR TALK. SO HERE IS THE FRAMEWORK. THIS SHOULD LOOK A LITTLE BIT FAMILIAR. THIS IS DESIGNED BASED ON THE FRAMEWORK THAT 7 OR 8 PRINCIPLES THAT WE DEVELOPED. AND THIS IS SUPPOSED TO BE AT LEAST ONE PROPOSAL FOR HOW TO SYSTEMATICALLY EVALUATE THE RISKS AND POTENTIAL BENEFITS OF CLINICAL RESEARCH TRIALS, WITH RESPECT TO SUBJECTS GAP, IN ORDER TO EVALUATE WHETHER THOSE TRIALS ARE ETHICALLY APPROPRIATE. I'M JUST GOING TO GO THROUGH EACH STEP AND YOU'LL HEAR A LITTLE BIT ABOUT EACH ONE I'M INTERESTED IF PEOPLE HAVE THOUGHTS ON STEPS THAT DON'T NEED TO BE DONE HERE OR STEPS THAT ARE LEFT OUT. SO, FIRST THING TO START IS, THIS IS A STANDARD VIEW. SO PEOPLE CALL THIS COMPONENT ANALYSIS. THE BASIC IDEA IS IF YOU THINK ABOUT ANY GIVEN RESEARCH TRIAL YOU'LL REALIZE THAT EACH TRIAL IS REALLY A PACKAGE OF A LOT OF DIFFERENT INTERVENTIONS, TESTS, AND SO THE ASSUMPTION IS WHAT YOU SHOULD DO, AT LEAST THE CLAIM OF COMPONENT ANALYSIS IS DON'T JUST EVALUATE THE OVERALL RISK-BENEFIT PROFILE OF THE ENTIRE STUDY. INSTEAD, WHAT YOU SHOULD FIRST DO IS EVALUATE THE RISK-BENEFIT PROFILE OF EACH INDIVIDUAL INTERVENTION THAT IS PART OF THAT PACKAGE. SO IF THERE IS BLOOD DRAWS, LOOK AT EACH BLOOD DRAW. IF THERE IS A MEDICINE, LOOK AT THE MEDICINE. IF THERE IS AN MRI, LOOK AT THAT. SO INDIVIDUAL COMPONENTS. THEN LOOK AT THE WHOLE THING. SO THAT IS WHAT I'M GOING TO TRY TO DO. I'M GOING TO GO BACK AND FORTH WITHIN A STUDY AND APPLY TO OVER ALL STUDY BUT THE GENERAL IDEA SAID YOU SHOULD DO BOTH, INTERVENTIONS FIRST AND THEN THE STUDY. I'M ALSO FOR THE MOST PART GOING TO FOCUS ON RESEARCH. SOME OF THOSE INTERVENTIONS THAT MIGHT BE PART OF THE PACKAGE OF A CLINICAL TRIAL, AT LEAST SOME TIMES, AND INCREASINGLY NOW TALKING ABOUT LEARNING HEALTH CARE SYSTEMS, MIGHT BE STANDARD OF CARE INTERVENTIONS. SO IF YOU'RE TESTING AN ADD ON TREATMENT, YOU MIGHT GIVE EVERYBODY IN YOUR TRIAL STANDARD OF CARE AND THEN YOU RANDOMIZE PEOPLE TO WHETHER THEY GET A PLACEBO OR EXPERIMENTAL ADD ON. AND THEN THE IDEA IS FOR THE MOST PART, WHAT IRBs AND OTHER STAKEHOLDERS SHOULD BE DOING TO ASSESS THE ETHICS OF CLINICAL RESEARCH, IS FOCUS ON THE EXPERIMENTAL OR THE RESEARCH INTERVENTIONS, THE ADD ONS IN MY EXAMPLE. SO ONE CAVEAT ON THAT IS, SOMETIMES YOU HAVE A FOCUS ON THE RESEARCH INTERVENTIONS BUT ONE OF THE WORRIES IS YOU HAVE TO ASK THE QUESTION OF WHETHER OR NOT THE INCLUSION OF A REACH INTERVENTION TOGETHER WITH A STANDARD OF CARE INTERVENTION MIGHT INFLUENCE THE POTENTIAL BENEFITS OR RISKS OF THE STANDARD OF CARE INTERVENTION. SO IT MIGHT BE POSSIBLE THAT HAVING AN ADD ON MIGHT NOT JUST POSE RISKS TO SUBJECTS FROM THE INTERVENTION ITSELF BUT IT MIGHT DECREASE FOR INSTANCE THE POTENTIAL BENEFITS OF THE STANDARD OF CARE INTERVENTION IN WHICH CASE THEN YOU'LL HAVE TO LOOK AT THE RELATIONSHIP BETWEEN THE TWO OF THEM. SO NOW HERE ARE THE STEPS OF THE FRAMEWORK THAT I MENTIONED. SOY THE FIRST ONE IS, FOR EACH INTERVENTION IN THE TRIAL YOU SHOULD ASK WHAT IS THE POINT OF HAVING THAT INTERVENTION AS PART OF THE PACKAGE OF THE TRIAL? AND AS CHRISTINE MENTIONED IN THE FIRST WEEK, WE ASSUME THAT TO ETHICALLY JUSTIFY BOTH INTERVENTIONS IN TRIALS AND TRIALS AS A WHOLE, THEY HAVE TO HAVE SOCIAL VALUE. THERE HAS TO BE DATA THAT YOU'RE COLLECTING AS A RESULT OF THAT INTERVENTION THAT HAS SOME POTENTIAL FOR SOCIAL VALUES. SOME POTENTIAL TO HELP WITH IMPROVING HEALTH OR WELL-BEING IN SOME WAY OR ANOTHER. SO THE FIRST BULLET ON THIS OR REMEMBER THE ARROWS FOR ME ARE JUST REMAINING CHALLENGES, OR QUESTIONS THAT I HAVE. HERE ARE THE CHALLENGES JUST THAT MAKING THESE DETERMINATIONS ALTHOUGH IT IS ETHICALLY IMPORTANT, REQUIRES A LOT OF SCIENTIFIC EXPERTISE, A LOT OF MEDICAL EXPERTISE. SO TO DECIDE WHETHER OR NOT TESTING SOME ADD ON INTERVENTION HAS SOCIAL VALUE, YOU NEED TO KNOW A LOT. YOU NEED TO KNOW A LOT OF WHAT ARE THE EXISTING TREATMENTS FOR THAT DISEASE? HOW BAD IS THAT DISEASE? HOW LONG DOES THAT DISEASE LAST? HOW MUCH WOULD THIS THING COST? IF WE COULD DEVELOP IT, AND IT'S EFFECTIVE BUT NOBODY COULD AFFORD IT OR HEALTH CARE SYSTEMS, NATIONAL HEALTH CARE SYSTEMS WON'T SUPPLY IT, THEN WHAT IS THE POINT OF DEVELOPING? SO YOU NEED TO KNOW A LOT ABOUT THE DISEASE, THE CONTEXT, MAYBE EACH THE HEALTH CARE SYSTEM IN ORDER TO ANSWER THESE QUESTIONS. SO A COUPLE OF QUESTIONS ABOUT SOCIAL VALUE. ONE OF THE ONES IS TYPICALLY WHAT IRBs WILL DO IS, YOU'RE THE INVESTIGATOR, YOU PRESENT THEM WITH A PROTOCOL. AND THEY'LL ASK THE QUESTION, WHAT IS THE SOCIAL VALUE OF THIS STUDY? AND DOES THE SOCIAL VALUE BASICALLY JUSTIFY THE RISKS TO SUBJECTS AND THE RESOURCES THAT ARE DEVOTED TO CARRYING OUT THE STUDY? SO IT'S BASICALLY WHAT YOU MIGHT THINK OF AS INTERNAL EVALUATION OF THAT STUDY. THAT IS IMPORTANT TO DO BUT FOR ME AT LEAST IT RAISES THE INTERESTING QUESTION OF THE EXTENT TO WHICH IRBs SHOULD BE DOING COMPARATIVE ASSESSMENTS OF STUDIES. SO, YOU SUBMIT A STUDY TO ME, SHOULD I JUST SAY, YES, LOOKS PRETTY GOOD. THERE IS SOME VALUE HERE ANY INFORMATION YOU'RE COLLECTING AND THAT VALUE JUSTIFIES THE RISK TO SUBJECTED. OR SHOULD I SAY NO! YOU DECIDE IT THIS WAY BUT IF YOU 69 IT THIS WAY YOU WOULD HAVE A BETTER STUDY. DON'T DO THAT STUDY. IT'S UNETHICAL GIVEN THIS ALTERNATIVE YOU HAVE. IS THAT SOMETHING IRBs SHOULD DO? OR SHOULD IRBs SAY DON'T STUDY THIS, THIS IS A LITTLE BIT IMPORTANT OR INTERESTING BUT THERE IS ANOTHER DISEASE OVER HERE OR ANOTHER INTERVENTION YOU CAN TEST THAT IS MUCH MORE IMPORTANT THAN THE ONE YOU'RE FOCUSED ON. IS THAT UNDER THE PER VIEW OF IRBs TO BASICALLY FORCE INVESTIGATORS TO EITHER CHANGE THE DESIGN OF THEIR STUDIES TO INCREASE THE VALUE OR TO ABANDON ONE STUDY OR ONE INTERVENTION AND DO SOMETHING ELSE? SO THIS IS JUST AN EXAMPLE. THIS WAS IN THE CONTEXT OF SOME OF THE RECENT REPORTS THAT CAME OUT AFTER THE EBOLA CRISIS IN WEST AFRICA AND HERE THE POINT WAS, IF WE ARE NOT MAKING COMPARISONS BETWEEN DIFFERENT STUDIES IN A CONTEXT OF WHICH WE HAVE AN OUTBREAK AND WE ONLY HAVE LIMITED TIME AND LIMITED RESOURCES TO DO TRIALS, WE MIGHT MAKE A MISTAKE AND END UP RUNNING THE TRIALS THAT WE WOULD RATHER NOT RUN INSTEAD OF RUNNING THE ONES THAT ARE PARTICULARLY VALUABLE, SUGGESTING THAT AT LEAST IN SOME CONTEXT YOU NEED TO MAKE THESE COMPARATIVE JUDGMENTS. OKAY. SO YOU HAVE LOOKED AT EACH INTERVENTION. THERE A S. A GOOD REASON FOR WHY THAT INTERVENTION IS INCLUDED IN THE PACKAGE OF THE TRIAL. SO THEN THE NEXT QUESTION IS, LOOK AT THE RISKS OF EACH OF THOSE INTERVENTIONS AND THEN AGAIN, AS I MENTION THE, THE STUDY AS A WHOLE. IDENTIFY WHAT THE RISKS ARE AND TO THE EXTENT YOU CAN REDUCE THEM, MINIMIZE THE RISKS TO THE EXTENT THAT YOU CAN. I'LL COME BACK TO THIS POINT IN A MINUTE BUT ONE OF THE THINGS THAT BASICALLY EVERYBODY WHO TALKS ABOUT THIS IN RESEARCH ETHICS AGREES ON IS THAT ALTHOUGH WE STEPPED TO FOCUS ON PHYSICAL, MEDICAL RISKS IN CLINICAL RESEARCH, THIS EVALUATION SHOULD TAKE IN ALL THE RISKS THAT ARE POSED TO SUBJECTS, NOT JUST CLINICAL MEDICAL ONES BUT PSYCHOLOGICAL ONES, SOCIAL ONES, SO IF I'M STUDYING ALCOHOLISM AND IS THERE A POTENTIAL FOR STIGMA, OR I'M STUDYING A PARTICULAR GENE IN A POPULATION AND THAT MIGHT LEAD TO THAT POPULATION BEING STIGMATIZED, THAT ALSO IS A RISK OF BEING IN THAT STUDY AND MY CONDUCTING A STUDY. SO LOOK AT ALL THE RISKS. I'M GOING TO COME BACK TO THAT IN A COUPLE OF MINUTES. HERE IS THE CHALLENGE. THE WHOLE POINT OF DOING CLINICAL RESEARCH TRIALS IS TO LEARN ABOUT THE IMACT OF THE INTERVENTION YOU'RE STUDYING. IT'S TO IDENTIFY WHAT RISKS THE INTERVENTION POSES AND WHAT I'M SAYING IN ORDER TO APPROVE THE STUDY, YOU HAVE TO IDENTIFY THE RISKS AND INVESTIGATORS, SAY THAT IS WHY I'M DOING THE STUDY TO IDENTIFY THE RISKS. IT FEELS AS THOUGH YOU'RE IN A CATCH-22 WHERE YOU NEED TO KNOW THE RESULTS OF THE TRIAL IN ORDER TO APPROVE IN THE FIRST PLACE AND AN INTERESTING DEBATE ABOUT HOW YOU THINK ABOUT THE EVIDENCE FOR THESE RISKS. MY THOUGHT IS THAT THERE IS ALWAYS SOME EVIDENCE THAT YOU HAVE IN THE REAL WORLD. EVEN IF THAT DRUG HAS NEVER BEEN TESTED IN HUMAN BEINGS, YOU MIGHT HAVE EVIDENCE FROM OTHER DRUGS IN THE SAME CLASS F THERE IS NO OTHER DRUG IN THE SAME CLASS THAT HAS BEEN TESTED ON HUMAN BEINGS, YOU MIGHT HAVE INFORMATION ON OTHER DRUGS FOR THAT DISEASE AND IF YOU DON'T HAVE THAT, YOU WILL HAVE DATA FOR INSTANCE ON OTHER PHASE I TRIALS NOW OBVIOUSLY DATA ON PHASE I TRIALS IN GENERAL ISN'T GOING TO BE AS RELEVANT TO THIS PARTICULAR DRUG BUT CAN GIVE YOU SOME INFORMATION ON WHICH TO BASE RISK-BENEFIT JUDGMENT. ANOTHER CHALLENGE AND THIS COMES BACK TO AS I MENTIONED, SUBJECT SELECTION FROM TWO WEEKS AGO WHICH IS THAT THE RISKS OF A PARTICULAR INTERVENTION AREN'T FIXED ACROSS ALL THE SUBJECTS YOU MUTE UNDERGO IT BUT CAN VARY. SO FOR INSTANCE, WHETHER MRI POSES RISKS COULD DEPEND ON WHETHER THE PERSON YOU'RE GIVING THE MRI TO IS SEVERE CLAUSTROPHOBIA OR NOT F THEY DO, AN MRI COULD BE RISKY. IF NOT, IT MIGHT POSE VERY LOW RISKS. SO ONE OF THE THINGS YOU NEED TO DO IS NOT JUST LOOK AT THE INTERVENTIONS BUT LOOK AT THE INTERVENTIONS IN RELATION TO THE INCLUSION EXCLUSION CRITERIA THAT WE DISCUSSED TWO WEEKS AGO. SO, THIS IS ONE OF THE POINTS I MADE IF YOU REMEMBER. IT WAS KIDNEY FUNCTION EXAMPLE TWO WEEKS AGO WHERE THERE IS A STANDARD MOVE WHAT IRBs WILL DO IS PEOPLE WHO FACE HIGH RISKS FROM INTERVENTION, THEY'LL EXCLUDE THEM FROM THE STUDY UNLESS THERE IS SOME SCIENTIFIC SOCIAL VALUE REASON WHY YOU SHOULD INCLUDE THEM. SO NOW WE GET TO THE A LITTLE BIT -- THE FIRST DOLLOP OF PHILOSOPHY FOR EVERYBODY. SO, IN A LOT OF CASE IT IS SEEMS LIKE LOOKING AT RISKS AND BENEFITS REALLY EASY. SO I SAY I'M GOING TO GIVE YOUAISE PARTICULAR DRUG AND YOU THINK, OKAY, WHAT ARE THE RISKS AND BENEFITS OF THAT DRUG? IT SEEMS AT LEAST IN THEORY A STRAIGHTFORWARD QUESTION TO ASK. BUT IF YOU START THINKING ABOUT EXAMPLES WHAT YOU REALIZE IS THAT ANY TIME YOU MAKE A RISK-BENEFIT JUDGMENT, YOU'RE DOING IT AGAINST SOME IMPLIED BASELINE OF WHAT WOULD HAPPEN TO THOSE PEOPLE OTHERWISE. SO HERE IS AN EXAMPLE TO TRY TO ILLUSTRATE THAT. A PHASE II STUDY OF TREATMENT HAS BEEN SHOWN SAFE AND OFFERS A SMALL CHANCE OF HELPING SUBJECTS QUALIFY AS PROSPECTIVE BENEFITED. IS THIS A PROSPECT OF BENEFITS STUDY FOR SUBJECTS OR A RISKY STUDY. I DON'T WANT TO MAKE ANYBODY TALK YET BUT THINK ABOUT THAT FOR 10 SECONDS. IS THAT A PROSPECT OF BENEFIT STUDY OR A RISKY STUDY? I THINK THE ANSWER IS, IT DEPENDS. SO IMAGINE WITH THE STANDARD OF CARE IS THAT EVERYBODY WOULD GET IF THEY DIDN'T ENROLL IN THAT TRIAL I DESCRIBED, THEY GET A TREATMENT THAT BASICALLY CURES EVERYBODY AND HAS LOW RISK. THEN YOU MIGHT THINK, THAT IS A RISKY TRIAL TO BE IN. RATHER THAN GETTING A TREATMENT THAT IS GOING TO CURE ME, I'M GOING TO GET A TREATMENT THAT JUST HAS SOME UNKNOWN SMALL CHANCE OF BENEFITING. THAT LOOKS WORSE THAN THE ALTERNATIVE OF BEING CURED SO TO THAT EXTENT YOU MIGHT THINK IT IS A RISKY TRIAL FOR PEOPLE TO BE IN. SO THE POINT HERE IS JUST THAT IN MAKING EVALUATIONS, WE NEED TO KNOW A LOT ABOUT THE CONTEXT. WE NEED TO KNOW ABOUT WHAT WOULD HAPPEN TO THESE PEOPLE IF THEY DIDN'T ENROLL IN A TRIAL AND ALSO THIS POINT, THIS COMES UP YOU'LL HEAR MORE ABOUT THIS WHEN YOU TALK ABOUT ETHICS OF MULTI-NATIONAL AND INTERNATIONAL RESEARCH, IT MIGHT TURN OUT A TRIAL COULD BE PARTICULARLY RISKY IN THE U.S. THAT HAS ONE STANDARD OF CARE BUT IT MIGHT BE POTENTIALLY BENEFICIAL IN SOME OTHER COUNTRY THAT HAS A LOWER STANDARD OF CARE OR MAYBE DEPARTMENT HAVE STANDARD TREATMENT FOR THE CONDITION IN QUESTION. THIS WAS A STUDY DONE 20 YEARS OR SO AGO NOW. SO, WE KNOW THAT LEAD PAINT AND EXPOSURE TO LEAD IS VERY BAD FOR BRAINS PARTICULARLY FOR THE BRAINS OF LITTLE KIDS WHO ARE DEVELOPING. UNFORTUNATELY, IT TURNS OUT THIS IS LESS TRUE THAN 20 YEARS AGO. I HOPE IT IS. BUT AT LEAST A FAIR NUMBER OF KIDS, PARTICULARLY POOR CHILDREN IN CITIES IN THE U.S. GREW UP IN HOUSES THAT HAVE LEAD PAINT. SO INVESTIGATORS PROPOSE -- THIS WAS A STUDY DONE AT THE KENNEDY KREIGER INSTITUTE WHICH IS IN BALTIMORE, ASSOCIATED WITH HOPKINS. AND HERE WAS THE PROPOSAL. WHAT WE ARE GOING TO DO IS RANDOMIZE KIDS IN THESE NEIGHBORHOODS TO HOUSES THAT EITHER PARTIALLY ABATED SO TAKE OUT SOME OF THE LEAD PAINT BUT NOT ALL OF IT AND COMPARE IT TO CHILDREN IN HOMES THAT HAVE NO LEAD PAINT AT ALL. SO RANDOM ICE AND IF YOU ENROLL YOUR CHILD, THEY WILL BE BE PUT IN A HOUSE THAT HAS NO LEAD PAINT -- THE WHOLE FAMILY GOES INTO THAT HOUSE. OR YOU'LL BE PUT IN A HOUSE WHERE THERE IS SOME LEAD PAINT BUT NOT AS MUCH AS STANDARD LEAD PAINT HOUSE. AND THE QUESTION IS WHAT IS THE RISK LEVEL OF THIS STUDY? SO HOPEFULLY IT'S CLEAR. AS EVERYBODY DID GYMNASTICS. I THINK THIS IS A REAL EXAMPLE THAT POSES THE POINT. SO PEOPLE ARE INTERESTED IN THIS. THIS IS CALLED KENNEDY KREIGER LEAD PAINT APAYMENT STUDY. IT LED TO A COURT CASE MARYLAND COURT OF APPEALS HAVING A SCATHING RULING ABOUT CLINICAL RESEARCH WITH CHILDREN. IT'S CALLED GRIMES. THERE IS A WHOLE LITERATURE ON THIS. I THINK THE POINT IS, IT'S HARD TO KNOW WHAT THE RISK LEVELS ARE. YOU MIGHT SAY LOOK IF THE KIDS WERE GOING TO BE IN A FULLY-LEADED HOUSE OTHERWISE, THEN THE OPPORTUNITY OF GETTING INTO AN ABATED OR CLEAN LEAD HOUSE, THAT'S A POTENTIAL BENEFIT. BUT ON THE OTHER HAND, THEY THINK IT'S ODD TO SAY THERE IS A POTENTIAL BENEFIT TO A TRIAL THAT MIGHT RANDOMIZE YOU TO A HOUSE THAT HAS SOME LEAD PAINT WHEN WE KNOW THE LEAD PAINT BAD FOR KIDS. IT SEEMS COUNTERINTUITIVE TO SAY THAT IT'S A POTENTIAL BENEFIT STUDY RATHER THAN A RISKY STUDY. SO PEOPLE MAY HAVE DIFFERENT RISK LEVELS DEPENDING ON WHAT THE CONTEXT IS AND WHAT HAPPENED HAPPEN OTHERWISE. ANOTHER QUESTION AND THIS IS A HUGE DEBATE IS WHETHER OR NOT WHEN YOU EVALUATE THE RISKS OF THE STUDY, DO YOU EVALUATE AGAINST WHAT PEOPLE WOULD GET IF THEY WEREN'T IN A TRIAL OR SHOULD YOU EVALUATE WHAT WOULD BE APPROPRIATE CARE FOR THOSE PEOPLE? AND WHEN THE STANDARD OF CARE IS SOMETHING THAT IS LESS THAN IDEAL, THOSE TWO EVALUATIONS MIGHT DIFFER. THE OTHER THING WHICH WE COULD TALK ABOUT IS, I THINK THE PROBLEM WITH THE KENNEDY KREIGER STUDY MIGHT NOT HAVE ANYTHING TO DO WITH RISKS AT ALL. IT MIGHT BE DIFFERENT ETHICAL CONCERNS AND SOMETIMES WE MAKE A MISTAKE OF THINKING EVERY ETHICAL SHALL COMES DOWN TO -- IF YOU DON'T LIKE A STUDY, YOU HAVE TO SOMEHOW SAY IT IS RISKY TO SUBJECTS. AND I THINK THE BETTER WAY TO GO IS TO REALIZE THERE ARE OTHER THINGS THAT WE CAN WORRY ABOUT WITH THE ETHICS AND CLINICAL TRIALS APART FROM THE RISKS TO THE INDIVIDUAL SUBJECTS. WE CAN TALK MORE ABOUT THAT IF PEOPLE ARE INTERESTED. SO WE MINIMIZE THE RISKS. IDENTIFY THE RISKS, MINIMIZE THEM SO ONE OF THE STANDARD IDEAS IS IF PEOPLE WILL UNDERGO A CLINICALLY-INDICATED BLOOD DRAW, TAKE YOUR EXTRA BROOD DURING THAT PROCEDURE RATHER THAN ADDING IN EXTRA STICKS TO PEOPLE. SO NOW WE HAVE SOCIAL VALUE OF ALL OF THESE INTERVENTIONS IN THE PACKAGE AND IDENTIFIED AND MINIMIZED THE RISKS AND NOW WE WANT TO LOOK AT POTENTIAL BENEFITS. WHAT ARE THE POTENTIAL BENEFITS AND ARE THERE WAYS TO ENHANCE THOSE POTENTIAL BENEFITS? AND AGAIN FOR THE MOST PART, WE ARE LOOKING HERE AT THE RESEARCH POTENTIAL BENEFITS AS OPPOSED TO POTENTIAL BENEFITS PEOPLE GET EVEN IF THEY WEREN'T IN THE TRIAL. SO WHAT COUNTS AS A POTENTIAL BENEFIT? SO CHRISTINE IS A EXPERT ON PAYING PEOPLE TO BE IN CLINICAL TRIALS AND WHAT SHE FOUND OUT IS THAT A LOT OF CLINICAL TRIALS MAY BE AT LEAST HALF OR MORE OF THE CLINICAL TRIALS PAY PEOPLE SOME COMPENSATION TO ENROLL. AND SO THE QUESTION IS, DOES PAYMENT COUNT AS A POTENTIAL BENEFIT OF BEING IN A CLINICAL RESEARCH TRIAL? SO, THIS COMES BACK TO THE POINT I WAS MAKING ABOUT GENERAL RISKS. HERE IS WHAT MOST COMMENTATORS WILL SAY. NO. PAYING SOMEBODY DOESN'T COUNT AS A BENEFIT OF BEING IN A CLINICAL TRIAL. THEY SHOULDN'T COUNT AS A BENEFIT TO JUSTIFY OR OUTWEIGH RISKS BUT ON THE OTHER HAND REMEMBER WHAT I SAID BEFORE, YOU'RE SUPPOSED TO COUNT ALL THE RISKS OF THE TRIAL SO THIS IS DAVE'S PHILOSOPHICAL RESEARCH CLINIC. YOU IMAGINE I HAVE A STUDY WHERE I'M GOING TO DO A BIOPSY ON YOU AND IF YOU AGREE AND UNDERGO THE BIOPSY, I'M GOING TO PAY YOU 100 DOLLARS FOR BEING IN THAT TRIAL. BUT IT JUST SO HAPPENS THIS IS A NICE PHILOSOPHICAL WEIGH IN. THE ONLY RISK IS THAT THE SITE OF THE BIOPSY MIGHT GET INFECTED AND IT HAPPENS IF IT DOES, IT COST EXACTLY 100 DOLLARS FOR THE ANTIBIOTICS TO TREAT THE INFECTION. SO NOW ON A STANDARD VIEW WHAT PEOPLE WOULD SAY IS, THIS IS A RISKY STUDY. BECAUSE THERE IS A $100 ECONOMIC YOU FACE BUT THEY WOULDN'T SAY, NO, NO, THAT 100 DOLLAR RISK IS BALANCED BY WORN00 DOLLAR COMPENSATION. SO PEOPLE ARGUE THE ECONOMIC RISKS COUNT BUT ECONOMIC BENEFITS DON'T COUNT. ONE OF THE QUESTIONS AND ONE OF OUR PREVIOUS COLLEAGUES PUSHED ON THIS A LOT, IS THERE ANY JUSTIFICATION FOR THAT DIFFERENTIAL ASSESSMENT OF ECONOMIC RISKS VERSUS ECONOMIC POTENTIAL BENEFITS. NOW WE HAVE IDENTIFIED THE POTENTIAL BENEFIT. DECIDED WHICH THINGS WE ARE GOING TO COUNT AS POTENTIAL BENEFITS AND THEN LIKE MINIMIZING RISKS YOU WANT TO ENHANCE BENEFITS TO THE EXTENT YOU CAN. ONE OF THE EXAMPLES I TALKED ABOUT TWO WEEKS AGO IS WHAT YOU MIGHT DO IS SAY OKAY, INCLUSION, EXCLUSION CRITERIA, WE'LL LIMIT THIS STUDY TO THE PEOPLE WHO ARE PARTICULARLY SICK WITH THE ASSUMPTION THEY GET MORE BENEFITS OUT OF BEING IN THE TRIAL THAN PEOPLE WHO ARE STILL RELATIVELY HEALTHY. WE KNOW THE POTENTIAL BENEFITS AND THEN THE NEXT THING TO COMPARE THE POTENTIAL BENEFITS TO THE RISKS THAT IT PHASES AND ASK TWO QUESTIONS. FIRST, DOT POTENTIAL BENEFITS TO THE SUBJECT OF THAT INTERVENTION JUSTIFY THE RISKS THAT THAT INTERVENTION POSES TO THEM. AND THE ASSUMPTION IS THE ANSWER TO THAT QUESTION IS YES, THE POTENTIAL BENEFITS TO THE SUBJECTS JUSTIFY THE RISKS OF THAT INTERVENTION THEN WITH RESPECT TO INDIVIDUAL RISKS AND BENEFITS THAT'S AN ETHICALLY ACCEPTABLE INTERVENTION TO INCLUDE IN THE STUDY. HOW DO YOU FIGURE THAT OUT? HERE IS ALL THESE METAPHORS THAT PEOPLE USE. DO. HOW ARE WE SUPPOSED TO IMPLEMENT THIS IN PRACTICE? I ARGUE THE INFORMED CLINICIAN TEST. WHAT YOU DO IS YOU JUST IMAGINE I HAVE A REALLY SMART CLINICIAN AND ASK THEM IF ALL YOU CARE ABOUT IS THE MEDICAL INTERESTS OF THESE SUBJECTS, WOULD YOU RECOMMEND THEY UNDERGO THIS INTERVENTION? THAT'S WITH RESPECT TO INTERVENTION. OR WOULD YOU RECOMMEND THEY ENROLL IN THIS STUDY. IF THE VERY IS YES, THEN THE ASSUMPTION IS, THE POTENTIAL BENEFITS DO JUSTIFY THE RISKS WITH RESPECT TO THOSE SUBJECTS. IF THE CLINICIAN SAYS NO, IT'S CONTRARY TO THE INTERESTS TO UNDERGO THAT INTERVENTION, THAT RESEARCH BLOOD DRAW FOR INSTANCE, THAT IS INTERVENTION THAT DOESN'T OFFER POTENTIAL BENEFIT. >> ONE OF THE INTERESTING QUESTIONS I WAS GIVING A TALK RELATED TO THIS IN NORWAY LAST YEAR AND CHRISTINE RAISED THIS QUESTION OF, SHOULD THE INFORMED CLINICIAN TESTED BE WHAT THEY WOULD RECOMMEND FOR THEMSELVES? OR SHOULD IT BE WHAT THE CLINICIAN WOULD RECOMMEND FOR THEIR MOTHER? ONE OF THE THINGS WE KNOW IS THAT A LOT OF PEOPLE, INCLUDING CLINICIANINGS TEND TO BE MORE CAUTIOUS WHEN THEY MAKE RECOMMENDATIONS FOR THEIR MOTHER THAN FOR THEMSELVES. SO WHAT IS THE STANDARD TO USE WHEN FIGURING OUT RESEARCH IS ETHICAL? AND ONE SUGGESTED THE TEST SHOULD BE WHAT YOU RECOMMEND FOR YOUR MOTHER-IN-LAW. THAT WOULD ALLOW A LOT MORE INTERESTING RESEARCH TO GO ON IF NOTHING ELSE. BASICALLY IF THE CLINICIAN INFORMED SMART CLINICIAN IN YOUR INTERESTS THEN THE POTENTIAL BENEFITS JUSTIFY THE RISKS IF NOT, THEN NO THEY DON'T. FOR THOSE INTERVENTIONS THEY ARE NET RISK. SO THE ASSUMPTION IS THAT THERE IS SOME EXTENT TO WHICH THE RISKS EXCEED THE POTENTIAL BENEFITS AND THAT DIFFERENTIAL IS THE NET RISKS OF THAT INTERVENTION AND/OR THAT STUDY. SO ASSUME IT POSES NET RISKS. SO TAKE A RESEARCH BLOOD DRAW AS A SIMPLE EXAMPLE. NO POTENTIAL BENEFITS FOR SUBJECTS UNDERGOING THIS. THERE IS A LITTLE BIT OF PAIN. MAYBE A TINY RISK OF BRUISING AND MAYBE A TINY RISK OF INFECTION. ALL OF THOSE RISKS ARE NET RISKS OF UNDERGOING THAT BLOOD DRAW GIVEN NO POTENTIAL BENEFITS OF THE BLOOD DRAW TO COUNTER ACT THEM. SO THEN WE HAVE TO ASK WHETHER OR NOT THE NET RISKS OF EACH INTERVENTION FIRST OF ALL WE'LL ASK TWO QUESTIONS? HOW GREAT THOSE NET RISKS. IS THAT AMOUNT OF NET RISK BASICALLY IS THAT ETHICALLY ACCEPTABLE? AND THEN SECOND, ASSUMING IT IS, WE WANT TO ASK WHETHER OR NOT THE SOCIAL VALUE OF INCLUDING THAT INTERVENTION IN THE TRIAL JUSTIFIES THAT EXTENT OF NET RISKS. PEOPLE CAN THINK ABOUT THIS, I'LL COME BACK TO THIS A LITTLE BIT. WHAT I SAID IS FIRST YOU ASK, ARE THE NET RISKS TOO HIGH? AND THEN ASK IF THEY ARE JUSTIFIED BY THE SOCIAL VALUE. AND ASK WHETHER OR NOT -- AND I'LL EXPLAIN IN A MINUTE, WHETHER OR NOT THE BULLETS SHOULD BE REVERSED IN ORDER THERE. SO NEXT PHILOSOPHICAL POINT. SOME PEOPLE SAY WHETHER A NET RISK INTERVENTION IS ACCEPTABLE DEPENDS UPON WHAT TYPE OF INTERVENTION IT IS AND THERE IS THIS LONG HISTORY IN CLINICAL RESEARCH OF THE DISTINGUISHING BETWEEN OR GIVING DIFFERENT NAMES BUT ONE CLASSIFICATION IS THERAPEUTIC INTERVENTIONS AND NON THERAPEUTIC INTERVENTIONS. AND THE ASSUMPTION ON SOME PEOPLE'S PART IS THAT THE ETHICAL STANDARDS FOR THERAPEUTICS ARE DIFFERENT. AND HERE ARE SOME PROPOSED WAYS TO DEFINE THAT DISTINCTION BETWEEN THE TWO. SO THIS IS -- CHARLES IS KNOW WHO OF THE STRONG PROPONENTS AND THIS IS HIS ARGUMENT. WE CAN TALK ABOUT IT MORE AND I DON'T WANT GO THROUGH THIS QUOTE BUT HE IS SAYING YOU SHOULD HAVE THESE DIFFERENT ETHICAL STANDARDS FOR EVALUATING THE RISKS OF THERAPEUTIC INTERVENTIONS AND NON THERAPEUTIC INTERVENTIONS AND THE BASIC IDEA HERE IS THAT WE UNDERSTAND THAT NON THERAPEUTIC INTERVENTIONS POSE SOME NET RISKS SO THAT IS OKAY AS LONG AS THE NET RISKS AREN'T TOO GREAT. ON THE OTHER HAND THERAPEUTIC INTERVENTIONS SHOULDN'T POSE NET RISKS BECAUSE THEY ARE THERAPEUTIC EVEN THOUGH THERE ARE RESEARCH INTERVENTIONS. SO THE POINT HERE IS THAT ON THE STANDARD THERAPEUTIC INTERVENTIONS ETHICALLY CLAIM SHOULDN'T POSE ANY NET RISKS AT ALL. THEY SHOULD HAVE POTENTIAL BENEFITS AND RISKS AND THAT SHOULD BE AT LEAST AS GOOD AS WHAT IS AVAILABLE OUTSIDE. SUSCEPTIBLE FOR NON THERAPEUTIC INTERVENTIONS POSE NET RISKS. HERE IS THE THEORETICAL POINT WHICH WE TALK ABOUT. IF YOU THINK THAT VIEW IS RIGHT, THEN WHAT THAT COMMITS YOU TO, I THINK, IS THE CLAIM THAT CLINICAL EQUIPOISE IS AN ETHICAL REQUIREMENT ON CLINICAL RESEARCH. SO CLINICAL EQUIPOISE IS THE IDEA YOU'RE IN A POSITION WHERE YOU HAVE ONE OR MORE INTERVENTIONS THAT YOU COULD GIVE PEOPLE FOR A CONDITION, SOME OF THEM MAY BE STANDARD OF CARE. SOME OF THEM MAYBE EXPERIMENTAL. AND CLINICAL EQUIPOISE OBTAINS WHEN YOU HAVE NO REASON OR NO GOOD REASON TO THINK THAT ANY OF THOSE INTERVENTIONS IS BETTER THAN THE OTHER. SO AN EQUAL POINT WITH RESPECT TO THE TWO OR MORE INTERVENTIONS. AND THE POINT IS THAT IF YOU BELIEVE THIS VIEW ABOUT THERAPEUTIC INTERVENTIONS, SAY YOU CAN ONLY DO A CLINICAL TRIAL WHEN YOU'RE IN EQUIPOISE. IF YOU WEREN'T IN EQUIPOISE, THAT WOULD MEAN YOU HAVE GOOD REASON TO BELIEVE THAT ONE OF THE INTERVENTIONS IS BETTER THAN THE OTHER AND IN THAT CASE, YOU CAN'T GIVE PEOPLE THE SORT OF INFERIOR INTERVENTION BECAUSE THAT WILL POSE NET RISKS TO THEM IN THE CONTEXT OF THERAPEUTIC RESEARCH AND THAT IS REGARDED AS UNETHICAL. I THINK THAT ANALYSIS IS A MISTAKE. MY BASIC VIEW IS I DON'T SEE WHY WE SHOULD HAVE DIFFERENT STANDARDS FOR THERAPEUTIC VERSUS NON THERAPEUTIC INTERVENTIONS. I'M NOT SURE WE CAN MAKE A CLEAR DISTINCTION BETWEEN THE TWO CLASSES AND EVEN IF WE COULD IT'S NOT CLEAR TO ME WHY WE SHOULD HAVE DIFFERENT STANDARDS FOR THE WAY WE ETHICALLY EVALUATE THEM. SO JUST TO GIVE ONE EXAMPLE THAT MIGHT HIGHLIGHT THIS IS, IMAGINE WE WANT TO LOOK AT SOME OLD INTERVENTION WHICH PROBABLY POSES MORE RISKS THAN SOME NEW FANCY THING BUT THE NEW FANCY THING IS REALLY EXPENSIVE. SO THE HEALTH CARE SYSTEM WANTS TO KNOW, IS THAT ADDED COST OF THE NEW FANCY INTERVENTION JUSTIFIED? HOW DO WE ANSWER THAT? LET'S DO A RANDOMIZED TRIAL WHERE WE COMPARE THE TWO IN THE SAME POPULATIONING AND SEE WHAT THE DIFFERENCE IS. GOING INTO THAT TRIAL, YOU KNOW THAT THE OLD ONE MAYBE IT POSES MORE RISK OF NAUSEA OR HEADACHE. ON THIS VIEW, THAT I'M DISCUSSING, YOU COOPERATE DO THAT TRIAL EVEN IF THERE IS A LOT OF SOCIAL VALUE TO THAT BECAUSE YOU CAN'T RANDOMIZE PEOPLE TO THE INTERVENTION KNOWN TO BE SLIGHTLY WORSE BECAUSE THERE IS SOME NET RISKS. THE INCREASE IN NAUSEA OR HEADACHE. BUT WHAT IS PUZZLING ON THAT VIEW, YOU COULDN'T GIVE THEM THAT INTERVENTION BUT IF YOU HAD TO DO A LUMBAR PUNCTURE, THAT WOULD BE OKAY. EVEN IF THE RISKS OF HEADACHE FROM THE LUMBAR PUNCTURE ARE GREATER THAN THE INCREASED RISK OF HEADACHE FROM TAKING THE CHEAPER INTERVENTION RATHER THAN THE BETTER INTERVENTION. AND I DON'T SEE WHY WE SHOULD WORRY ABOUT THIS IS A SMALLER RISK OF HEADACHE BUT IT'S FROM A THERAPEUTIC INTERVENTION AND THAT'S ETHICALLY BAD WHEREAS OVER HERE, THIS LUMBAR PUNCTURE IS NOT THERAPEUTIC SO I DON'T CARE ABOUT THAT. ETHICAL AND UNITUTATIVELY THAT DOESN'T MAKE SENSE TO ME. HERE IS THE ALTERNATIVE BASICALLY LOOK AT THE NET RISKS OF EACH INTERVENTION AND ASK YOURSELF WHETHER OR NOT THOSE NET RISKS FOR THE INTERVENTIONS THAT POSE NET RISKS ARE ACCEPTABLE OR NOT. SO HERE IS BASICALLY THE WAY THAT TEST WORKS. DOES IT POSE NET RISKS AND THAT IS THROUGH THE INFORMED CLINICIAN TEST THAT I MENTION THE. IF IT DOES POSE NET RISKS, ASK WHETHER OR NOT THOSE NET RISKS ARE ACCEPTABLE, HOW BIG ARE THEY IN MAGNITUDE? AND ARE THEY JUSTIFIED BY THE SOCIAL VALUE OF HAVING THAT INTERVENTION IN THE TRIAL? AND THEN AGAIN, THAT'S INDIVIDUAL INTERVENTIONS. DO THE WHOLE STUDY. SO THIS IS AN IMPORTANT POINT. SKIP MY TALK ABOUT THIS FOR PEDIATRIC RESEARCH BUT IMAGINE A FANCIFUL PEDIATRIC STUDY WHERE THEY DO A NUMBER OF BLOOD DRAWS. SO MOST PEOPLE THINK ONE IS MINIMAL RISK. A SECOND BLOOD DRAW MAYBE MINIMAL. MAYBE A THIRD IS STILL MINIMAL RISK. BUT IF YOU LOOK AT EACH INDIVIDUAL BLOOD DRAW, SOMEBODY COULD PUT 100 OF THEM IN A TRIAL AND IT'S A MINIMAL RISK STUDY. SO YOU NEED TO DO. ACCUMULATIVE. WHAT IS THE ACCUMULATIVE NET RISKS FROM ALL THE INTERVENTIONS IN THE TRIAL? SO WHAT I SAID BEFORE IS I SAID, IF THERE ARE NET RISKS, ASK YOURSELF WHETHER OR NOT THEY ARE ACCEPTABLE. AND THEN THE QUESTION HERE IS, WHAT IS A STANDARD OR HOW DO YOU DETERMINE WHETHER SOME AMOUNT OF NET RISKS, SO A PURELY RESEARCHED BLOOD DRAW. ARE THOSE RISKS ACCEPTABLE? PURELY RESEARCH LP ACCEPTABLE? PURELY RESEARCH LIVER BIOPSY? ARE THOSE NET RISKS ACCEPTABLE? SO HOW DO YOU FIGURE THAT OUT? SO AT LEAST WITH RESPECT TO SUBJECTS WHO CAN'T GIVE INFORMED CONSENT, THE ANSWER IN ALMOST ALL REGULATIONS I KNOW IN THE U.S. AND AROUND THE WORLD ARE PRETTY STRICT. THEY ARE PRETTY STRICT STANDARDS OR LIMITS ON THE NET RISKS TO WHICH YOU CAN EXPOSE SUBJECTS WHO CAN'T GIVE INFORMED CONSENT. SO PEOPLE WITH SEVERE ALZHEIMER'S, PEOPLE UNCONSCIOUS AS A RESULT OF A CAR ACCIDENT. PEOPLE WHO ARE THREE YEARS OLD. SO WHAT ARE MINIMAL RISKS? SO, BASICALLY THERE IS A CLEVER MOVE IF YOU ASK YOURSELF ONE THING WE KNOW ABOUT HUMAN EVALUATION OF RISKS IS THAT WE ARE PRETTY TO REALLY BAD AT EVALUATING ABSOLUTE RISKS. IF I TOLD YOU I HAVE THIS INTERVENTION AND I WANT TO DO IT IN 10 YEARS OLDS AND POSES ONE-8,SUCH30 CHANCE OF A BONE FRACTURE -- 837 CHANCE -- IS THAT A LOW OR MEDIUM OR HIGH RISK? IF YOU'RE LIKE ME, 1-80730 RISK OF BONE FACTATURE. I DON'T KNOW. IT'S HARD TO EVALUATE THAT. SO THE CLEVER MOVE THAT WAS MADE HERE IS, WHAT WE'LL DO IS GIVE A COMPARATIVE. AND WHAT THE IDEA IS, IF WE CAN COME UP WITH A COMPARATOR OF RISKS THAT WE THINK ARE ROUGHLY ACCEPTABLE, THEN RATHER THAN HAVING TO EVALUATE THAT ABSOLUTE RISK, INSTEAD WE JUST COMPARE IT TO RISKS WE KNOW ARE ACCEPTABLE. FOLLOW IT'S LOWER OR THE SAME AS ACCEPTABLE RISKS, THAT ROUGHLY JUST IDEA IT IS ACCEPTABLE, IF IT'S GREATER THEN THAT MIGHT BE A RED SIGN THAT IT IS MAYBE ETHICALLY PROBLEMATIC. SO THE WAY THE REGULATIONS DO THAT IN THE U.S., A LOT OF OTHER REGULATIONS HAVE TAKE THEN UP, THAT COMPARATOR IS ROUGHLY THE RISKS THAT ORDINARY PEOPLE FACE IN DAILY LIFE. THE RISKS OF DAILY LIFE STANDARD. I'M GOING TO GIVE YOU ONE THOUGHT ABOUT AND HOPEFULLY WE'LL GO INTO THIS A LITTLE BIT MORE. WHILE I THINK HAVING A COMPARATOR MAKES SENSE, NOTICE A LOT OF THE RISKS THAT WE FACE IN DAILY LIFE ARE THE RESULT OF ACTIVITIES THAT OFTEN POTENTIAL BENEFITS. SO SNOW SKIING POSES FAIRLY HIGH RISKS TO PEOPLE WHO SKI. IT'S NOT THAT WE THINK THAT SOMEHOW THOSE ABSOLUTE RISKS ARE ACCEPTABLE, WE GO SNOW SKIING AND LET 10-15-YEAR-OLD SKI BECAUSE WE THINK THE POTENTIAL BENEFITS JUSTIFY THE RISKS. AND IF THAT IS WHAT JUSTIFIES THE RISKS OF SNOW SKIING THEN THOSE RISKS AREN'T GOING TO BE APPROPRIATE FOR EVALUATING THE RESEARCH THAT DOESN'T OFFER THE POTENTIAL BENEFIT. SO, ROUGHLY MY THOUGHT ON THAT IS, OKAY, WE NEED TO MODIFY THE RISKS A LITTLE BIT. INSTEAD OF LOOKING AT ALL THE RISKS OF DAILY LIFE, LET'S LOOK AT MORE COMPARABLE ACTIVITIES. LOOKING AT RESEARCH THAT DOESN'T OFFER THE POTENTIAL BENEFIT SO LOOT COMPARE TO THE RISKS OF ACTIVITIES IN DAILY LIFE LIKE CHARITABLE ACTIVITIES THAT DON'T OFFER POTENTIAL BENEFIT. THAT'S WHY I CALL CHARITABLE PARTICIPATION STANDARD. ONE OF THE REAL CHALLENGES MAGGIE WILL TALK ABOUT IS, HOW THE HECK DO YOU APPLY A STANDARD LIKE THAT TO MINIMAL RISK IN FETUSES? WHAT IS AN ACCEPTABLE RISK OF DAILY LIFE FOR A FETUS? STILL HAVEN'T FIGURED IT OUT. IF ANYBODY HAS THE ANSWER, WE WOULD LOVE TO HEAR IT. BACK TO MY CLINIC ONCE MORE. WHAT ABOUT REALLY HIGH NET RISKS WHEN THE POTENTIAL SOCIAL VALUE OF THE STUDY IS REALLY HIGH? IS THAT OKAY? WHAT IF WE HAVE THIS DESIGN WHERE WE ARE GOING TO INFECT A COUPLE OF PEOPLE WITH EBOLA? INFECT A COUPLE OF PEOPLE WITH AIDS. IT COULD BE A REALLY IMPORTANT STUDY. IS THAT AN ETHICALLY ACCEPTABLE THING? OR A LIVER BIOPSY. HEALTHY VOLUNTEERS. MAYBE THIS IS A REALLY IMPORTANT STUDY. NO BENEFITS TO THEM AND LOTS OF BENEFITS TO SOCIETY. CAN HUGE AMOUNTS OF SOCIAL BENEFITS JUSTIFY SIGNIFICANT RISKS LIKE THAT TO RESEARCH SUBJECTS? IMAGINE WE ONLY DO THIS IN PEOPLE WHO ARE COMPETENT. THIS IS THE POINT I MADE BEFORE ABOUT WHAT DO YOU SEAS FIRST? THE LEVEL OF THE RISKS TO SEE WHETHER THEY ARE ACCEPTABLE OR DO YOU SEE WHAT THE POTENTIAL BENEFITS OF THAT INTERVENTION IS? HERE THE THOUGHT IS, MAYBE WITH RESPECT TO COMPETENT ADULTS AT LEAST, THERE IS NO THRESHOLD OR MARKS MUM NET RISK. IT DEPENDS ON HOW MUCH SOCIAL VALUE IS IN IT. IF YOU PUT ENOUGH SOCIAL VALUE IT CAN JUSTIFY THINGS LIKE MAYBE A RESEARCH LIVER BIOPSY. OR IF ANYBODY HAS QUESTIONS OR ANSWERS FOR ME, THAT WILL BE ONE OF THE QUESTIONS I'M GOING TO ASK YOU WHEN WE GET TO THE END HERE. ONE LAST FILL SOLVE CALL POINT. HERE IS THE STANDARD -- PHILOSOPHICAL POINT -- HERE IS THE STANDARD VIEW. I THINK THERE IS AT LEAST WAYS TO WONDER WHETHER OR NOT THIS IS THE RIGHT VIEW. BASICALLY THE IDEA IS THAT YOU SHOULD DO WHAT I HAVE BEEN DOING. LOOK AT THE RISKS AND POTENTIAL BENEFIT OF EACH INDIVIDUAL INTERVENTION WITHIN A STUDY AND IT HAS TO BE THE CASE THAT EITHER OF THE POTENTIAL BENEFITS TO THE SUBJECTS OF THAT INTERVENTION JUSTIFY THE RISKS, OR, THE NET RISKS OF THAT INTERVENTION HAVE TO BE SUFFICIENTLY LOW MAYBE DEFINED BY MINIMAL RISKS OR SOME OTHER STANDARD. NOTICE WITH THAT PRECLUDE IT SAYS WHAT YOU CAN'T DO IS YOU CAN'T HAVE A LIVER BIOPSY THAT POSES REALLY HIGH NET RISKS AND JUSTIFY THOSE RISKS BY SOME OTHER INTERVENTION LIKE A TREATMENT THAT IS INCLUDED IN THE STUDY. A LOT OF PEOPLE REFER TO THAT AS THE FALL SEE OF THE PACKAGE DEAL. THE POTENTIAL BENEFITS OF ONE INTERVENTION IN A STUDY AREN'T SUPPOSED TO JUSTIFY THE RISKS OF SOME OTHER INTERVENTION IN THE SAME TRIAL. I THINK THERE IS A GOOD REASON WHY PEOPLE HAVE THIS VIEW IS IF YOU DIDN'T HAVE THIS VIEW, WHAT INVESTIGATORS COULD DO IS SNEAK IN ALL THE RESEARCH PROCEDURES. I HAVE GOT THIS GREAT NEW POTENTIALLY CURATIVE TREATMENT BUT IF YOU WANT TO GET INTO MY TRIAL, I WANT TO TAKE A BRAIN BIOPSY FROM MY LAB. IT'S UNRELATED BUT I HAVE GOT YOU AND THERE ARE BENEFITS OF THIS TREATMENT AND I CAN JUSTIFY SOME OTHER RESEARCH INTERVENTION THAT IS POSE A LOT OF RISKS. THAT SEEMS ETHICALLY PROBLEMATIC. THAT SEEMS LIKE TAKING ADVANTAGE OF THESE SUBJECTS AND SITUATIONS IN SOME WAY. THIS VIEW THAT YOU CAN'T HAVE THE POTENTIAL BENEFITS OF ONE INTERVENTION JUSTIFY THE RISKS OF ANOTHER, IS A WAY TO BLOCK THAT. I THINK THAT MAKES SENSE BUT NOW IMAGINE THIS SORT OF STUDY. IMAGINE THE STUDY WITH A NEW TREATMENT FOR LIVER CANCER AND IT'S NOT THAT I'M ADDING IN A LIVER BIOPSY TO GET SAMPLES OR FOR THE FUN OF IT. I HAVE GOT TO DO A LIVER BIOPSY IN ORDER TO EVALUATE THE EFFICACY OR SAFETY OF THE TREATMENT. IS THAT AN OKAY THING TO DO WHERE THE POTENTIAL BENEFIT OF THE INTERVENTION, THE TREATMENT, JUSTIFY THE RISKS OF LIVER BIOPSY? BUT THE LIVER BIOPSY ON ITSELF POSES A LOT OF HIGH NET RISKS. CAN I DO THAT TRIAL OR NOT? A LOT OF PEOPLE IN RESEARCH SAY NO. AND SO HERE IS JUST ONE OF THE ANALOGIES I WANT TO LEAVE PEOPLE WITH. I THINK THERE IS A SIMPLICIT DISTINCTION THAT PEOPLE DRAW AND THE QUESTION FOR US IS WHETHER OR NOT IT IS JUSTIFIED BETWEEN WHAT I THINK OF AS CLINICAL NECESSITY VERSUS RESEARCH NECESSITY. SO EVERYBODY THINKS THAT IT IS OKAY TO DO CLINICAL INTERVENTIONS THAT OFFER NO POTENTIAL BENEFITS IF THEY ARE NEEDED FOR SOMETHING ELSE. SO I CAN STICK A LINE IN PEOPLE'S NECKS. IT'S A RISKY THING TO DO. NO POTENTIAL BENEFITS OF HAVING THE LINE THERE, BUT THE LINE ALLOWS ME TO PUT A DRUG INTO THE PEOPLE'S BODIES THAT IS GOOD FOR THEM. SO THE WAY WE JUSTIFY THE RISKS OF THE LINEUP IN THEIR NECK IS SOMETHING IT DOES ITSELF, IT ALLOWS SOMETHING ELSE TO HAPPEN. THE ADMINISTRATION OF THE DRUG. SO IT LOOKS LIKE THERE THERE IS A SENSE IN WHICH THE POTENTIAL BENEFITS OF SOME OTHER INTERVENTION ARE JUSTIFYING THE RISKS OF ANOTHER. THAT SEEMS LIKE CLINICAL MEDICINE HAPPENS ALL THE TIME. AND TEAMS APPROPRIATE. DOESN'T THAT WORK IN THE RESEARCH SETS? SOMETHING DIFFERENT BETWEEN THAT AND MY LIVER BIOPSY STUDY WHERE I TELL YOU, THE ONLY WAY I CAN EVALUATE MY NEW TREATMENT FOR THIS LIVER CANCER IS BY DOING A LIVER BIOPSY. IF YOU WON'T LET ME DO THE LIVER BIOPSY, I CAN'T DO THE TREATMENT AND WE SEEM LIKE WE ARE STUCK. KEPT I JUSTIFY THE RISKS TO THE SUBJECTS OF THE LIVER BIOPSY BY THE POTENTIAL BENEFITS THAT THEY GET FROM THE TREATMENT THAT I WOULDN'T BE ABLE TO TEST OTHERWISE? HOPEFULLY THERE IS ENOUGH QUESTIONS AND ALL THAT FOR HOPEFULLY PEOPLE AREN'T FULLY -- THIS IS MY VERY QUICK SUMMARY. DOING THIS RISK-BENEFIT ASSESSMENT I THINK IS CENTRAL. A LOT OF PEOPLE THINK THAT PROTECTING SUBJECTS FROM RISK, IF YOU LOOK AT A LOT OF THE LEADING DOCUMENTS IN RESEARCH ETHICS, THEY WILL BE DESCRIBED IN A LOT OF REGULATIONS DESCRIBED AS PROTECTIONS FOR SUBJECTS, WHICH SUGGESTS THIS IS THE CENTRAL, MOST IMPORTANT PART OF DOING ETHICAL CLINICAL RESEARCH. MY HOPE IS THE PROPOSALS I NEVER TEST TODAY DOING SYSTEMATIC APPROACH LIKE THIS FOR SOMETHING ELSE MIGHT HELP GET THESE DETERMINATIONS RIGHT. ALTHOUGH HOPEFULLY, I HAVE ALSO CONVINCED EVERYBODY THAT THERE IS LOTS OF IMPORTANT QUESTIONS AND CHALLENGES THAT REMAIN THAT I AT LEAST HAVEN'T FIGURED OUT THE ANSWERS TO AND NOW WE HAVE GOT AT LEAST LIKE 100 SMART WELL-INFORMED PEOPLE IN THIS AUDIENCE AND MAYBE HUNDREDS OF SMART INFORMED PEOPLE ONLINE WITH TWITTER ACCOUNTS WHO WILL GIVE US THE ANSWERS TO ALL OF THESE QUESTIONS. THANK YOU. [ APPLAUSE ] JUST REMINDER, THIS IS STREAMING ON LINE TO LOTS OF PEOPLE SO IF YOU HAVE A QUESTION, PLEASE TRY TO GET TO THE AISLE MICS SO IT GETS PICKED UP. >> IN DOING THE MINIMAL RISK ASSESSMENT WHO DOING A COMPARISON WITH RISKS OF DAILY LIFE, IF IT IS VARIABLE AMONG THE SUBJECTS WHAT THEIR RISKS OF DAILY LIFE ARE, HOW IS THAT DONE? IN THE AGGREGATE OR HOW DO YOU DO THAT? >> SO THERE IS A LOT OF DEBATE EXACTLY ON THAT QUESTION IN THE LITERATURE. AND HERE IS THE WORRY THAT PEOPLE HAVE. IF THE COMPARATORS OF RISK OF DAILY LIFE AND I HAVE A RISKY INTERVENTION, I DON'T HAVE TO MAKE IT LESS RISKY. WHAT I HAVE TO DO IS SCOUR AROUND THE WORLD TO FIND KIDS WHO HAVE REALLY RISKY DAILY LIVES SO MAYBE I GO TO ALEPPO OR AFGHANISTAN AND I DO MY STUDY THERE IT WILL BE LESS RISKY THAN THE RISKS THOSE KIDS ARE FACING. THAT SEEMS LIKE A PROBLEM. FIGURE OUT WHAT IS WRONG WITH THAT IS HARD BUT IT LOOKS LIKE THERE IS SOMETHING ETHICALLY PROBLEMATIC ABOUT THAT. AND BASICALLY EVERYBODY AGREES ON THAT. SO THE SOLUTION TO THAT CHALLENGE IS TO SAY RATHER THAN IT'S NOT THE RISKS IN THE DAILY LIFE OF THESE KIDS, IT'S SOMETHING LIKE, AND THIS IS FROM THE IOM REPORT. IT'S SOMETHING LIKE THE RISKS OF DAILY LIVES OF AVERAGE HEALTHY NORMAL CHILDREN. THAT'S ONE OF THE STANDARDS. ONE OF THE THINGS THAT IS VERY INTERESTING, I DON'T KNOW IF YOU'RE GOING TO TALK ABOUT PRISONERS, BUT THE PEDIATRIC REGULATIONS, THE FOCUS OF THIS IS, DOESN'T HAVE THAT STIPULATION BUT IN THE PRISON REGS IT DOES TALK ABOUT HEALTHY PEOPLE RATHER THAN THESE SUBJECTS. SO THE IDEA IS, IT'S NOT THESE SUBJECTS, IT'S SOME SORT OF AVERAGE. >> I'M WONDERING IF YOU COULD TALK ABOUT WHAT YOU THINK THE PROBLEM WITH THE DUAL TRACK ANALYSIS IS BECAUSE IT SEEMS LIKE ON THE DUAL TRACK ANALYSIS YOU COULD DO A NON THERAPEUTIC INTERVENTION THAT HAD VERY HIGH RISKS LIKE THE HEADACHE FROM THE LUMBAR PUNCTURE BUT YOU COULDN'T DO A THERAPEUTIC INTERVENTION WHERE ONE OF THE INTERVENTIONS HAD A RISK OF HEADACHE. BUT ISN'T THE DIFFERENCE THERE THAT FOR THE NON THERAPEUTIC INTERVENTION EVERYBODY IS GETTING THAT RISK BUT FOR THE THERAPEUTIC, ONLY SOME PEOPLE ARE GETTING IT? COULDN'T THAT BE -- >> SO IT DEPENDS ON HOW YOU DESIGN THE TRIAL. SO, TO GIVE YOU -- GIVE THIS EXAMPLE TO SEE IF THIS HELPS TO SEE WHAT SEEMS LIKE THE WORRY THAT I HAVE WITH THE APPROACH. SO, I DON'T WANT KNOW IF THE EXAMPLE IS GOOD. LET'S USE THIS A DIFFERENT EXAMPLE. IMAGINE THAT SOMEBODY COMES UP -- SO HERE IS ONE OF THE PROBLEMS WE FACE IN CLINICAL MEDICINE. THERE IS VERY LITTLE INCENTIVE FOR PEOPLE LIKE DRUG COMPANIES TO DO HEAD-TO-HEAD COMPARISONS OF THEIR NEW THING AGAINST THE OTHER COMPANIES. BECAUSE THEY MIGHT LOSE. SO WHAT A LOT OF PEOPLE DO INSTEAD IS COMPARE THEIR THING JUST TO THE SAY PLACEBO OR TO NOTHING AND TRY TO GET IT APPROVED THAT WAY. AND THEN AS A RESULT, WE HAVE LOTS AND LOTS OF INTERVENTIONS THAT HAVE NEVER BEEN COMPARED HEAD-TO-HEAD AND WE DON'T KNOW WHICH IS BETTER. OR HOW MUCH BETTER OR HOW MUCH WORSE. SO IMAGINE WE HAVE A SITUATION LIKE THAT. MANUAL IN SOME COME COMPANIES ALONG WITH A NEW DRUG -- IMAGINE -- AND IT LOOKS GREAT. LET'S SAY NO SIDE EFFECTS AT ALL BUT IT'S REALLY EXPENSIVE. AND IMAGINE THE OLD THING. ITS EFFICACY IS JUST AS GOOD AS THAT THING BUT IT HAS A RISK OF HEADACHE THAT THE NEW ONE DOESN'T OR THE NEW ONE DOESN'T HAVE RISKS AT ALL THE OLD ONE HAS A RISK OF HEADACHE. AND LET'S SAY YOU'RE IN CHARGE OF THE NATIONAL HEALTH SYSTEM IN ENGLAND AND YOU WANT TO SAY, DO WE WANT TO FUND THIS NEW ONE GIVEN HOW EXPENSIVE IT IS? IS THAT DIFFERENCE IN HEADACHE WORTH THE PRICE? ONE WAY TO ANSWER THAT QUESTION IS DO A STUDY OF THEM SIDE-BY-SIDE. NOW HERE IS THE FANCY FULL THING. IMAGINE THAT THAT STUDY REQUIRES AN LP. SO IT'S SOME SORT OF DISEASE OF THE BRAIN OR SOMETHING AND YOU YOU HAVE TO GET CEREBRAL SPINAL FLUID FOR IT. IS THAT TRIAL ACCEPTABLE? HERE IS WHAT THE DUAL TRACK ANALYSIS WILL SAY. IT WILL SAY THE LUMBAR PUNCTURE PROBABLY IS ACCEPTABLE. THE BIGGEST RISK TYPICALLY IS POST LP HEADACHE. MOST PEOPLE THINK THAT IT IS A RISK. IT COULD BE A SERIOUS HEADACHE AND MOST PEOPLE THINK THAT RISK ISN'T GREAT ENOUGH. SO THAT PROCEDURE IS IT OKAY EVEN THOUGH THERE IS THAT LP HEADACHE. NOW TAKE THE -- THE NEW THING WITH NO CHANCE OF HEADACHE OR THE OLD THING THAT HAS A SLIGHT CHANCE OF HEADACHE. ON DUAL TRACK ANALYSIS YOU CAN'T DO THAT. BECAUSE THAT OLD THING IS A THERAPEUTIC INTERVENTION. YOU CAN ONLY GIVE IT IF IT IS AS GOOD AS EVERYTHING ELSE YOU CAN GIVE. SO IT LOOKS LIKE WHAT THAT IS SAYING IS, THAT RISK OF LP HEADACHE IS ETHICALLY ACCEPTABLE FOR THE LP BUT IT'S NOT ACCEPTABLE FOR THAT OLD INTERVENTION EVEN WHEN THE RISK OF HEADACHE IS LOWER FROM THE THERAPEUTIC INTERVENTION THAN THE LP. AND TO MY MIND, THAT LOOKS WIERD. I THINK IF I'M A SUBJECT, I THINK WHAT I CARE ABOUT IS THE CHANCES I'M GOING TO GET A HEADACHE AND HOW BAD IT IS. I DON'T CARE IF IT COMES FROM THE NEEDLE YOU STICK IN MY BACK OR THE NEEDLE YOU STICK IN MY ARM TO GIVE THE DRUG DOES. THAT ANSWER YOUR QUESTION, HELP OR NO? >> IT HELPS BUT I MEAN, STILL THE CONCERN IS, WHEN WE ARE TALKING ABOUT HEADACHE IT DOESN'T SEEM VERY SERIOUS. BUT WHEN YOU'RE RANDOMIZING PEOPLE TO TWO DIFFERENT INTERVENTIONS AND ONE HAS A RISK AND ONE DOESN'T, THEN THE PROBLEM TO ME SEEM, SOME OF THE PEOPLE ARE GETTING THE RISK. SOME OF THE PEOPLE WILL GET THE RESULT AND SOME WON'T WHEREAS IN THE LUMBAR PUNCTURE EVERYBODY IS GETTING THAT SAME RISK. >> SO THE IDEA IS WHAT YOU DO IS YOU'RE IN THE THERAPEUTIC PART, YOU'RE RANDOMIZING PEOPLE AND SO ONLY HALF OF THE PEOPLE ARE GETTING THE ADDED RISK OF HEADACHE FROM THE LESS AFFECT? IS THAT THE IDEA? WHEREAS HALF ARE GETTING THE BEST THING SO IT'S OKAY FOR THEM? >> RIGHT. >> SO THIS IS ONLY BAD FOR HALF AND THE LP IT'S BAD FOR EVERYBODY. BUT IF YOU THOUGHT THAT, WOULDN'T YOU SAY THE LP IS WORSE? EVERYBODY IS GETTING THE RISK OF THE LP. I'M ONLY DOING HALF OF THE PEOPLE FOR THE -- I DON'T KNOW IF THAT IS -- >> IT HAPPENS. >> OKAY. AND SO MORE PHILOSOPHY THAN PEOPLE CARE FOR. THAT EXAMPLE RAISES REALLY INTERESTING QUESTION WHICH I DIDN'T TALK ABOUT TOO MUCH ABOUT, AT WHAT POINT IN THE PROCESS OF BEING IN THE TRIAL DO YOU EVALUATE THE RISKS? SO, HERE IS ONE WAY TO DO IT. IMAGINE I HAVE A STUDY, PEDIATRIC STUDY. SO THESE ARE PHILOSOPHICAL EXAMPLES EVERYBODY. SO I HAVE A STUDY WHERE WHAT I'M GOING TO DO IS I'M GOING TO DO A LIVER BIOPSY. I'M GOING TO DO A STUDY IN 5-YEAR-OLDS AND I'M GOING TO HAVE ONE OF THE 5-YEAR-OLDS UNDERGO LIVER BIOPSY FOR RESEARCH PURPOSES. BUT I HAVE A REALLY GREAT DRUG AND SO WHAT I'M GOING TO DO IS, I'M GOING TO GIVE EVERYBODY THAT REALLY GRATED DRUG AND I'M GOING TO RANDOMIZE THEM SO ONE KID GETS THE LIVER BIOPSY. IMAGINE IF I ENROLL 1000 KIDS. YOU MIGHT THINK SO IF PRIOR TO THE RANDOMIZATION, THAT IS A POTENTIAL BENEFIT STUDY EVEN THOUGH THERE IS EYE 1-1,000 CHANCE OF GETTING THE LIVER BIOPSY. I'M GOING TO GET THIS DRUG AND THAT JUSTIFIES IT. DO YOU DO IT THERE OR DO YOU SAY NO, WHAT YOU HAVE TO DO IS EVALUATE THE RISK-BENEFIT OF THE BIOPSY ITSELF AFTER RANDOMIZATION? >> NO OTHER QUESTIONSES? >> I HAVE ONE. >> I WONDERED. YOU SAID YOU WERE TALKING ABOUT RISK AND BENEFIT TO INDIVIDUAL PARTICIPANTS. BUT I WONDER ABOUT HOW WE THINK ABOUT RISK MORE BROADLY. SO SOCIETAL RISK OR THE IMPLICATIONS OF THE RESEARCH OR SOMETHING LIKE THAT. IS THAT PART OF RISK-BENEFIT ANALYSIS OR HOW WE -- DO WE INCLUDE THAT UNDER SOCIAL VALUE ANALYSIS OR NOT DO IT? >> RIGHT. SO, PEOPLE MIGHT NOT KNOW, THIS IS AN INTERESTING CLAUSE IN THE U.S. FEDERAL REGULATIONS OF THESE WHICH SAYS EXPLICITLY THAT IRBs AREN'T SUPPOSED TO CONSIDER RISKS OF THE LONG-TERM CONSEQUENCES OF THE USE OF WHATEVER IS BEING TESTED. YOU MIGHT THINK, WHY NOT DO THAT? THEY ARE SUPPOSED TO LOOK AT THE LONG TERM POTENTIAL BENEFITS. THAT'S THE WHOLE POINT OF DOING THE RESEARCH. WHY NOT THE LONG TERM RISKS? SO I THINK THIS OR THE ONE PLACE THIS COMES UP -- WE DID A GRAND ROUNDS ON THIS A COUPLE OF YEARS AGO. WHAT SOME PEOPLE CALL DUAL-USE RESEARCH. PEOPLE HEARD OF THIS. SO WHAT YOU DO IS IMAGINE SOMEBODY IS TESTING SOME INTERVENTION THAT HAS IMPORTANT MEDICAL POTENTIAL BUT ALSO IF IT GOT INTO THE WRONG HANDS PEOPLE COULD USE IT FOR DOING SOMETHING VERY BAD TO PEOPLE, LIKE EXPOSING IT IN AN ENVIRONMENT AND HURTING A LOT OF PEOPLE. SO THE QUESTION IS, TO POTENTIAL BENEFITED THEY ARE GREAT. IF THIS IS REALLY AN INTERVENTION THAT COULD HELP PEOPLE, BUT IF IT GETS INTO THE WRONG HANDS, IT COULD LEAD TO A LOT OF SERIOUS PROBLEMS. SO, HOW AND TO WHAT EXTENT SHOULD THE IRB TAKE INTO ACCOUNT LONG TERM RISKS? AND I THINK THAT IS A GREAT QUESTION. I THINK SEEMS TO ME CONTRARY TO THE U.S. REGULATIONS, TO SOME EXCEPT, YOU HAVE TO THINK ABOUT THAT. YOU CAN'T JUST IGNORES THOSE. HOW YOU TAKE THEM INTO ACCOUNT IS REALLY HARD. AND THE OTHER THING IT UNDERSCORES IS THE POINT I MADE BEFORE ABOUT THE EXTENT TO WHICH ALL JUDGMENTS REQUIRE A LOT OF KNOWLEDGE AND EXPERTISE AND A LOT OF REALLY SMART PEOPLE TO THINK THROUGH ALL OF THIS STUFF. >> ANY OTHER QUESTIONS? >> ANY OTHER QUESTIONS? >> JUST WANTED TO ASK REGARDING THIS TOPIC IS ABOUT RISK AND BENEFIT. SO HOW DOES ETHICAL ISSUES COME INTO IT? BECAUSE YOU MENTIONED ABOUT CHILDREN BEING PUT INTO MINIMALLY LED PAINTED HOUSES VERSUS NO LEAD PAINT HOUSES. SO HOW CAN YOU JUSTIFY? IS IT ETHICAL TREATMENT TO DO THAT? >> RIGHT. YES. GREAT QUESTION. MAYBE THIS WILL SET UP HARD QUESTIONS FOR SKIP NEXT. SO, FOR ME, THE WAY TO THINK ABOUT THE ETHICS OF IT IS JUST, JUST IMAGINE. HERE IS STUDIES THAT THEY DO. CLINICALLY FOR A LOT OF THINGS, IT'S GOOD TO KNOW WHAT NORMAL VALUES ARE. SO YOU HAVE SOME KID WHO COMES IN WITH A SODIUM OR SOMETHING OR OTHER AND YOU WANT TO KNOW WHETHER THAT IS PROBLEMATIC OR NOT. HOW DO YOU DO THAT? YOU COMPARE IT AGAINST WHAT STANDARD OR WHAT IS NORMAL. HOW DO YOU FIND OUT WHAT SAY NORMAL SODIUM IS IN AN 8-YEAR-OLD? IT SEEMS LIKE THE ONLY WAY TO DO ITUX THE OBVIOUS WAY TO DO IT IS, DO A COUPLE OF BLOOD DRAWS IN A BUNCH OF WHAT YOU REGARD AS NORMAL HEALTHY 8 YEAR OLDS AND TAKE IT AND SEE WHAT THE SODIUM IS. THAT CAN BE A REALLY IMPORTANT THING TO DO FOR SOCIETY, FOR SCIENCE. BUT HERE IS THE QUESTION. MAYBE I SHOULD REPEAT YOUR QUESTION. HOW DO YOU JUSTIFY THAT TO THAT KID? TYPICALLY WE SAY YOU CAN ONLY DOE SOMETHING TO AN INDIVIDUAL KID WHEN IT IS IN THEIR INTEREST. HOW DO WE JUSTIFY STICKING NEEDLES INTO THE ARMS OF 8-YEAR-OLDS IN ORDER TO LEARN THINGS THAT WILL HELP OTHER PEOPLE? THAT'S THE CHALLENGE. I THINK THAT IS AND CONTINUES TO BE A SERIOUS CHALLENGE AND I'M NOT SURE THAT THAT CHALLENGE HAS BEEN ADEQUATELY RESOLVED YET. SO MAYBE PRESS SKIP ON HOW TO JUSTIFY THAT. HERE IS WHAT THE STANDARD RESPONSE IS. AS LONG AS THOSE RISKS ARE SUFFICIENTLY LOW AND THE VALUE OF THE STUDY IS SUFFICIENTLY HIGH, IT IS OKAY. SO IT'S SORT OF A UTIL TARYN ANALYSIS WHERE YOU SAY, IT'S NOT GOING TO HELP THIS KID. HE CAN'T CONSENT BUT I'M DOING IT TO HIM TO HELP OTHER PEOPLE AND THE INITIAL QUESTION IS HOW IS THAT EVER ACCEPTABLE NO MATTER HOW LOW THE RISKS ARE? I THINK THAT IS THE REAL CHALLENGE. THE STANDARD VIEW IS IT IS OKAY IF THE RISKS ARE LOW ENOUGH. THAT'S THE MINIMAL RISK STANDARD BUT IT LEAVES YOUR QUESTION HOW DO YOU JUSTIFY IT AT ALL. >> SO THAT WAS A GOOD SET UP FOR OUR NEXT SPEAKER. WE ARE PRIVILEGED TO HAVE WITH US TODAY DR. SKIP NELSON WHO IS THE SENIOR PEDIATRIC ETHICIST AT THE OFFICE OF PEDIATRIC THERAPEUTICS AT THE U.S. FOOD AND DRUG ADMINISTRATION AND HE WILL TALK ABOUT RESEARCH WITH CHILDREN. >> THANK YOU. SO LEFT RIGHT ON THIS THING, I GUESS? SINCE I LIKE TO WANDER AROUND. WELL, A COUPLE OF QUICK COMMENTS. YOU'LL SEE SOME INTERESTING JUXTAPOSITION OF SOME OF THE THINGS THAT DAVID IS FAULKING ABOUT WITH WHAT I PLAN TO TALK ABOUT. -- TALKING ABOUT. I MIGHT MAKE ONE CORRECTION. I BELIEVE IN THE KENNEDY KREIGER STUDY, HOUSES WERE RANDOMIZED BUT NOT THE CHILDREN AND THEN THEY MOVED FAMILIES WITH CHILDREN INTO THE HOUSES. SO THE HOUSES WERE RANDOMIZED TO TWO FORMS OF LEAD ABATEMENT. THERE IS A BOOK ABOUT 10 YEARS AGO HAS A CHAPTER ON THAT STUDY THAT I WROTE. THERE IS AN INTERESTING BACK STORY TO THAT. I VISITED THE PLAINTIFF'S ATTORNEY IN THAT CASE TO GET ALL THE DETAILS BECAUSE THEY ARE HAPPY TO SHARE. AND I DON'T KNOW IF THAT CASE WAS SETTLED YET. IT MIGHT HAVE BEEN SETTLES BUT WHAT HAPPENS IS ONE OF THE CHILDREN'S BLOOD LEVEL TESTS WAS HIGH AND IT'S NOT THAT THE STUDY WAS QUOTE UNETHICAL BUT THEY DROPPED THE BALL IN MAKING THE REFERRAL FROM THAT BLOOD LEVEL TEST TO TREATMENT. IN OTHER WORDS THERE WAS A PLAN AND THEY DROPPED THE CLINICAL BALL SO THE MOTHER SUED. AND DAVID'S COMMENT IS THERE IS OFTEN OTHER ETHICAL ISSUES ARE IMPORTANT. BECAUSE WHAT REALLY HAPPENED THERE IS THE ATTORNEY WHO WAS BROUGHT INTO THAT WAS SOMEONE WHO WORKED TO GET LEAD OUT OF HOUSES AND WAS SUING LANDLORDS IN EAST BALTIMORE FOR NOT -- FOR LETTING THEIR HOMES FALL IN DISREPAIR. IT FELL INTO POLITICS OF CORE AND LEAD APAYMENT AND HOUSING AND ALL OF THAT, WHICH BECAME COMPLICATED RELATIVE TO THE ISSUE OF THE ETHICS OF THE RESEARCH. I THINK PERSONALLY THE RESEARCH WAS ETHICALLY DESIGNED BUT THE PROBLEM IS THAT IMPLEMENTATION AND THE POLITICS WERE PROBLEMATIC. BUT THAT WOULD BE A LONG CONVERSATION. TYPICAL DISCLAIMER. I'M GOING TO COVER FOUR TOPICS. I'M GOING TO SPEND MOST OF THE TIME ON THE LAST TWO BECAUSE THAT SORT OF THE MEAT IF YOU WILL OF WHAT DAVID WAS TALKING ABOUT BUT I WANTED TO TALK A LITTLE BIT ABOUT WHAT I CALL -- CALL REGULATORY BIOETHICS. SO WHEN PEOPLE ASK ME WHAT I DO, I DO REGULATORY BIOETHICS AND I'LL TALK ABOUT WHAT THAT IS. AND THEN I'LL TALK A LITTLE BIT ABOUT EXTRAPOLATION BUT NOT A LOT AND THEN MOST OF THE WORK WILL BE THIS. SO WHAT DO I MEAN BY REGULATORY BIOETHICS? I'M IN A FEDERAL AGENCY THAT HAS REGULATORY OVERSIGHT. IF YOU'RE DOING A FDA REGULATED TRIAL WE HAVE OVERSIGHT OVER YOUR TRIAL. AND SO, IF I'M ASKED AN OPINION ABOUT WHETHER A OPINION OUGHT TO GO FORWARD OR NOT, I TAKE SERIOUSLY THAT MY OPINION OUGHT TO BE INFORMED BY THE REGULATORY FRAMEWORK, WHICH I FUNDAMENTALLY THINK IS ETHICAL IF YOU LOOK BACK AT THE NATIONAL COMMISSION SUPPORT BUT ALSO PRECEDENCE AND OTHER APPROACHES TO WHERE IT SHOULDN'T BE JUST MY VIEW OF WHAT SHOULD HAPPEN, WHICH IN FDA, SHOULD MEANS PRETTY PLEASE. BUT WHAT MUST HAPPEN. AND I'LL SHOW YOU SOME OF THOSE DESIGNS. SO, THE IDEA HERE IS THAT WHAT I SAY OUGHT TO BE BASED ON IDEALLY OPEN AND DELIBERATIVE PROCESS WHETHER INSTITUTE OF MEDICINE REPORTS OR OTHER SORTS OF CASES. AND NOT JUST BASED ON MY PERSONAL OPINION. ALTHOUGH OBVIOUSLY THERE IS A A LITTLE BIT OF A INTERSECTION THERE. SO THAT'S WHAT I CALL REGULATORY BIOETHICS. THE OTHER POINT ABOUT FDA REGULATED RESEARCH IS WE DON'T REGULATE RESEARCH. WE REGULATE PRODUCTS. AND WHAT MAKES IT AN FDA-REGULATED CLINICAL INVESTIGATION IS IF YOU'RE GIVING INVESTIGATIONAL PRODUCT TO A PERSON, SO IT'S A CLINICAL INVESTIGATION TO GIVE AN INVESTIGATIONAL PRODUCT TO ONE PERSON. EVEN THOUGH THERE IS NO GENERALIZABLE KNOWLEDGE THAT YOU MAY GET IN THAT SETTING. HHS REGULATIONS TO FIND RESEARCH IS GENERALIZABLE KNOWLEDGE, SYSTEMATIC REGULATION DESIGNED TO YIELD GENERALIZABLE KNOWLEDGE. I'M HAPPY NOT TO HAVE THAT DEFINITION BECAUSE I DON'T HAVE TO DEAL WITH THE ISSUE OF WHETHER OR NOT QUALITY IMPROVEMENT AND OTHER SORTS OF ACTIVITIES THAT GO ON ARE THEN RESEARCH. IT'S PRETTY EASY FOR ME. I SEE A DRUG. GIVE IT TO ONE PERSON AND I CAN SAY THAT IS AN FDA REGULATED CLINICAL INVESTIGATION. IT'S A VERY DIFFERENT SET UP AND THERE IS SOME INTERESTING IMPLICATIONS OF THAT BUT WE REGULATE RESEARCH THROUGH REGULATING THE PRODUCT. SO THIS IS HOW I LIKE TO TALK ABOUT THE BASIC ETHICAL FRAMEWORK. NOW THIS IS IN JUXTAPOSITION WITH THE REGULATIONS AND I'LL TALK ABOUT THIS AND THE FIRST THREE YOU'LL SEE. SO, THE FIRST POINT IS YOU SHOULDN'T ENROLL CHILDREN IN RESEARCH UNLESS THERE IS AN IMPORTANT QUESTION YOU'RE ANSWERING ABOUT THE HEALTH AND WELFARE OF CHILDREN. SO THE SCIENTIFIC NECESSITY IS IMPORTANT AND THAT IS WHERE WE START. AND I'LL TALK ABOUT THIS. THEN ABSENT PROSPECT OF DIRECT THERAPEUTIC BENEFIT, THE RESEARCH CHICK TO WHICH CHILDREN ARE EXPOSED MUST BE LOW. WE'LL TALK ABOUT COMPONENT ANALYSIS AND I'LL HAVE TWO SLIDES, WHICH WE'LL GET TO AROUND COMPONENT ANALYSIS. THE THIRD ONE IS CHILDREN SHOULD NOT BE PLACED AT A DISADVANTAGE BY BEING ENROLLED IN THE CLINICAL TRIAL. EITHER THROUGH EXPOSURE TO EXCESSIVE RISKS OR NECESSARY HEALTH CARE. AND YOU'LL SEE HOW I FRAME THIS IN THE CONTEXT OF THE REGULATIONS. THEN VULNERABLE POPULATIONS UNABLE TO CONSENT SHOULD HAVE A SUITABLE PROXY. I'M NOT GOING TO TALK ABOUT PARENTAL PERMISSION. IF YOU HAVE QUESTIONS I'M HAPPY TO ANSWER BUT I THINK MY OWN BIAS IF YOU GET THE RESEARCH PROTOCOL RIGHT, ANYBODY CAN SORT OUT HOW YOU WRITE A PARENTAL PERMISSION DOCUMENT AND CHILD CONSEN FORM. ALL MY WORK IS DONE AT THIS LEVEL. WE MIGHT GET TO THIS IN CERTAIN CIRCUMSTANCES BUT MOSTLY WHAT I DO IS FRAMED BY THESE THREE QUESTIONS. I LIKE TO THINK OF THESE AS NESTED PROTECTIONS. WHAT DO I MEAN BY THAT? SCIENTIFIC NECESSITY IS THE FIRST THING YOU WANT TO ADDRESS. THAT'S THE TREE, THEN YOU HAVE THE APPROPRIATE BALANCE OF RISK AND BENEFIT THAT IS PRINCIPLE ONE. 2 AND 3 IS THE NEST. AND THEN YOU HAVE PARENTAL PERMISSION AND CHILD ASCENT. MOM-AND-POP BLUEJAY AND THE BABY BLUE JAYS. SO THAT IS WHAT I MEAN BY NESTED PROTECTION. THAT'S HOW YOU START. DO IT IN THAT ORDER. DON'T START HERE AND THEN WORK YOUR WAY BACK. SO THE ETHICAL PRINCIPLE OF SCIENTIFIC NECESSITY. CHILDREN SHOULDN'T BE ENROLLED UNLESS IT'S NECESSARY TO ANSWER IMPORTANT SCIENTIFIC QUESTIONS ABOUT THE HEALTH AND WELFARE OF CHILDREN. NOW EXTRAPOLATION BECOMES AN APPLICATION OF THAT AND I'LL SHOW YOU HOW THAT IS. AGAIN DOING REGULATORY BIOETHICS, THE QUESTION IS WHERE DO I FIND THIS IN THE REGULATIONS? I FIND IT IN WHAT IS CALLED SUBPART A, THE GENERAL RULES AROUND MINIMIZATION OF RISK AS WELL AS FOR EQUITABLE SELECTION. IF YOU LOOK BACK AT THE NATIONAL COMMISSION'S REPORT, WHEN THEY TALKED ABOUT EQUITABLE SELECTION, THEY WEREN'T JUST TALKING ABOUT RACE, GENDER, ETHNICITY. THEY BASICALLY SAID THAT YOU SHOULD ENROLL INDIVIDUALS WITH CONSENT BEFORE YOU ENROLL INDIVIDUALS WHO CANNOT CONSENT. AND SO THEY TALKED ABOUT EQUITABLE SELECTION FROM THE STANDPOINT OF PEDIATRIC RESEARCH. WE DON'T SEE THAT EXPLICITLY THERE BUT THIS IS WHERE WE DO THIS AND I WILL SAY THERE ARE CLINICAL TRIALS PUT ON CLINICAL HOLD AT THE FDA YOU DON'T NEED TO ANSWER THE QUESTION USING CHILDREN. NOW THE GENERAL JUSTIFICATION. SO IF YOU LOOK AT THE LANGUAGE IF YOU YOU'RE GOING TO DO A STUDY IN ADULTS, HERE IT IS. THE RISKS ARE REASONABLE IN RELATIONSHIP TO ANTICIPATED BENEFITS IF ANY AND THE IMPORTANCE OF THE KNOWLEDGE. SO A LOT OF COMPLEXITY IN THE ADULT WORLD IS THIS IS NOT A CLEAR -- YOU'RE BALANCING RISK AGAINST KNOWLEDGE AND AGAINST BENEFITS AND SORT OF SORTING THAT OUT. BUT THIS, IF ANY IS THE IMPORTANT ONE. YOU CAN HAVE SIGNIFICANT RISKS TO AN ADULT. YOU CAN ASK A COMPETENT ADULT TO UNDERGO SIGNIFICANT RISKS FOR KNOWLEDGE SAKE. EVEN IN THE ABSENCE OF BENEFITS. BUT IN CHILDREN, THAT IS NOT THE CASE. SO IN CHILDREN THIS IS THE BROAD LANGUAGE. YOU HAVE TWO CATEGORIES. IT MUST BE RESTRICTED TO MINIMAL RISK OR MINOR INCREASE OVER MINIMAL RISK AND WE'LL TALK ABOUT THAT ABSENT DIRECT BENEFIT. AND THESE ARE THE SATES. OR, THE RISKS MUST BE JUSTIFIED BY THE ANTICIPATED DIRECT BENEFIT, THE BALANCE OF WHICH IS AT LEAST FAVORABLE. I'LL TALK ABOUT THE INTERPRETATION OF THAT AS WE GO ON. BUT THAT IS BASICALLY THE DISTINCTION. IF YOU'RE LOOKING FOR KNOWLEDGE ONLY, AND THERE IS NO PROSPECT OR DIRECT BENEFIT TO THAT CHILD, THE RISKS EVER CAPPED. YOU CAN GET A COMPETENT ADULT TO AGREE TO ANYTHING. THIS IS WHERE YOU END UP WITH SUBPART D. AND THIS THE MINER INCREASE. THERE IS A FOURTH CATEGORY, WHICH I WON'T GO INTO WHICH IS AN IRB THINKS IT'S WORTH DOING, IT CAN REFER IT. SO THERE ARE TWO KEY CONCEPTS I WOULD ARGUE IN PEDIATRICS. FIRST IS A PROSPECT OF DIRECT BENEFIT. THE RISKS TO WHICH A CHILD MAY BE EXPOSED DEPEND ON WHETHER OR NOT THE CHILD HAS A PROSPECT OF DIRECT BENEFIT. DEFINING WHAT THAT IS ESSENTIAL ASPECT OF DECIDING WHETHER THE TRIAL IS APPROPRIATE OR NOT AND WE'LL TALK ABOUT COMPONENT ANALYSIS. COMPONENT ANALYSIS IS BUILT INTO THE PEDIATRIC REGULATIONS. IT'S NOT BUILT INTO THE ADULT REGULATIONS. THEN COMPONENT ANALYSIS AS DAVID MENTIONED, ONE PROTOCOL WILL HAVE MEANT DIFFERENT INTERVENTIONS. SOME THAT DO OR DO NOT OFFER IT AND SO YOU NEED TO ANALYZE THESE COMPONENTS OF THE PROTOCOL SEPARATELY AND TOGETHER. I'LL SHOW YOU SOME EXAMPLES THERE AND THEN SO YOU HAVE TO EVALUATE IT UNDER SEPARATE PARTS OF THE REGULATIONS. AND I WILL SHOW YOU. I HAVE 2 SLIDES ONE ABOUT NET RISKS AND THE OTHER ABOUT DUAL TRACK AND I'LL GIVE YOU MY OPINIONS ABOUT BOTH OF THOSE. SO LET'S TALK BRIEFLY ABOUT EXTRAPOLATION. SO, BACK IN 1998, THE FDA BASICALLY SAID IT COULD BE FLEXIBLE GENERALLY WE REQUIRE TWO ADEQUATELY CONTROLLED STUDIES WHERE THIS DERIVES IF YOU LOOK AT THE REGULATIONS IT TALKS ABOUT WELL CONTROLLED INVESTIGATIONS. SO THE FACT THAT THIS IS PLURAL, THE FDA INTERPRETS AND SAYS THERE NEEDS TO BE TWO LINES OF EVIDENCE. YOU WANT TWO LINES OF EVIDENCE IN SUPPORT OF SOMETHING IN SCIENCE. THEY ARE LIKELY TO BE REPLICATED. NOW THE FDA CAN BE FLEXIBLE. IF WILL HAVE ONE ADEQUATE WELL CONTROLLED STUDY AND SOME CONFIRMATORY EVIDENCE. THIS IS SUBSTANTIAL EVIDENCE OF EFFECTIVENESS. THIS IS WHAT WE GENERALLY LOOK FOR. NOW AN EXTRAPOLATION IF THE COURSE OF THE DISEASE AND THE RESPONSE TO TREATMENT IS SUFFICIENTLY SIMILAR BETWEEN THE ADULTS AND CHILDREN, FDA MIGHT BE WILLING AND AGAIN DEPENDING ON THE DATA, TO EXTRAPOLATE EFFICACY PROVIDED YOU CAN SHOW EVIDENCE OF DOSING AND SAFETY. SO I WOULD ARGUE THAT THIS IS A WILLINGNESS TO APPLY THE PRINCIPLE SCIENTIFIC NECESSITY. IF YOU DON'T NEED TO DO EFFICACY TRIAL IN CHILDREN, THEN YOU SHOULDN'T HAVE TO. AND YOU SHOULDN'T DO IT TO EXPOSE THEM TO THAT WOULD BE UNNECESSARY. NOW, I'LL SKIP THIS QUICKLY. IF YOU LOOK AT PEDIATRIC APPROVAL T IS USED FAIRLY OFTEN. WITHOUT GOING INTO GREAT DETAIL, NO EXTRAPOLATION, ONLY 17% OF THE TIME. SO SOME FORM OF EXTRAPOLATION, 14% OF THE TIME AND AT LEAST THIS LOOK AT SOME FDA STUDIES, THERE WAS PK AND SAFETY OR SAFETY DATA ONLY AND THEN PEDIATRIC APPROVAL. THE MAJORITY OF TIME HAD PARTIAL EXTRAPOLATION RANGING FROM DOING A PK/PD, FINDING SOME BIOMARKER SHOWING THAT YOU CAN MAKE THAT CHANGE, OR YOU MIGHT HAVE TO DO A FULL CLINICAL TRIAL IF YOU DON'T HAVE A BIOMARKER. THE POINT OF THIS IS, IF YOU DON'T GET THIS RIGHT, OBVIOUSLY IF YOU ONLY HAVE TO DO PK ONLY, IN OTHER WORDS YOU HAVE AN ADULT STUDY, THE ADULT STUDY HAS SHOWN EFFICACY, AND CORRELATE THAT EFFICACY RESPONSE WITH THE BLOOD LEVEL OF THE DRUG AND YOU SAY WE THINK WE CAN EXTRAPOLATE SO ALL WE NEED TO DO IS FIND THE RIGHT DOSE TO GIVE A KID AND GET THAT BLOOD LEVEL AND WE ARE DONE. CLEARLY THAT IS A FAIRLY LOW BAR TO GET THE INDICATION. IF THAT'S ALL YOU NEED TO DO, YOU GET THE I COULD INDICATION. IF YOU'RE NOT -- YOU GET THE INDICATION. IF YOU'RE NOT RIGHT, YOU'RE PUTTING DRUGS ON THE MARKET THAT DON'T WORK. THAT'S A VERY IMPORTANT ASSUMPTION AND THERE NEEDS TO BE DATA IN SUPPORT OF THAT. THIS IS AN EXAMPLE IN MY MIND ABOUT HOW WE APPLY PRINCIPLE OF SCIENTIFIC NECESSITY TO SAY WHAT WE NEED OR DON'T NEED. I'M NOTHING NOT GOING TO SPEND TIME HERE. GET THE SLIDES IN A GUIDANCE THAT TALKS ABOUT EXTRAPOLATION WHICH ARE HAPPY TO LOOK AT AND THERE IS NONE PARTIAL AND FULL. SO, FOR THOSE WHO ARE INTERESTED IN PEDIATRIC CLINICAL TRIALS, PARTICULARLY IF YOU'RE A CLINICAL PHARMACOLOGIST, THIS IS A PEDIATRIC CLINICAL PHARMACOLOGY GUIDANCE AND IT'S INCLUDED IN THAT GUIDANCE. BUT I THINK WHERE I WANT TO SPEND MOST OF MY TIME IS ON THESE LAST TWO. BECAUSE THIS IS WHERE ALL OF THE INTERESTING TOPICS THAT DAVID TOUCHED ON COME UP. SO THE FIRST IS AROUND PROSPECT OF DIRECT BENEFIT AND COMPONENT ANALYSIS. WHAT SAY DIRECT BENEFIT? A DIRECT BENEFIT OF AN EXPERIMENTAL INTERVENTION OR PROCEDURE SHOULD IMPROVE THE HEALTH OR WELL-BEING OF THE INDIVIDUAL CHILD. SO THE POINT THERE IS THAT A DIRECT BENEFIT MEANS IT'S MY BENEFIT AND NOT YOURS. SO IF I'M NOT BENEFITING BUT YOU MIGHT BE BESTING FROM THE KNOWLEDGE, THEN IT'S NOT A DIRECT BENEFIT TO ME. WE OFTEN USE THE TERM INDIRECT PERHAPS TO TALK ABOUT THAT. SO IT NEEDS TO BE A BENEFIT TO THE CHILD. NOW IT IS TRUE THAT PAYING ME IF ALL OF YOU DECIDED TO PAY ME FOR THIS LECTURE, THIS WOULD BE A EUROPEAN-STYLE OLD SCHOOL EUROPEAN-STYLE WHERE I ONLY MAKE A LIVING IF YOU PAY ME FOR MY LECTURE. THAT'S A DIRECT BENEFIT TO ME. BUT WE GENERALLY DON'T THINK OF PAYMENT AS A DIRECT BENEFIT. WE DON'T OFFSET THE RISK OF THE STUDY IN PEDIATRICS BY THAT PAYMENT. I PERSONALLY THINK YOU CAN PAY ADULTS TO DO MANY RISKY THINGS AND I'LL BE MORE CONTROVERSIAL AND I DON'T THINK ANY FORM OF PAYMENT IS UNDULY INFLUENTIAL. THAT WOULD BE A WHOLE ANOTHER DISCUSSION OF THE MEANING OF VOLUNTARY CHOICE. SO ALL OF US HERE ARE HERE I ASSUME, WE ARE GETTING PAID. IF YOU WEREN'T GETTING PAID, HOW MANY EVER YOU WOULD VOLUNTEER TO CONTINUE IN YOUR JOB? ANY? YOU WOULD? YOU'RE NOT PAID? [ OFF MIC ] >> OKAY. BUT YOU'RE PAID SOMEWHERE I ASSUME. NO? INDEPENDENTLY WEALTHY? WE SHOULD ALL BE SO LUCKY. SO ANYWAY, THE QUESTION IS WHETHER AN INTERVENTION OFFERS A DIRECT BENEFIT MUST BE EVIDENCE-BASED AND IT COULD BE ADULT HUMAN DATA, ANIMAL DATA, COULD BE OFF-LABEL PEDIATRIC USE DATA IF SOMETHING IS ALREADY ON THE MARKET. THE QUESTION IS, ARE YOU REASONABLY COMFORTABLE? THIS IS A PRETTY SQUISHY LANGUAGE BUT I HAVE CHOSEN THAT BECAUSE THIS RISK-BENEFIT EVALUATION IS SQUISHY AS MUCH AS WANT TO HAVE DATA IT DOES INVOLVE JUDGMENT. LOOKING AT THE DOSE OR DURATION OF TREATMENT, DOES IT OFFER THAT? NOW WHETHER IT OFFERS A PROSPECT OF DIRECT BENEFIT IS SEPARATE FROM WHEN YOU THINK IT IS SUFFICIENT TO JUSTIFY THE RISK. AND DAVID WAS TALKING ABOUT THIS INFORMED CLINICAL JUDGMENT IF YOU WILL. IF YOU LOOK BACK AT THE NATIONAL COMMISSION'S REPORT WHEN THEY DEVELOPED THE ETHICS BEHIND THESE REGULATIONS, THEY EXPLICITLY SAID, THAT THIS JUDGMENT IS LIKE THE JUDGMENT OF CLINICIAN. IS IT REALLY WORTH DOING THAT? IS THE BENEFIT WORTH DOING THAT RELATIVE TO THE RISK? AND THERE IS SOME VARIABILITY THERE. I'LL TALK A LITTLE BIT ABOUT NA RISK JUDGMENT. AND THE JUSTIFICATION MAY INCLUDE THE IMPORTANCE, POSSIBLY OF AVOIDING GREATER CHARGE FROM THE DISEASE, DEGREE OF TOLERABLE UNCERTAINTY, DISEASE SEVERITY, POSSIBILITY OF ALTERNATIVE TREATMENTS. THIS IS NOT A SIMPLE JUDGMENT. THAT'S THE WHOLE POINT. NOT A SIMPLE JUDGMENT. THERE IS A LOT OF FACTORS THAT COME INTO PLAY IN MAKING THIS ASSESSMENT ABOUT WHETHER THIS PROSPECT OF DIRECT BENEFIT IS SUFFICIENT TO JUSTIFY THE RISKS. AGAIN, TWO STEPS. IS THERE A PROSPECT OF DIRECT BENEFIT, YES/NO. IS IT SUFFICIENT TO JUSTIFY THE RISKS? YES/NO. NOW, COMPONENT ANALYSIS. MANY PEOPLE CHARLES WEAR FOR EXAMPLE, WHO IS CANADIAN MIGHT THINK THEY INVENTED COMPONENT ANALYSIS BUT HERE IS A QUOTE FROM 1978. I THINK THE NATIONAL COMMISSION IN DISCUSSING PEDIATRIC RESEARCH EXPLICITLY TALKED ABOUT COMPONENT ANALYSIS WHERE THEY SAID TO DETERMINE THE OVERALL ACCEPTABILITY YOU HAVE TO LOOK AT THE ACTIVITIES DESCRIBED IN THE PROTOCOL AND EVALUATE THEM INDIVIDUALLY AS WELL AS COLLECTIVELY. SO I WOULD ARGUE AT THE ROOT OF OUR PEDIATRIC REGULATIONS IS COMPONENT ANALYSIS. SO, THE SIMPLIFICATION HERE IS YOU HAVE THINGS THAT ARE MINIMAL RISK, THEY MAY OR MAY NOT OFFER DIRECT BENEFIT SO YOU CAN FINESSE THE MINIMAL RISK STUFF WHEN DOING COMPONENT ANALYSIS. ABOUT YOU IF THERE IS A LOT OF THEM IN THERE, YOU NEED TO LOOK AT IT. SO WHEN I WAS CHAIR OF AN IRB, I'D GET A PIECE OF PAPER AND DRAW A LINE DOWN THE MIDDLE AND BAR ACROSS THE TOP AND PDB, PROSPECT OF DIRECT BENEFIT ON THE LEFT AND NO PDB ON THE RIGHT-HAND SIDE AND AS I READ THE PROTOCOL, I WOULD WRITE THINGS TO EITHER SIDE OF THAT LEDGER AND THAT GIVES YOU A SENSE OF WHAT THAT IS AND IF YOU GOT A LOT OF TESTS, HOW MANY, HOW CLOSE BECOMES AN ISSUE. SO HERE IS WHAT I CALL CLASSIC COMPONENT ANALYSIS. AND THIS IS BASED ON THE NATIONAL COMMISSION. SO A CLINICAL INVESTIGATION MAY INCLUDE MORE THAN ONE INTERVENTION OR PROCEDURE. FAIRLY STRAIGHTFORWARD. EACH OF THESE MUST BE EVALUATED SEPARATELY TO DETERMINE WHETHER IT DOES OR DOES NOT HOLD OUT A PROSPECT OF CREST BENEFIT. NOW THE INTERESTING THING HERE, THE EXAMPLE OF A LIVER BIOPSY DAVID HAS, IF YOU COULD ARGUE THAT BIOPSY WAS ABSOLUTELY ESSENTIAL AND THERE WOULD BE A CLINICAL DECISION BASED TO CONTINUE OR NOT CONTINUE AN EXPERIMENTAL DRUG, YOU MIGHT BE ABLE TO ARGUE THAT THE RISK OF THAT BIOPSY COULD BE OFFSET AGAINST THE BENEFIT. THAT IS AN OPEN QUESTION. I WANT TO SEE THE DETAILS OF THAT TRIAL AND THE BURDEN OF PROOF WOULD BE FAIRLY HIGH TO ARGUE THAT YOU WOULD NEED TO DO THAT BUT THERE ARE CLINICAL SETTINGS WHERE YOU MIGHT HAVE TO DO AN INVASIVE PROCEDURE TO KNOW IF IT IS WORKING OR NOT AND YOU MIGHT HAVE TO DO THAT. THAT IS NOT OFF THE TABLE. INTERVENTION THAT IS DO HOLD IT OUT SHOULD BE CONSIDERED UNDER 5052 AND WE'LL TAKE ABOUT THAT GOING FORWARD. AND THEN THOSE THAT DO NOT WOULD BE UNDER THESE OTHER CATEGORIES. THIS IS MINIMAL RISK. THIS IS MINOR INCREASE OF MINIMAL RISK. SO BASICALLY, YOU EVALUATE THOSE PROCEDURES UNDER TWO DIFFERENT ASPECTS OF OUR REGULATIONS. AND YOU'LL SEE HOW THAT PLAYS OUT. NOW HOW IS THIS CLASSIC DIFFERENCE FROM WHAT IS DISCUSSED IN THE LITERATURE? YOU HAVE COMPONENT ANALYSIS AND THIS IS WHAT DAVID WAS REFERRING TO AS DUAL TRACK AND THAT HE WAS BEING CRITICAL AND I'LL PROPOSE WHY I THINK HE IS BEING CRITICAL. AND THEN THE NET RISK TEST, THIS IS DAVID AND FRANK MILLER. THEY REFER TO THIS AS DUAL TRACK AND I HAVE THIS AS COMPONENT ANALYSIS W WITH EQUIPOISE. SO LET'S LOOK AT THAT DIFFERENCE. SO HERE IS WHAT CHARLES WEAR PROPOSED. SO, STARTS WITH A DISTINCTION BETWEEN THERAPEUTIC AND NON THERAPEUTIC PROCEDURES. NOW THIS LANGUAGE YOU COULD ARGUE HAS ISSUES WITH IT. PEOPLE SAY LET'S NOT TALK ABOUT THERAPEUTIC RESEARCH PROCEDURE JUST REINFORCES THE THERAPEUTIC MISCONCEPTIONS AND SO FORTH. SO WE COULD BE CLEAR AND SAY THIS IS A DISTINCTION ABOUT WHETHER THEY DO OR DO NOT OFFER A PROSPECT OF DIRECT BENEFIT AND FOR THOSE THERAPEUTIC PROCEDURES, CLINIC ALEC WI POISE FINDS ITS WAY IN HERE -- CLINICAL EQUIPOISE -- AND THIS IS WHERE THAT ARGUMENT COMES THAT A RESEARCHER WHO SAY CLINICIAN RELATIVE TO THAT PATIENT HAS AN OBLIGATION TO IN FACT ACT IN THE SAME FIDUCIARY CAPACITY TO THAT INDIVIDUAL AS THEY WOULD IF THEY WERE THEIR CLINICIAN. AND SO THAT IS WHERE YOU GET THIS ARGUMENT THAT YOU CANNOT HAVE ANY USING DAVID'S LANGUAGE, NET RISKS IN THIS THERAPEUTIC RESEARCH. THAT IS WHERE THIS COMES FROM. NOW, THIS IS THE NET RISKS TEST THAT DAVE AND FRANK DID. YOU MINIMIZE AND ENHANCE THE BENEFITS. YOU SHOULD DO THAT ANYWAY. AGAIN, DOES THE INTERVENTION OFFER POTENTIAL FOR CLINICAL BENEFIT? IT DISTINGUISHES WHETHER THEY DO OR DO NOT OFFER THE PROSPECT. YES OR NO. AND THEN IT GOES DOWN THIS WAY ABOUT NET RISKS. SO YOU HAVE THIS NET RISK LANGUAGE. BUT MY POINT IS THAT -- LET ME TALK ABOUT CLINICAL EQUIPOISE. IF YOU LOOK AT THE LITERATURE ON CLINICAL EQUIPOISE, THE CONCEPT OF EQUIPOISE IS AMBIGUOUS. BECAUSE IT INCLUDES AT LEAST TWO IDEAS. ONE IS THAT THERE IS ADEQUATE UNCERTAINTY TO JUSTIFY THE CLINICAL TRIAL. MEANING I AM AN EQUIPOISE ABOUT THE ANSWER TO THIS QUESTION. AND I SUSPECT IF MOST OF YOU USE THE WORD EQUIPOISE IN YOUR EVERYDAY LIFE, THAT THAT IS WHAT YOU MEAN. THAT IS WHAT I SUSPECT YOU MEAN. BUT CHARLES IMPORTS THIS SECOND MEANING THAT KNOWN EFFECTIVE TREATMENT SHOULD BE PROVIDED TO SUBJECTS BASED ON THIS FIDUCIARY DUTY TO CARE. SO EQUIPOISE WITHIN THE LITERATURE HAS THIS OTHER MEANING. AND I WOULD ARGUE THAT THIS DISPUTE ABOUT COMPONENT ANALYSIS IS ABOUT THIS FIDUCIARY DUTY TO CARE AND I AGREE WITH DAVID AND FRANK'S CRITICISM THAT IN THE RESEARCH SETTING WE MIGHT HAVE A DUTY TO THE SUBJECT BUT IT'S NOT NECESSARILY THE SAME AS A DUTY TO CARE AS IF YOU WERE A CLINICIAN. AND WHAT THAT SETS UP IS THIS ABILITY TO WITH HOLD KNOWN EFFECTIVE TREATMENT, WHICH I'LL TALK ABOUT A LITTLE BIT. WHAT DOES THAT MEAN? SO I AGREE WITH THE CRITICISM. BUT BOTH -- THEY ARE BOTH DOING COMPONENTINALIS AND I WOULDN'T WANT YOU TO WALK AWAY SAYING THEY ARE NOT. THEY ARE. BECAUSE THEY ARE DISTINGUISHING WHETHER IT DOES OR DOESN'T OFFER A PROSPECT OF DIRECT BENEFIT. AND AS WE TALK ABOUT 50/50 TOO, THERE IS SOME RESEMBLANCE TO CLINICAL EQUIPOISE. THIS IDEA THAT CHILDREN SHOULDN'T BE DISADVANTAGED BY BEING ENROLLED IN A CLINICAL TRIAL. THERE IS SOME RESEMBLANCE TO THAT BUT YOU CAN WITH HOLD KNOWN EFFECTIVE TREATMENT AS I'LL SHOW YOU UNDER OUR PEDIATRIC GUIDELINES. SO I THINK I MENTIONED THIS. BOTH OF THE THEM AGREE BOTTOM LINE IS, I DON'T USE THE LANGUAGE OF NET RISKS AT ALL IN THE WORK I DO. I DON'T THINK IT'S NECESSARY. AND I'LL ALSO SAY I DON'T USE THE WORD, EQUIPOISE IN THE WORK I DO. WHY? BECAUSE I DON'T WANT PEOPLE TO GET CONFUSED. SO I TELL PEOPLE THAT IF YOU'RE TALKING ABOUT EQUIPOISE IN THE CONTEXT OF SUFFICIENT SCIENTIFIC UNCERTAINTY, JUST USE THE WORD, PERFECTLY GOOD WORD, UNCERTAINTY. PERFECTLY GOOD WORD. BUT WE USE EQUIPOISE BECAUSE IT SOUNDS YOU KNOW, JUST SOUNDS SO GOOD. BUT WHY IS THIS IMPORTANT? AND I'LL SHOW YOU A CASE. IF YOU DON'T CAREFULLY DISTINGUISH BETWEEN THE DIFFERENT PROCEDURES, YOU DO RUN THE RISK THAT SOMETHING THAT DOESN'T HOLD THE PROSSUSPECT OF DIRECT BENEFIT WILL EXCEED THIS ALLOWABLE CEILING OF A MINOR INCREASE OVER MINIMAL RISK AND WE'LL TALK ABOUT THAT AS WE GO FURTHER. RETT ME GIVE YOU AN EXAMPLE. WE HAVE A MULTINATIONAL PLACEBO-CONTROLLED STUDY OF AN INVESTIGATIONAL PRODUCT IN CHILDREN OVER 7 YEARS OLD. THIS IS A PRODUCT THAT WAS MEANT TO SORT OF IMPACT ON THE IMMUNE SYSTEM AND REDUCE -- FOR TYPE I DIABETES. HOPE TO REDUCE THE IMPACT ON ISLET CELLS. I GOT A PHONE CALL BY AN IRB CHAIR I KNEW THAT WAS CONCERNED ABOUT THEY WERE ASKED ABOUT PLACING CENTRAL CATHETERS IN THESE CHILDREN. AND THAT IRB CHAIR THOUGHT THAT WAS PROBLEMATIC BECAUSE THIS IS A BLINDED TRIAL SO YOU WOULD BE PUTTING IN A CENTRAL LINE FOR THE ADMINISTRATION OF A PLACEBO. SO THOSE KIDS ARE NOT GETTING BENEFIT AND THEY HAVE GOT THE RISK OF THE CENTRAL LINE. WHAT WAS INTERESTING AND I WON'T GO INTO GREAT DETAILS. THE LETTER WAS LEAKED. I CAN -- ON OUR WEBSITE. THERE IS A WHOLE DISCUSSION. WE ANALYZED THE PROTOCOL AND WROTE A LETTER TO THE SPONSOR AND ASKED THE SPONSOR TO ASK THE IRBs HOW TO JUSTIFY THIS AND THE IRBs RESPONDED AND WE WROTE A LETTER DEBUNKING ALL RESPONSES BECAUSE IT MADE NO SENSE. IT WAS LIKE WE PLACE CENTRAL LINES AS PART OF CLINICAL CARE ALL THE TIME. THIS IS NOT CLINICAL CARE. SO ALL OF THAT IS IN THE PUBLIC DOMAIN BECAUSE ONE OF THE IRBs WHO GOT IT FROM THE SPONSOR MUST HAVE LEAKED IT TO SOMEONE SO YOU CAN -- IF YOU'RE INTERESTED, E-MAIL ME, I CAN PROVIDE YOU A LOT OF INFORMATION ABOUT THAT. WHAT WAS INTERESTING IS, THE PROTOCOL HAD NOTHING IN IT ABOUT PLACING A CENTRAL LINE SO THE FDA, UNTIL A GOT THE CALL FROM THE CHAIR, WAS IGNORANT ABOUT WHETHER OR NOT CENTRAL LINES WERE BEING USED. IT WAS ALL BEING DONE WITH PERIPHERAL CAT TERES AND IN FACT, AT THE END OF THE DAY, SO BOTTOM LINE IS, AT THE END OF THE DAY, THEY HAD 104 SITES AND 16 HAD APPROVED A CENTRAL LINE AND THE TRIAL WAS COMPLETED WITHOUT USING THE CENTRAL LINE. THERE WAS NO REASON TO USE A CENTRAL LINE IN THIS TRIAL. THERE MAY BE SOME TRIALS WHERE YOU COULD ARGUE IT IS TO DO AN INVASIVE PLACEBO. BUT IT WASN'T EVEN NECESSARY HERE BUT WE AUTHOR PLACEMENT OF A CENTRAL CATHETER IS MORE THAN A MINOR INCREASE OVER MINIMAL RISK? SO IT'S NOT JUSTIFIED IN THE PLACEBO GROUP. SO NOTICE WHAT WE ARE DOING HERE IS COMPONENT ANALYSIS OF THE PLACEBO GROUP SEPARATE FROM THE GROUP WHO IS RECEIVING THE INTERVENTION. AND THAT IS KEY. AND THAT IS CALLED A PRERANDOMMIZATION ANALYSIS OF BENEFIT. SO WHAT I'M SUGGESTING IS THAT THAT IS OFFICIALLY HOW THE FDA GOES ABOUT ITS BUSINESS OF PRERANDOMMIZATION ANALYSIS OF BENEFIT. NOT POSTER RANDOMIZATION SAYING WE ARE FLIPPING A COIN SO YOU HAVE A 50% CHANCE IS WHAT JUSTIFIES THE CENTRAL LINE. WE ARE NOT DOING THAT. AND I WOULD ARGUE AT THIS POINT WE HAVE ENOUGH PRECEDENT WHERE I HOPE I CAN SAY MUST, IN FRONT OF THAT SENTENCE INSTEAD OF SHOULD. SO, THIS TRIAL WOULD HAVE BEEN PLACED ON CLINICAL HOLD FOR THIS EXCEPT THEY HAD ALREADY STOPPED IT BECAUSE IT TURNS OUT IT WASN'T WORKING WELL IN ADULTS. NOW, CLINICAL HOLD. THIS IS THE LANGUAGE. AND UNREASONABLE AND SIGNIFICANT RISK OF ILLNESS OR INJURY. AND AT THIS POINT IN TIME, ALTHOUGH WE MAY GET IT WRONG, I'M NOT SUGGESTING WE ARE ALWAYS RIGHT BUT AS A POLICY MATTER AT THIS THE POINT IN TIME, THE FDIED AGREE THAT SUBPART D SETS A STANDARD FOR WHAT IS REASONABLE RISK IN PEDIATRICS. SO FAILURE TO BE IN COMPLIANCE WITH SUBPART D IS SUFFICIENT REASON FOR PLACING A TRIAL IN CLINICAL HOLD. NOW I WILL SAY THAT THAT THRESHOLD WAS CROSSED SOMEWHERE AROUND 2009-2010 AND I THINK THAT WAS A VERY IMPORTANT WIN IF YOU WILL FOR PEDIATRIC ETHICS WITHIN FDA WHERE PEOPLE BEGAN TO REALIZE THEY HAVE TO PAY CLOSE ATTENTION TO SUBPART D. AND JUST BECAUSE SOMETHING MIGHT BE QUOTE SAFE IN AN ADULT THEY SHOULDN'T JUST SORT OF LET IT GO FORWARD WITHOUT THINKING ABOUT THAT. THERE IS A BE IN OF EXAMPLES AND I WILL SAY THE FIRST TIME I GAVE AN OPINION ABOUT SUBPART D AND THE DIVISION PLACED ON CLINICAL HOLD, WAS A TRIAL SPONSORED BY NIH. I WON'T SAY WHO OR WHAT. ANYWAY, SO LET'S TALK ABOUT LOW RISK AND HIGH RISK PATHWAYS AND WE'LL LEAVE SOME TIME FOR QUESTIONS. SO, LOW RISK PATHWAY AND HIGH RISK PATHWAY. THE IDEA HERE IS IF YOU THINK YOU HAVE SUFFICIENT DATA TO ARGUE SOMETHING IS EITHER MINIMAL RISK -- WE'LL TALK ABOUT THAT. OR MILE PER HOUR INCREASE OVER MINIMAL RISK, THEN YOU DON'T HAVE -- OR A MINIMAL INCREASE -- THEN YOU DON'T HAVE TO WORRY ABOUT THE DIRECT BENEFIT. YOU CAN TAKE THE LOW RISK PATH WAY. BUT YOU NEED DATA ON WHICH TO MAKE THAT ARGUMENT. DO YOU HAVE SUFFICIENT DATA OR NOT? IT'S NOT THAT, WELL I THINK IT IS MINIMAL RISK OR I THINK IT WILL BE MINOR INCREASE. YOU NEED DATA. YOU NEED TO BRING DATA. AND THEN HIGH RISK PATHWAY IS, ABSENT DATA HERE, THEN YOU HAVE TO FIGURE OUT A WAY TO FORMULATE YOUR PROTOCOL OR APPROACH THE TRIAL IN A WAY THAT THAT CHILD IS GETTING DIRECT BENEFIT FROM THAT INTERVENTION. SO IF YOU HAVE GOT A HIGH RISK DRUG FOR EXAMPLE, WHERE THERE IS NO WAY TO ARGUE THAT GIVING IT TO A CHILD IS ONLY SLIGHTLY MORE THAN MINIMAL RISK, YOU'RE GOING TO HAVE TO BEEN HOW TO STRUCTURE THAT TRIAL AND THAT EXPOSURE TO PROVIDE A DIRECT BENEFIT TO THAT CHILD. NOW THIS CAN SOUND SOMEWHAT COUNTERINTUITIVE BUT IT MEANS YOU'RE INCREASING THE RISKS TO THAT CHILD AT THE SAME TIME YOU'RE TRYING TO INCREASE THE BENEFIT TO GET THOSE INTO BALANCE. IF YOU CAN NEVER GET THEM INTO BALANCE, THEN THE QUESTION IS, DO YOU HAVE ENOUGH DATA FROM ADULTS? DO YOU HAVE ENOUGH DATA FROM DISEASE ANIMAL MOD ELSE? THERE ARE CIRCUMSTANCES WHERE THERE ARE NO SUITABLE ADULTS. SO, YOU NEED TO HAVE A GOOD DISEASE ANIMAL MODEL AND WE WILL USE THAT TO ARGUE FOR THE JUSTIFICATION OF PROSPECT OF DIRECT BENEFIT. IS THIS IS THE STANDARD DEFINITION. NOW THE NATIONAL COMMISSION ORIGINALLY PROPOSED THAT THE WORD, OF HEALTHY CHILDREN, SHOULD BE HERE. SO THE NATIONAL COMMISSION WHEN THEY PROPOSED IT, TOOK WHAT IS OFTEN CALLED THE UNIFORM DEFINITION OF MINIMAL RISK. IT IS TRUE. WE GET NERVOUS IF WE, LET'S JUST GO INTO A RISKY NEIGHBORHOOD AND DO IT THERE INSTEAD OF A NON-RISKY NEIGHBORHOOD. I MEAN THERE ARE SERIOUS ISSUES OF SOCIAL JUSTICE WITH THAT APPROACH. NOW GENERALLY, GIVING A DRUG IS NOT MINIMAL RISK SO AT LEAST IN THE FDA, WE ARE USUALLY NOT WORRIED ABOUT WHAT MINIMAL RISK RESEARCH IS BUT THERE IS A LOT OF EXAMPLES OF MINIMAL RISK RESEARCH IN OTHER SETTINGS. NOW, YOU COULD HAVE THIS MINOR INCREASE OVER MINIMAL RISK -- NO DEFINITION OF WHAT THAT MEANS. WE ONCE HELD AN ETHICS SUBCOMMITTEE MEETING AND ONE OF THE MEMBERS WHERE WE WERE TALKING ABOUT WHETHER A CERTAIN PROTOCOL MET A MINOR INCREASE OVER MINIMAL RISK AND SHE SAID, IT'S LIKE SPEEDING. 9 YOUR FINE. 10 YOU'RE MINE. MY WIFE IS CANADIAN AND I TRAVEL TO CANADA A LOT AND I'M ON 81 AND I SET MY CRUISE CONTROL AT ABOUT 73. I'M NOT WILLING TO GO TO 74. THAT'S TOO CLOSE TO 75. BUT IF I CAN GET GO IT TO 72 OR 73 I'M HAPPY THE WHOLE WAY. IF YOU'RE CURES, USUALLY NO STATE POLICE IN PENNSYLVANIA ON 81 ANYWHERE EXCEPT NEAR A CONSTRUCTION SITE. IF THERE IS A SIGN THAT SAYS SLOW DOWN, SLOW DOWN BECAUSE THEY MIGHT BE SITTING RIGHT THERE. BUT NEW YORK STATE MUST HAVE A LOT OF MONEY TO HAVE A LOT OF STATE POLICE OUT. SO, THERE IS A LOT OF STATE POLICE. ONE JUST NORTH OF BINGAL TON, NEW YORK -- BINGHAMPTON -- ONE JUST BEFORE SYRACUSE. I KNOW WHERE THEY ALL HIDE IF YOU'RE TRAVELING 81. SEND ME AN E-MAIL. BUT THERE IS NO DEFINITION OF A MINOR INCREASE OVER MINIMAL RISK. IT'S JUST SLIGHTLY MORE. SO JUDGMENT. NOW, HOW DO WE DEFINE ACCEPTABLE RISK? DAVID TALKED ABOUT THIS THIS IS SORT OF A QUICK SNAPSHOT. RISK IS DEFINED IF YOU HAD TO SAY TELL ME THE RISK, YOU SAY IT'S THE PROBABILITIY AND MAGNITUDE. SO THERE IS SOME SENSE OF HOW OFTEN IT OCCURS AND SOME SENSE OF THE SEVERITY OF IT. BUT THAT DEFINITION KIND OF IMPLIES YOU CAN DO MATHEMATICS AROUND RISKS. YOU CAN'T DO MATHEMATICS. PEOPLE THAT ARE DECISION THEORISTS CAN TRY TO PUT UTILITIES TO DIFFERENT ONES OR POINT 8 ON THIS AND .2 HERE AND TRY TO TURN IT INTO A MATHEMATICAL EQUATION. IT'S VERY DIFFICULT. SO, THE DISVALUE OF THIS HARM OR RISK CAN'T BE QUANTIFIED TO WHERE YOU HAVE A UNIFORM OR COMPARATIVE STANDARD. SO, THE RISK -- IF THERE WAS A TRIAL WELL THERE WERE TWO DRUGS INVOLVED AND ONE RISK OF ONE DRUG WAS STERILITY AND THE OTHER RISK WAS BALDNESS -- WE MAY ALL HAVE VERY DIFFERENT OPINIONS ABOUT WHICH DRUG WE WOULD WANT TO GET. BUT, IT'S NOT LIKE WE DO THAT BY HAVING A SORT OF STANDARD SCALE AND WE PUT THEM ON THAT SCALE AND COMPARE THEM. THE PROBLEM IS ALSO IF YOU DEFINE MINIMAL RISK BY REFERENCE TO DAILY LIFE, IT REDUCES A MORAL EVALUATION IN COMPARISON TO FACTUAL RISKS AND JUST BECAUSE SOMETHING OCCURS DOESN'T MAKE IT MORALLY ACCEPTABLE IN RESEARCH. SO, I DO A LOT OF BICYCLING. IT TURNS OUT THAT IF YOU LOOK AT PERMANENCY ROOM RECORDS, AND CONCUSSION WHICH IS A BIG DISCUSSION -- EMERGENCY ROOM RECORDS -- PARTICULARLY IN ADOLESCENT SPORTS AND ADULTS AS WELL, BICYCLING ACCIDENTS ACCOUNT FOR THE HIGHEST INCIDENTS OF CONCUSSIONS IN AN EMERGENCY ROOM. IF I WANTED TO DESIGN A BETTER HELMET, ARE YOU GOING TO PUT MY HEALTH MET WITH ALL THE SENTENCE SENSORS ON IT ON 12-YEAR-OLD SAY, GO OUT AND CRASH FOR ME? PROBABLY NOT. EVEN THOUGH I COULD ARGUE THAT APPEARS TO BE A RISK OF DAILY LIFE. WOULD YOU ALLOW ME TO TO DESIGN A COURSE, DOWNHILL MOUNTAIN BIKE COURSE THAT HAS ENHANCED DANGER BECAUSE I PUT ALL THE FANCY JUMPS IN IT? YOU MIGHT GET NERVOUS ABOUT THAT. BUT NO THAT'S STANDARD OF CARE. KIDS RIDE DOWNHILLS ALL THE TIME AND I'M EVEN GOING TO WAIVE CONSENT BECAUSE IT'S MINIMAL RISK. THERE IS MORAL JUDGMENT HERE AND WE CAN'T JUST DO THAT. I DON'T THINK DAVID IS ARGUING FACTS ARE VERY IMPORTANT AS A STARTING PLACE, BUT THAT DOESN'T FINISH THE QUESTION. NOW THE OTHER PROBLEM IS THAT THIS MINOR INCREASE OVER MINIMAL RISK REQUIRES KIDS TO HAVE A DISORDER OR CONDITION. NOW THIS IS A VERY CONTROVERSIAL CATEGORY IN THE NATIONAL COMMISSION'S DISCUSSION BECAUSE IT GIVES THE ACTIONER PARENT IMPRESSION THAT IF -- APPARENT -- IF KIDS ARE SICK PUT THEM AT HIGHER RISK. THE RESPONSE FOR THAT WAS, NO. WE ARE JUST SAYING THAT SOMETHING IS SCIENTIFICALLY NECESSARY THAT WE CAN ONLY ANSWER CERTAIN QUESTIONS WITH KIDS WHO HAVE A DISEASE. AND THAT MAY BE TRUE. SO YOU GET THIS DISORDER OR CONDITION IN HERE AND THIS IS THEINS FUTOF MEDICINE'S SUGGESTION. YOU HAVE GOT THAT THEY HAVE A DISEASE OR THEY ARE AT RISK. AND THE WORLD HEALTHY IN MY MIND IS MISLEADING BECAUSE YOU CAN HAVE A CHILD WITH LEUKEMIA AND YOU PUT THEM IN A TRIAL AS A CONTROL GROUP FOR SOMETHING ELSE. THEY ARE HEALTHY RELATIVE TO THE SOMETHING ELSE. SO I DON'T LIKE THE WORD HEALTHY. VACCINE, PEOPLE DOING VACCINE RESEARCH HERE, THEY USE THE WORD HEALTHY ALL THE TIME. BUT IF IT'S MEASLES, KIDS ARE AT RISK FOR MEASLES. SO I PREFER THIS, AT RISK NOTION. BUT I WILL SAY THAT IF THIS SCIENTIFIC NECESSITY IS APPROPRIATE, THERE ARE SITUATIONS WHERE YOU MAY APPROPRIATELY EXPOSE A HEALTHY CHILD TO A MINOR INCREASE OVER MINIMAL RISK IF THEY ARE NECESSARY AS A CONTROL GROUP FOR SOME INTERVENTION THAT YOU'RE DOING. THE PROBLEM IS, YOUR IRB CANNOT APPROVE THAT UNLESS IT GOES TO A FEDERAL PANEL REVIEW. BECAUSE OF THIS DISORDER OR CONDITION. BUT I DON'T THINK IT SUN ETHICAL TO DO THAT. IT JUST MEANS LOCAL IRBs DON'T HAVE THE AUTHORITY TOW APPROVE THAT. SO, I THINK I MENTIONED YOU NEED TO BE ABLE TO HAVE ACCURATE RISK ASSESSMENT. SO YOU NEED DATA. AND IF YOU DON'T HAVE THE DATA, YOU END UP WITH A HIGHER RISK PATHWAY. YOU CAN GET SINGLE DOSE PK STUDIES MAY CONSIDERED LOW RISK BUT LONG-TERM DOSING IS GENERALLY NOT CONSIDERED LOW RISK. AND LET ME GIVE YOU A QUICK EXAMPLE. OVER-THE-COUNTER COUGH AND COLD PRODUCTS. A FEW YEARS AGO THERE WAS A FAIR AMOUNT OF ENERGY EXPENDED AT THIS POINT IT IS DISSIPATED MAINLY BECAUSE A REVISION TO THE FDA'S OVER-THE-COUNTER MONOGRAPH FOR COUGH AND COLD PRODUCTS HAS GONE INTO THE BLACK HOLE OF LEGAL REVIEW. NOT SURE WHEN IT WILL EMERGE. BUT, THERE IS NOT A LOT OF DATA IN SUPPORT OF USING OVER-THE-COUNTER COUGH AND COLD PRODUCTS IN PEDIATRICS. SO COMPANIES WERE ASKED TO DO SINGLE DOSE PK STUDIES. SO THE IDEA HERE IS THAT IS NOT MINIMAL RISK. IT'S A MINOR INCREASE OVER MINIMAL RISK. YOU'RE GIVING KIDS DRUGS. PARENTS DON'T GIVE HEALTHY KIDS DRUGS. IT'S NOT PART OF THE DAILY LIFE. SO THEY HAVE TO HAVE A DISORDER OR CONDITION. BUT THE QUESTION IS, DOES EVERY CHILD GET A COLD? NOW WE ENDED UP COMING UP WITH CRITERIA SYMPTOMATIC, THAT IS EASY BUT IF THEY ARE ASIMPLE MATIC -- ARGUE -- ASYMPTOMATIC -- THIS INCLUDES 80% OF CHILDREN. IT MIGHT EXCLUDE CHILDREN THAT ARE SINGLE CHILD, HOME SCHOOLED THAT DESCRIBES MY BROTHER'S DAUGHTER. I DON'T THINK SHE EVER HAD A COLD FROM WHAT I CAN TELL. I WILL SAY IF THOSE WHO ARE PAYING ATTENTION TO THE USE OF PROBIOTICS AND EXPOSURE IN EARLY CHILDHOOD YOU'RE BETTER OFF IF YOU LET YOUR KID WHO IS ONE, TWO OR THREE PLAY IN THE DIRT AND DO A LOT OF DIRTY THINGS BECAUSE ULTIMATELY THEY'LL END UP WITH LESS ASTHMA AND PSORIASIS. SO THIS IDEA YOU PROTECT CHILDREN AND LET THEM GROW UP TO WHERE THEY CAN DEFEND THEMSELVES, THEY DEFEND THEMSELVES WHEN THEY ARE OLDER BY HAVING BEEN EXPOSED TAINTEDIGENCE. THERE IS A LOT OF DATA COMING OUT ABOUT THAT. -- ANTIGENS. SO THIS IS THE REGULATION. RISK JUSTIFIED BY BENEFIT AND THEN THE RELATIONSHIP IS AT LEAST AS FAVORABLE. YOU HAVE TWO. THE JUSTIFICATION ONE AND THEN THIS COMPARABILITY. SO AGAIN, THE JUSTIFICATION IS A CLINICAL JUDGMENT. WHAT ARE THE DATA? IS THIS BALANCED OR FAVORABLE? COMPLEX JUDGMENT? WE TALKED ABOUT THAT. THE OTHER INTERESTING QUESTION IS WHAT ABOUT TIMING OF PEDA AT RICK STUDIES -- PEDIATRIC STUDIES? WHEN YOU IS THAT RIGHT THE STUDDIE? WHEN YOU HAVE -- WHEN DO YOU START THAT? WHEN YOU HAVE SUFFICIENT DATA TO DRAW THIS CONCLUSION. SO YOU NEED PROOF-OF-CONCEPT EITHER FROM ADULT HUMAN, WHICH I OFTEN SAY IS THE BEST ANIMAL MODEL FOR A CHILD. AN ADULT HUMAN WITH THE SAME DISEASE. OR YOU MIGHT USE ANIMAL DISEASE MODELS. THERE ARE MANY RARE IN-BORN AREAS OF METABOLISM WHERE NO ONE SURVIVES. SO THERE IS NO ADULT TO USE. SO YOU'RE STUCK WITH USING A DISEASED ANIMAL MODEL. SO THIS REQUIREMENT DOESN'T IMPLY THAT YOU HAVE TO COMPLETE ALL YOUR ADULT STUDIES BEFORE PEDIATRIC STUDIES. YOU JUST NEED SUFFICIENT DATA TO MAKE THIS JUDGMENT. AND I OFTEN FIND AT THE FDA, I'M PUSHING PEOPLE TO DO PEDIATRICS BECAUSE WHAT DO I SEE AS A PEDIATRICIAN IF THINGS GET OUT ON THE MARKET IN THE ADULT WORLD, PEDIATRICIANS ARE USING THEM WITHOUT ANY DATA. SO, WE TRY TO PUSH FOR AS EARLY AS POSSIBLE FIRST IN CHILDREN. UNDER 50 .52. CAN YOU INFER SUFFICIENT PROSPECT OF DIRECT BENEFIT FROM ANIMAL STUDY ALONE TO SAY THIS OFFERS SUFFICIENT BENEFIT TO THE JUSTIFY THE RISKS? IS THERE IS A SLIDING THRESHOLD. SO YOU MIGHT HAVE A CHANGE IN STRUCTURE. SO LET'S SAY YOU'RE INTERESTED IN DEMYELINATING DISEASES AND YOU THROW IN STEM CELLS AND YOU CAN SEE THEY REMILE EN 8 THE NERVES. BUT YOU HAVE NO DATA THE IMPULSE GOES THROUGH THAT NERVE ANY FASTER OR THAT THE MOUSE CAN PREVENT HIM OR HERSELF FROM DROWNING BY IMCHOOING ON THE PLATFORM. YOU COULD POTENTIALLY -- PROBABLY AS FUNCTION HERE IN TERMS OF ACTIVITY ON THE PART OF THE ANIMAL MODEL WE ARE WILLING TO APPROVE EFFICACY ON THE DISEASE ANIMAL MODEL ALONE. AND OFTEN WE ARE FOR IN THIS SETTING FIRST IN CHILDREN AND RARE METABOLIC INBORN DISEASE. WE ARE IN THIS AREA. WE WON'T EVER HAVE ADULT DATA. SOMETHING THAT HAS TO BE DEVELOPED. HOW DO YOU DO THAT? NOW, THE IMPORTANT ISSUE HERE THEN GOES TO DOSE. IN ANIMAL TOXICOLOGY, THERE IS NO ADVERSE EFFECT LEVEL SO INCREASE IN THE ANIMAL MODEL AND FIND WHAT IS THE DOSE AT WHICH YOU GET UNACCEPTABLE TOXICITY? AND THEN THAT WOULD DEFINE THE DOSE BEFORE YOU GOT THAT UNACCEPTABLE TOXICITY. THE CHALLENGE IS, YOU NEED NOT ONLY TO LOOK AT THIS NOEL BUT WHICH COULD BE THE SAFE STARTING DOSES BUT YOU HAVE TO LOOK AT THIS NOTION OF WHAT THE MAXIMUM STARTING DOSE MIGHT BE. YOU HAVE TO OFFER A PROSPECT OF DIRECT BENEFIT. SO, EVEN IF BASED ON ADULT DATA YOU MIGHT START LOW AND WORK YOUR WAY UP, COUNTERINTUITIVELY YOU MIGHT HAVE TO START WITH A HIGHER DOSE TO OFFER THE POSSIBILITY OF BENEFIT WHEREAS AN ADULT YOU MIGHT NOT. IT'S VERY IMPORTANT WHEN WE GET THESE KINDS OF CONSULTATIONS AND CLINICAL PHARMACOLOGISTS TO SAY BASED ON THIS ANIMAL MODEL, IT COULD BE A NON HUMAN PRIMATE OR MAYBE A DOG OR SOMETHING BUT IF IT'S A RAT OR MOUSE, YOU'RE SAYING THIS IS WHAT THEY GAVE TO THE RAT OR MOUSE. HOW DO YOU DECIDE WHAT TO GIVE TO A CHILD? NOW A SHAM PROCEDURE DOESN'T OFFER ANY PROSPECT OR DIRECT BENEFIT. SO THERE ARE TWO TYPES OF RISKS FOR PLACEBO. AGAIN, THE FIRST IS THE RISK OF THE INTERVENTION ITSELF. AND MOST PLACEBOS ARE MINIMAL RISK. THERE ARE PROCEDURES THAT ARE NOT MINIMAL RISK. SO FOR EXAMPLE, IF A DRUG NEEDS TO BE ADMINISTERED INTO THE SPINAL FLUID TO BE EFFECTIVE, YOU WANT TO DO A BLINDED CONTROL. SO TRIALS IN SPINAL MUSCULAR ATROPHY TYPE I WHERE WE ARE DOING A SHAM LUMBAR PUNCTURE. THE PARENT IS NOT IN THE ROOM. THE PERSON DOING IT KNOWS THEY ARE NOT PUTTING THE NEEDLE IN AND THE CHILD IS GETTING A LITTLE WHIFF SO WHEN THE CHILD COMES OUT YOU KNOW THE PARENTS WILL START COMPARING NOTES AND IF HALF OF THE PARENTS SAID MY CHILD CAME OUT WITH NO DIFFERENCE IN TERMS -- I KNOW HE DIDN'T GET ANY ANESTHESIA, THEN THE BLIND WILL BE BROKEN. SO A WHIFF, TWO MILLIGRAMS AND YOU WOULDN'T REMEMBER ANYTHING SO ABOUT A MILLIGRAM. SO THOSE THAT HAD PROCEDURES BUT THEN THE OTHER IS THE RISK OF HARM FROM NOT RECEIVING PROVEN OR EFFECTIVE TREATMENT. AND THE ARGUMENT IS THAT THIS RISK MUST BE NO GREATER THAN A MINOR INCREASE OR MINIMAL RISK: YOU CAN HOLD KNOWN EFFECTIVE TREATMENT WHICH IF YOU WERE A STRICT EQUIPOISE PERSON YOU CAN'T DO BUT WE ARE WILLING TO DO THAT IF THE RISK OF DOING THAT IS NO HIGHER THAN THIS RISK WE ALLOW THE LACK OF BENEFIT TO PROVIDE. AND A LONGER DISCUSSION AND I THINK THIS IS CONSISTENT WITH THE INTERNATIONAL CONFERENCE ON HARMONIZATION AND CHOICE OF CONTROL GROUP AS WELL AS THE 2013 DECLARATION OF HELL SINKY WITH A BIT OF A HIGHER STANDARD. BUT THAT WOULD BE A LONGER CONVERRIZATION. WHAT IS THE RISK? ONE INJECTION? INTRAMUSCULAR? FOR HOW LONG? ONE DAY, 5 DAY,, 7 DAYS. I TOLD YOU WE DON'T AGREE TO CENTRAL CATHETERS. SHAM SURGERY GENERALLY NOT DONE. HERE IS TWO EXAMPLES. ONE YEAR DUMMY DUMMY STUDY FOR MS. TO THE HAS TO BE A DUMMY DUMMY. WE HAVE AB APPROVED TREATMENT THAT IS ORAL SO MAYBE A NEW ORAL COULD BE AGAINST THE ORAL. BUT A DUMMY DUMMY MEANS HALF OF THESE KIDS ARE GOING TO BE RANDOMIZED TO GETTING INJECTION OF PLACEBO EVERY WEEK FOR A YEAR. IS THAT IS THAT OKAY? THIS GOES BACK TO REGULATORY BIOETHICS. IN 1993, THERE WAS A TWO YEAR PLACEBO-CONTROLLED TRIAL USING DAILY INJECTIONS OF HUMAN GROWTH HORMONE. AND THEY HAD A PLACEBO GROUP. AND IT TURNS OUT GROWTH HORMONE CAN BE STIM LATED BY INJECTIONS AND SO IT WAS IMPORTANT TO HAVE THAT GROUP. THIS IS IN THE DARK AGES OF RESEARCH ETHICS AND THIS WENT TO A PANEL OF OF WHICH NIH PUT IT TOGETHER AND THAT PANEL COULDN'T AGREE. COULDN'T AGREE THAT THIS WAS MORE THAN A MINOR INCREASE OVER MINIMAL RISK. SO, I TAKE THIS TO MEAN IF THIS KIND OF STUDY WAS PROPOSED, EVEN IF I SAY, THAT IS STRETCHING IT A BIT, SINCE THIS PANEL OF PEOPLE MANY OF WHOM I KNOW COULDN'T DECIDE. SO THERE IS WHITE AND BLACK AND IN BETWEEN. IN MY ROLE, YOU HAVE TO TAKE THAT GRAY AND DIVIDE IT INTO BLACK AND WHITE. I APPRECIATE THAT. BUT AT THE FDA, IF I SAID IT'S BLACK OR WHITE, REMEMBER CLINIC WILL HOLD. SO IF SOMETHING IS GRAY, YOU MIGHT SAY IN OUR OPINION WE MAY NOT APPROVE THIS. WE MAY ONLY FIND NOW WITHIN NIH GOING TO ONE CENTRAL IRB AND YOU GUYS ARE ELIMINATING THE POSSIBILITY OF PLAYING THAT GAME ANYMORE. I WOULDN'T SAY TO FDA WE COULD PUT THIS ON CLINICAL HOLD. NOW HERE IS AN EXAMPLE THAT WOULD CONSIDER ACCEPTABLE. YOU HAVE THREE INJECTIONS OF PLACEBO. NOW WE WOULDN'T SAY IT DOES BUT THREE INJECTIONS NOT THAT BIG A DEAL. HERE IS ANOTHER EXAMPLE OF ENRICHMENT DESIGN WITH RANDOMIZED WITHDRAWLS. YOU TAKE CLINICAL RESPONDERS AND RANDOMIZE THESE SO THAT IS ENRICHMENT TO ENRICH FOR CLINICALLY AND RANDOMIZE NEEDS TO WITHDRAWAL SO THEY GO TO THE DOSE THEY ARE ON. AND THE ENDPOINT IS A FLAIR WITH WITHDRAWAL AND TREATMENT AND THE IDEA HERE IS THAT SINCE YOU CAN RECAPTURE THEIR THERAPEUTIC RESPONSE, AT THIS PERIOD OF TIME, TO BE OFF OF ACTIVE TREATMENT IS A MINOR INCREASE OVER MINIMAL RISK. THAT IS HOW -- AND THIS IS DONE FOR HYPERTENSION AND USED FOR THESE FOUR DRUGS. THERE WAS ONE DRUG THAT WAS USED A STANDARD CONCURRENT PARALLEL GROUP DESIGN BECAUSE THERE WAS FEARS, TURNS OUT TO BE UNFOUNDED THAT YOU WOULD NOT BE ABLE TO REINDUCE CLINICAL RESPONSE. IT TURNED OUT THAT WASN'T THE CASE BUT THERE WAS ONE THAT DID A CLASSIC RANDOMIZED WITHDRAWAL TRIAL. THAT IS AN EXAMPLE WE WOULD SAY NOW -- IT IS LIMITED IN SCOPE. A VALID TEST OF A KNOWN HYPOTHESES BUT YOU LOSE THINGS BY DOING THIS KIND OF DESIGN. IT OVER ESTIMATES DRUG RESPONSE RATE AS IT INCLUDES PLACEBO RESPONSE BUT YOU COULD ARGUE THAT IS NOT A PROBLEM BECAUSE IN CLINICAL SETTINGS YOU'RE COMBINING. SO THAT'S PROBABLY NOT A BIG DEAL. BUT, WHAT IT ALSO ELIMINATES IS YOU HAVE GOT NO PLACEBO-CONTROLLED SAFETY DATA. SO INTERPRETING THE SAFETY DATA BECOMES MORE DIFFICULT. SO I HAVE COVERED THESE TOPICS AND I THINK I HAVE MAYBE 10 MINUTES FOR SOME QUESTIONS. [ APPLAUSE ] IT'S WORTH A SHOT. SO THE SLIDING SCALE IN SOME SENSE THE LEVEL OF EVIDENCE THAT YOU WOULD REQUIRE, TO SOME EXTENT IS SHAPED BY THE CONTEXT OF THAT CHILD'S DISEASE. SO A STRUCTURE WOULD LIKELY NOT GET IT. BUT IN TERMS OF FUNCTION, THERE CAN BE MANY WAYS OF DOING THAT AND ONE OF MY MAIN COMPLAINTS ABOUT PEOPLE, THE TOXICOLOGY IS OFTEN THEY'LL TAKE A DISEASE MODEL AND THEN JUST SACRIFICE AND LOOK AT HISTOLOGY AND TOXICOLOGY AND NOT TAKE IT TO A FUNCTIONAL ENDPOINT. LIKE IF IT'S A MOUSE MODEL, CAN THEY WALK THE MAZE FASTER OR SWIM TO GET ON THE PLATFORM AND KINDS OF TESTS YOU DO. DO THEY SURVIVE MORE SO YOU DON'T SACRIFICE THEM. YOU LET THEM LIVE AND DIE NATURAL. THE ANIMAL RULE WOULD BASICALLY SAY -- LIKE THE EXTRAPOLATION I MENTIONED IN PEDIATRICS. IF YOU CAN SHOW THAT THE COURSE OF THE DISEASE IN RESPONSE TO TREATMENT IN THE ANIMAL IS WHAT YOU WOULD PREDICT IN THE HUMAN, THEN THERE ARE INTERVENTIONS LET'S SAY FOR ANTHRAX, THERE IS ONE THAT SAY MONOCLONAL APPROVED FOR ANTHRAX IN ADULTS AND IN CHILDREN BASED ON PK MODEL OR DATA IN HEALTHY ADULTS. SO THEY GAVE IT AND GOT PK DATA AND ANIMAL DATA HAD TO BE OBVIOUSLY EXPOSURE TO THE ANIMALS TO ANTHRAX AND THEN THEY HAD TO SHOW THAT THE CLINICAL HISTORY OF THAT WAS SIMILAR TO WHAT YOU COULD TELL WITH ANTHRAX IN HUMANS BASED ON THE LIMITED HUMAN DATA YOU HAD. AND THEN THE INTERVENTION OF THE TESTED IN THAT ANIMAL MODEL ENOUGH TO SEE RANDOMIZED CONTROL TRIALS. SO BASICALLY YOU'RE REPLACING THE HUMAN WITH THE ANIMAL ASSUMING THAT THAT EXTRAPOLATION IS APPROPRIATE. SO THAT IS SORT OF THE ANIMAL RULE. SO VERY IMPORTANT IN MEDICAL COUNTERMEASURES. >> OTHER QUESTIONS FOR SKIP? LAST CHANCE. OKAY. TAKE A BREAK. 15 MINUTES. [ APPLAUSE ] >> PROMOTE AWARENESS AND ATTENTION TO THE IMPORTANCE OF DOING RESEARCH WITH PREGNANT WOMEN THAN ANYBODY. WE ARE LUCKY TO HAVE MAGGIE WITH US TODAY. >> THANK YOU VERY MUCH. GOOD MORNING, EVERYONE. IT'S SO WONDERFUL TO BE HERE. LET ME START BY SAYING AS CHRIS MENTIONED, I'M UP THE STREET AT GEORGETOWN UNIVERSITY IN WASHINGTON, D.C. I'M TRAINED AS A PHILOSOPHER BUT ONE OF MY PASSIONS IS CLINICAL RESEARCH ETHICS AND I WAS LUCKY ENOUGH TO HAVE TWO DIFFERENT STINTS HERE AT THE NIH IN THE DEPARTMENT OF BIO ETHICS WITH CHRIS AS A VISITING SCHOLAR WHERE I WORKED ON ISSUES LIKE THIS. SO I WANT TO BEGIN BY SAYING THIS IS A LITTLE BIT OF COMING HOME FOR ME. I ALWAYS LOVE COMING BACK. AND YOU WILL SEE MY ADMIRATION FOR THE NIH THROUGH THE TALK. SO AS CHRIS MENTIONED, WE ARE TURNING OUR ATTENTION TO REACH WITH PREGNANT WOMEN. SO OFTEN, WHEN WOMEN ARE EXPECTING A CHILD AND ARE PREGNANT, AT LEAST IF THEY DECIDED TO CONTINUE THE PREGNANCY, IT'S A TIME OF JOY AND ANTICIPATION. PERHAPS SWOLLEN ANKLES BUT JOY AND ANTICIPATION. BUT FOR A SIGNIFICANT PROPORTION OF PREGNANT WOMEN, BOTH IN THE U.S. AND GLOBALLY, PREGNANCY IS COMPLICATED BY SEVERE DISEASE AND ILLNESS. CARDIOVASCULAR DISEASE, AUTOIMMUNE DISORDERS, CANCERS, SEVERE PSYCHIATRIC DISORDERS, HIV, TB, MALARIA. IN THE UNITED STATES ALONE, 500,000 WOMEN EVERY YEAR HAVE PREGNANCIES COMPLICATED BY SIGNIFICANT ILLNESS. AND WHEN WE LOOK GLOBALLY, IT'S OF COURSE IN THE MILLIONS. SO THIS IS A POPULATION THAT HAS SIGNIFICANT CLINICAL NEED OF SAFE AND EFFECTIVE MEDICATION. BUT WHEN WE TURN TO THE EVIDENCE BASE THAT WE HAVE AVAILABLE TO US WITH MEDICINE WHEN USED IN PREGNANCY, WE FIND THAT IT IS ALMOST ZERO. SO GUESS HOW MANY MEDICATIONS ARE APPROVED BY THE FDA, WONDERFUL SKIP? BY THE FDA FOR USE IN PREGNANCY? SOMEBODY GIVE ME A GUESS. ZERO. 100. THANK YOU FOR BEING HELPFUL. CLOSER TO THE FIRST THAN THE SECOND? 54. IT'S A DOZEN. AND THEY ARE ACTUALLY ALL MEDICATIONS FOR USE IN EITHER PREVENTING PRETERM LABOR OR SPEEDING UP LABOR OR CONTROLLING PAIN DURING LABOR. THAT IS, THEY ARE ALL OBSTETRICAL TREATMENTS. BUT FOR THE WOMAN WHO IS PREGNANT BUT ALSO HAS LINE UP US OR CARDIOVASCULAR DISEASE OR PSYCHOSIS OR AIDS, THAT'S NOT MUCH HELP. NOT TO SAY THAT PREGNANT WOMEN DON'T USE MEDICATION OR NEED TO USE MEDICATION. SO, AGAIN HERE IN THE UNITED STATES, TWO-THIRDS OF WOMEN WHO ARE PREGNANT USE 4-5 PRESCRIPTION MEDICATIONS AT SOME POINT DURING THE PREGNANCY. AND AGAIN, WHEN YOU TAKE THE NUMBER OF WOMEN WHO FACE ILLNESS WHILE PREGNANT, YOU UNDERSTAND WHY. IT'S NOT A GOOD IDEA TO LEAVE A WOMAN WITH CANCER UNTREATED FOR 9 MONTHS OF MEG SEE. NOT GOOD FOR HER. PROBABLY NO THE GOOD FOR THE CHILD WHO MIGHT BE OVER ANED. -- ORPHANED. IT IS NOT GOOD FOR A WOMAN WITH SEVERE ASTHMA NOT TO BE MEDICATED. NOT GOOD FOR HER AND NOT GOOD FOR THE BABY. LOW OXYGENATED BLOOD NOT A GOOD IDEA. NOT A GOOD IDEA FOR A WOMAN WITH DIABETES TO BE UNMEDICATED DURING PREGNANCY NOT ONLY FOR HER -- NOT JUST TALKING ABOUT THE HEALTH AFFECTS IT MIGHT HAVE HAD HER FOR 9 MONTHS BUT IF YOU LEAVE A IMPORTANT ILLNESS UNTREATED FOR ALMOST A YEAR, YOU CAN HAVE SEQUELAE OF UNTOWARDS AFFECTS FOR THE REST OF THE WOMAN'S LIFE. AND THEN ALSO NOT GOOD FOR THE FETUS. WITH DIABETES WE KNOW BLOOD SUGAR LEVELS CAN BE TOXIC FOR THE FETUS. THEY ARE CALLED A TERAT JEN BY SOME. SO FOR BOTH OF THE HEALTH AND THE WOMAN AND THE CHILD WHO WILL BE BORN, WE NEED SAFE AND EFFECTIVE MEDICATIONS. KIND OF SOUNDS LIKE COMMON SENSE. BUT IN FACT, PREGNANT WOMEN ARE WHAT SOME PEOPLE CALLED THE LAST SIGNIFICANT THERAPEUTIC ORPHAN. WE DON'T HAVE A REACH BASE. WE DON'T HAVE AN EVIDENCE BASE FOR HOW TO TREAT THEM. AND INSTEAD WHAT WE DO IS AS IT WERE, SHIFT THE RISK AWAY FROM THE RESPONSIBLE, HIGHLY REGULATED CONTEXT OF CLINICAL RESEARCH, SHIFTING IT INTO THE CLINIC. WHERE THE WOMAN WHO IS ILL HAS TO HAVE A CONVERSATION WITH HER PROVIDER AND BOTH OF THEM BURDENED BY THE FACT THAT THEY HAVE TO MAKE VERY IMPORTANT DECISIONS WITH LARGE IMPLICATIONS FOR WOMAN AND CHILD IN THE ABSENCE OF EVIDENCE. IN OTHER WORDS, THEY ARE TOLD TO GUESS. NOW THE GOOD NEWS IS, THAT ATTENTION IS STARTING TO BE PAID TO THIS ISSUE SORT OF LIKE HOW IT HAPPENED WITH THE PEDIATRICS COMMUNITY. WHEN SKIP WAS JUST NOW TALKING TO YOU, IF HE TALKED TO YOU ABOUT THE STATE OF PEDIATRICS RESEARCH 20 YEARS AGO, IT WOULD HAVE SOUNDED LIKE WHAT I'M SAY BEING PREGNANT WOMEN. CHILDREN WERE RESEARCH ORPHANS AND EVERYBODY JUST KEPT SAYING, CHILDREN ARE REALLY JUST SHORT ADULTS. SO LET'S JUST EXTRAPOLATE AND DOSE THEM SMALLER AND THEN THEY REALIZED CHILDREN ARE NOT JUST SHORT ADULTS. THEIR PHYSIOLOGIES ARE DIFFERENT AND OFTEN SALIENT WAYS AND IF THEY ARE GOING TO USE MEDICATIONS, WE NEED TO DO RESEARCH WITH THEM. THE MANTRA BECAME IN PEDIATRICS, PROTECT CHILDREN THROUGH RESEARCH NOT FROM RESEARCH. AND I AM HAPPY TO SAY THAT UNDERSTANDING IS NOW FINALLY COMING TO THE SITUATION WITH PREGNANT WOMEN. SO THERE IS A VANGUARD OF PROGRESSIVE RESEARCHERS, INCLUDING MANY AT THE NIH, BUT ALSO AROUND THE WORLD, WHO ARE DOING INCREDIBLY IMPORTANT, HIGHLY ETHICAL, HIGHLY RESPONSIBLE RESEARCH WITH PREGNANCY. SO WHAT I WANT TO TALK WITH YOU ABOUT IS, WHAT THE ETHICS LOOKS LIKE AND SKIP SAID, WHAT THE REGULATORY BIOETHICS LOOKS LIKE. AND GIVE YOU SOME CASE EXAMPLES OF HOW CREATIVE TRIAL DESIGNS CAN REALLY HELP US TO GET THAT NEEDED EVIDENCE BASE WHILE BEING VERY PROTECTIVE OF THE WOMAN AND THE FETUS'S HEALTH AS WE SHOULD BE. SO, LET'S START WITH THAT IDEA OF REGULATORY BIOETHICS. SO IN THE UNITED STATES THE REGULATIONS THAT ARE RELEVANT HERE ARE SUBPART B. THAT DETAIL WHAT ADDED PROTECTIONS WE NEED TO HAVE IN PLACES IF WE ARE GOING TO RESEARCH WITH PREGNANT WOMEN. STILL INFORMED CONSENT AND STRONG REVIEWS SO ANY RISK IS MINIMIZED, BUT THEN WE'LL ADD A LAYER OF PROTECTIONS AND EXTRA REGULATIONS IF YOU'RE CONTEMPLATING RESEARCH WITH PREGNANT WOMEN. NOW AS CHRIS MENTIONED, WHEN SHE INTRODUCED ME, THIS IS BECAUSE IN THE REGS, PREGNANT WOMEN ARE CATEGORIZED AS A VULNERABLE POPULATION. NOW I DON'T KNOW HOW THAT HITS YOUR EARS BUT WHEN YOU FIND THAT THE REGS DEFINED VULNERABLE POPULATION AS A POPULATION THAT HAS DIMINISHED CAPACITY TO CONSENT, YOU MIGHT REALIZE THAT WAS A PROBLEMATIC MOVE THEY MADE WITH PREGNANCY. CONTRARY TO WHAT SOME PEOPLE THINK, PREGNANCY ITSELF DOES NOT DIMINISH YOUR RATIONAL OR ABILITY TO CONSENT OR MAKE YOU MORE OPEN TO COERCION AND UNDUE INFLUENCE. INSTEAD, CLEARLY WHAT THE REGULATIONS WERE TRYING TO GET AT IS UNDERSTANDING AND EMPHASIS THAT PREGNANT WOMEN IN RESEARCH WITH THEM INTRODUCED MORAL COMPLEXITIES AND IN FACT THAT IS NOW WHAT THE WORLD RESEARCH COMMUNITY PREFERS AS A WAY OF DESCRIBING. PREGNANCY NOT A VULNERABLE CONDITION WITH RESPECT TO RESEARCH BUT IT IS A COMPLEX CONDITION. AND I THINK WE CAN ALL AGREE THAT IF WE ARE CONTEMPLATING DOING RESEARCH WITH PREGNANT WOMEN, WE WANT TO HAVE ADDED REGULATIONS, ADDED CARE AND ADDED SCRUTINY. NOT BECAUSE THE PREGNANT WOMAN IS LESS RATIONAL OR CAN'T CONSENT TO THE RISKS SHE IS UNDERTAKING. THAT IS JUST STANDARD RESEARCH. BUT BECAUSE IN THIS CASE, THERE IS ANOTHER ENTITY INVOLVED, THE FETUS, WHOSE HEALTH COULD BE SIGNIFICANTLY IMPACTED AND CAN'T CONSENT. NOW HERE I WANT TO PAUSE FOR A MOMENT AND SIGH, I REALLY DO BELIEVE -- AND SAY I REALLY DO BELIEVE THAT THIS DESIRE FOR WHAT SOME PEOPLE WILL CALL FETAL PROTECTION, IS INCREDIBLY IMPORTANT AND I WANT TO ASSURE YOU IN MY VIEW, IT'S A CONSENSUS ISSUE. SOMETHING YOU CAN BELIEVE IN WHOLE HEARTEDLY WHATEVER YOUR VIEWS FOR INSTANCE ABOUT ABORTION, WHATEVER YOUR VIEWS FOR INSTANCE ABOUT WHAT WE'LL CALL THE MORAL STATUS OF THE EM BEEO OR FETUS. IN THE REGS SAYING THERE SHOULD BE ADDED PROTECTIONS, THEY ARE NOT TAKING A SIDE ON THE FETUS BEING A CONSTITUTIONAL PERSON EQUIVALENT TO YOU AND I SAYING YES OR NO. INSTEAD WE ARE TALKING ABOUT RESEARCH IN PREGNANCY THAT WILL BE CONTINUED AND THERE WILL BE A CHILD WHO WE ALL AGREE HAS MORAL STATUS AND IS A MEMBER OF OUR COMMUNITY. AND WHAT HAPPENS IN UTERO CAN SIGNIFICANTLY AFFECT THAT CHILD'S HEALTH. AND SINCE THE CHILD CAN'T RETROSPECTIVELY CONSENT TO HAVING ABOUT KNOW IN RESEARCH, WE WANT TO SAY LET'S INTRODUCE ADDED PROTECTIONS THAT MAKE SURE THAT WE ARE ASKING NOT JUST THE WOMAN TO WHAT SHE WOULD CONSENT TO BUT OUT OF APTING TO PROTECT THE FUTURE CHILDA SO MORALLY COMPLEX AND NOT VULNERABLE AND IMPORTANT MORALLY COMPLEX WHATEVER YOUR VIEWS ABOUT FETAL STATUS PERSON HOOD AND THE LIKE. SO SUBPART B CENTRALLY INVOKE A KEY DISJUNCTIN THE ANALYSIS OF WHEN RESEARCH WITH PREGNANT WOMEN IS PERMISSIBLE AND IT MIMICS WHAT THE STRUCTURE IS WITH PEDIATRICS RESEARCH. SO THE DISTANCE OF EITHER-OR. ONE PATHWAY AS HE PUT IT, THE LOW RISK PATHWAY F IT'S RESEARCH THAT DOES NOT CARRY OUT EVEN THE PROSPECT OF DIRECT BENEFIT TO THE WOMAN OR THE FETUS, IT IS VERY EARLY-STAGE RESEARCH, THEN THE RESEARCH KEPT IMPOSE ANY MORE THAN MINIMAL RISK ON THE FETUS. VERY MUCH. IN PREGNANCY WE DON'T HAVE THAT ADDED CATEGORY OF THIS IS A MOUTHFUL -- MINOR INCREASE OVER MINIMAL RISK THAT PEDIATRICS DOES. AND SIMPLY BECAUSE WE ARE NOT IN THE SAME PLACE LEGISLATIVELY WITH IT. IF IT DOESN'T HOLD OUT THE PROSPECT OF DIRECT BENEFIT TO THE WOMAN OR THE FETUS THEN NO MATTER WHAT THE WOMAN MIGHT BE WILLING TO DO BY VOLUNTEERING, THE RESEARCHERS AREN'T ALLOWED TO IMPOSE MORE THAN MINIMAL RISK ON THE FETUS. THE OTHER DISJUNCT, IF THE REACH HOLD OUTS THE PROSPECT OF SOME DIRECT MEDICAL BENEFIT TO THE WOMAN OR THE FETUS, THEN WE DO THE TRADITIONAL BALANCING OF MAKING SURE THE RISK IS REASONABLE RELATIVE TO THAT PROSPECT OF BENEFIT. A KEY ISSUE ON THIS SIDE THAT WE'RE GOING TO LOOK AT IS, UNLIKE PEDIATRICS CASE OR THE USUAL CASE OF RESEARCH WITH ONE OF YOU, NOTICE IT SAID IT BEARS THE PROSPECT OF DIRECT BENEFIT TO EITHER THE WOMAN OR THE FETUS, THEN YOU CAN JUSTIFY MORE THAN MINIMAL RISK TO THE FETUS AND THAT IS A REALLY INTERESTING COMPLEXITY WE ARE INTO. BUT LET'S TAKE THESE ONE AT A TIME AND I WANT TO START WITH THE ONE THAT IS ABOUT MINIMAL RISK OR WHAT SKIP CALLED LOW-RISK OPTION. AS SKIP SAID, AND DAVE WENDLER BEFORE HIM, THE CONCEPT OF MINIMAL RISK IS A VEXING ONE. IT'S NOT CLEAR IT MAKES ANY SENSE AT ALL AS THE REGULATORS DEFINE IT, THIS IDEA OF THE RISKS OF ENCOUNTERED IN EVERYDAY LIFE OR THE BURDENS -- IT SOMETIMES PUTS THE BURDENS YOU MIGHT ENCOUNTER IN A PHYSICAL EXAMINATION. THOSE ARE JUST A STRANGE WAY TO INDEX WHAT WE THINK IS MORALLY RESPONSIBLE AND ACCEPTABLE TO IMPOSE TO A CREATURE THAT CAN'T CONSENT. EVERYDAY LIFE INCLUDES THINGS LIKE KIDS PLAYING FOOTBALL. TERRIBLE. WHOSE EVERY DAY IF HOW DO WE FIND OUT THE UNIFORM CHILD OR FETUS AND ITS LEVEL OF EVERY DAY RISK? DOES THAT EVEN MAKE SENSE? SO IT'S EXTREMELY VEXING AND STUDIES HAVE SHOWN WHEN INSTITUTIONAL REVIEW BOARDS ARE ASKED WITH A BUNCH OF SCENARIOS WHETHER IT'S A FETUS OR CHILD OR COMPETENT ADULT, WHAT DIFFERENT INTERVENTIONS COUNT AS MINIMAL RISK, SCATTER PLOT. THEY ARE ALL OVER THE PLACE. SO IN THIS SENSE, RESEARCH WITH PREGNANT WOMEN INHERITS THE COMPLEXITY OF ANY OTHER RESEARCH WHERE WE WANT TO INVOKE THE CONCEPT OF MINIMAL RISK. AGAIN WITH PEDIATRICS, PART OF WHAT THEY DID BECAUSE THEY ENCOUNTERED THIS ISSUE OF WE NEED TO EXPAND THE RESEARCH WITH CHILDREN IN ORDER TO PROTECT CHILDREN FROM THE RISKS OF USING MEDICINE IN THE CLINIC THAT DON'T HAVE AN EVIDENCE BASE. THEY MADE A MORE GENEROUS STANDARD AND SAID, YOU CAN ALSO DO RESEARCH THAT OFFERS NO PROSPECT OF DIRECT BENEFIT IF IT'S MINIMAL RISK OR MINOR INCREASE OVER MINIMAL RISK. PREGNANCY WE ARE STILL STUCK WITH THE SUPER CONSERVATIVE VERSION THAT WE DON'T KNOW HOW TO INTERPRET ANYWAY. I DON'T WANT TO SPEND MUCH TIME THEN ON TRYING TO ADJUDICATE WHAT MINIMAL RISK LOOKS LIKE BECAUSE IT IS KNOWN EVEN OUTSIDE OF THE CONTEXT OF PREGNANCY AS CRAZY MAKING. WHAT I DO WANT TO SAY IS THERE ARE REALLY CREATIVE AND EFFECTIVE WORK AROUND THAT AGAIN VANGUARD RESEARCHERS ARE USING IN EARLY STAGE PREGNANCY RESEARCH WITH PREGNANT WOMEN WHEN WE DON'T KNOW ENOUGH YET OR NOT GIVING A BIG ENOUGH DOSE TO CLAIM PROSPECT OF DIRECT BENEFIT. THAT NONETHELESS STAYS AWAY FROM SORT OF THOSE CHOPPY WATERS OF MINIMAL RISK. LET ME JUST GIVE YOU TWO EXAMPLES. SO LET'S SAY AN EXAMPLE FROM HIV, A NEW ANTI-RETROVIRAL CAME ONBOARD THAT WAS PRODUCING REALLY, REALLY STELLAR RESULTS IN RECALLS TRENT HIV CASES IN ADULTS AND IT LOOKED LIKE IT WAS GOING TO BE A REALLY IMPORTANT DRUG TO USE WITH PREGNANT WOMEN. OF COURSE WE REALLY WANT GOOD MEDICINE TO TREAT HIV IN PREGNANCY BOTH FOR THE SAKE OF THE WOMAN AND TO KEEP FROM TRANSMITTING TO THE FETUS. RIGHT? ANYWAY, NEW MEDICATION GOOD POSITIVE RESULTS IN THE STANDARD ADULT POPULATION. BUT WE KNOW THAT THE PREGNANT BODY CAN ACT AS A WILDCARD WITH THE PHARMACOKINETICS AND DYNAMICS OF A DRUG. ONE RESEARCHER CALLED THE MATERNAL FETAL PLACENTAL INFRASTRUCTURE. IT'S JUST REALLY COMPLICATED. QUICK EXAMPLE. THERE WAS ONE STUDY DONE WHERE IN THE CLINIC SOME WOMEN, JUST A FEW, WITH AN AGGRESSIVE CANCER, WERE HAVING TO BE ON CHEMO WHILE PREGNANT. HAD TO BE. DIDN'T HAVE A CHOICE. AND THEY DID THE BLOOD DRAWS ON THE CHEMO THERAPEUTIC REGIME, AND IT TURNED OUT THIS PARTICULAR CHEMO, YOU KNOW THERE ARE SO MANY. BUT THIS PARTICULAR ONE, IT WAS BEING METABOLIZED SO QUICKLY BY THE PREGNANT BODY THAT IT WAS NEVER ACHIEVING THERAPEUTIC RESULTS, EVEN AS IT DID CROSS THE PLACENTAL BARRIER SO THE FETUS IS GETTING ALL THE TOXICITIES. SO DOING BASIC PK/PD STUDIES IN THE PREGNANT COULD IS UNBELIEVABLY IMPORTANT. BUT NOTICE IF WE WERE TO DO THE STANDARD SORT OF APPROACH TO HOW DO YOU DO PK/PD, IT'S A PHASE I STUDY. WE'LL TRY TO MINIMIZE THE DOSE WE GIVE YOU BECAUSE IT'S AN EARLY PHASE AND ALL WE ARE DOING IS TESTING FOR HOW YOUR BODY IS REACTING TO IT AND IT'S REACTING TO YOUR BODY. SO IT'S A NO PROSPECT OF DIRECT BENEFIT TRIAL BUT YOU'RE A GROWNUP AND YOU CAN CONSENT AND YOU'RE DOING IT AS A VOLUNTEER. IT'S USUALLY MORE THAN MINIMAL RISK SO HOW DO WE DO THAT WITH PREGNANCY IN WITH THIS HIV DRUG THE PROPOSAL IS MADE TO DO INGLE DOSE INJECTION OF THIS IN A PREGNANT WOMAN WHO WAS HIV POSITIVE, AND AN IRB WAS DIVIDED. THE MAJORITY OF THEM THOUGHT THAT WAS JUST MINIMAL RISK AND MINORITY SAID IT IS MORE THAN MINIMAL AREISK AND THAT WAS ENOUGH TO STOP THE STUDY. BUT HERE IS WHAT THEY DID. THEY DIDN'T GIVE UP. THEY SAID LET'S DO OPPORTUNISTIC PK STUDIES. SO IF -- IT MEANS YOU HAVE TO WAIT. UNTIL THE DRUG IS BEING USED BY PREGNANT WOMEN OUT IN THE CLINIC. SO THERE A TRANSFER OF RISK. WE ARE GOING TO LET THE DOCTOR AND THE WOMAN DECIDE TO GO AHEAD AND USE IT. BUT THEN AT LEAST WE WILL DO PK STUDIES TO SEE IS THE DOSE WE THINK IS GOING TO WORK, IS IT ACTUALLY WORKING? AND HAPPILY IN THE STUDY THEY DIDN'T NEED TO MAKE ANY ADJUSTMENTS TO DOSING. BUT OPPORTUNISTIC PK STUDIES A GOOD WORK AROUND TO MINIMAL RISK. IT COMES AT A COST BECAUSE IT MEANS YOU'RE WAITING. SECOND ONE IS ALSO A TECHNIQUE THAT IS BORROWED FROM THE PEDIATRICS RESEARCH, EXPERIENCE. WHICH IS TO DO MIXED PHASE I PHASE II TRIALS. SO, THE STANDARD IS TO DO VERY SMALL PHASE I TRIALS FIRST AND AFTER YOU GET ALL THE DAYA IN, YOU MOVE TO PHASE II TO TRY TO FIGURE OUT EFFICACY SO YOU CAN START TO CLAIM PROSPECT FROM DRUG BENEFIT. THE IDEA IS TO TAKE A SMALL COHORT OF PREGNANT WOMEN, WAIT UNTIL WE HAVE GOT WHAT SKIP SAID WAS EVIDENCE OF A PROSPECT OF BENEFIT AND DON'T GIVE THEM THE TINY MICRODOSE. YOU HAVE TO GIVE THEM ENOUGH DOSE YOU CAN CLAIM PROSPECT OF DIRECT BENEFIT. BUT THEN THE ONLY QUESTIONS YOU'RE ASKING WITH THAT SMALL INITIAL COHORT ARE PHASE I-TYPE QUESTIONS LIKE DOES IT CROSS THE PLACENTAL BARRIER? DOES PREGNANCY CHANGE THE PK VALUE? SO YOU DON'T NEED TO ENROLL LOTS OF PEOPLE. STILL DOING PHASE I QUESTIONS BUT IN THE CONTEXT WHERE WE KNOW THAT WE CAN SAY THERE IS PROSPECT OF DIRECT BENEFIT SO WE CIRCUMVENT THE WORRY ABOUT MINIMAL RISK. DOES THAT MAKE SENSE? SO CREATIVE TRIAL DESIGNS ARE NEEDED WITH RESEARCH WITH PREGNANT WOMEN AT EARLY PHASES. NOW LET'S MOVE TO THE RESEARCH THAT REALLY IS THE LION'S SHARE OF RESEARCH WE NEED TO DO WITH PREGNANT WOMEN, WHICH IS RESEARCH THAT IS GOING TO OFFER THE PROSPECT OF DIRECT BENEFIT. SO WE WAITED AND GOTTEN PRELIMINARY EVIDENCE OF SAFETY AND EFFICACY IN THE GENERAL POPULATION WE HAVE DONE OUR TOX STUDIES AND KNOW WHAT MIGHT BE RISKS TO THE FETUS AND WE HAVE MADE A GOOD RISK ASSESSMENT. AND HERE IN GENERAL, THE FIRST PASS THROUGH IS TO SAY LIKE WITH ANY OTHER RESEARCH POPULATION, YOU SEE WHAT THE EVIDENCE IS FOR A POSSIBILITY OF BENEFIT AND WHAT THE EVIDENCE IS FOR POSSIBILITY OF RISK HERE TO THE WOMAN OR FETUS AND YOU MAKE SURE THAT THEY ARE SORT OF A GOOD RATIO. THE OBVIOUS COMPLEXITY, THOUGH, IS THAT HERE WE HAVE TWO ENTITIES. SO WE WANT TO KNOW WHOSE RISK AND WHOSE POTENTIAL BENEFIT. SO THIS IS ACTUALLY AN AREA THAT MAKES SOME RESEARCHERS VERY NERVOUS BECAUSE IT FEELS LIKE IT HAS AN UNANSWERED QUESTION. CAN THE PROSPECT OF DIRECT MATERNAL BENEFIT JUSTIFY RISK TO THE FETUS? THAT WOULD BE VERY UNLIKE PEDIATRICS RESEARCH. THE PROSPECT OF DIRECT BENEFIT TO YOUR MOM WALKING AROUND DOESN'T JUSTIFY DOING RESEARCH ON A CHILD. DOESN'T WORK THAT WAY. BUT PREGNANCY IS DIFFERENT. SO THIS IS THE PLACE WHERE I REALLY DO WANT TO UNDERSCORE THAT THE ETHICAL MODEL AND THE REGULATORY MODEL FOR RESEARCH ON PREGNANT WOMEN, IS NOT LIKE THE ONE FOR PEDIATRICS. OFTEN THEY MIRROR EACH OTHER BUT NOT HERE. SO LET'S GO THROUGH A COUPLE OF SCENARIOS TO SEE WHAT IT SAYS. THE FIRST THING TO POINT OUT IS THE REGS SAY YOU CAN IMPOSE MORE THAN MINIMAL RISK ON THE FETUS IF THERE IS PROSPECT OF DIRECT BENEFIT TO EITHER THE WOMAN OR THE FETUS. EITHER ONE OF THOSE IS CAPABLE OF JUSTIFYING AN INCREMENT OF FETAL RISK. NOW DOES THAT MAKE SENSE? I THINK IT DOES, LET ME EXPLAIN. HERE IS THE FIRST POINT. IMAGINE A CASE WHERE WE SEE SIGNIFICANT PROSPECT OF DIRECT BENEFIT TO THE WOMAN. AND WE SEE SOME, MODEST, BUT SOME RISK TO THE FETUS. OFTEN, IF IT IS SIGNIFICANT ILLNESS OF THE WOMAN, PROSPECT OF BENEFITING HER WITH HER ILLNESS IS A PROSPECT OF DIRECT MEDICAL BENEFIT TO THE FETUS. SO GO BACK TO WHAT I WAS SAYING ABOUT THE PROBLEM, IF A WOMAN IS EXPERIENCING SIGNIFICANT ILLNESS. NOT ONLY NOT GOOD FOR HER, IT'S REALLY BAD FOR THE FETUS. SO MATERNAL FEELS MEDICINE EXPERTS, THE SUPER OBs OF THE WORLD AND THAT'S WHO PREGNANT WOMEN HOPE TO GO TO IF THEY HAVE SIGNIFICANT ILLNESS WHILE PREGNANT. THEY HAVE A GREAT MANTRA. WHAT IS BEST FOR A HEALTHY BABY IS A HEALTHY MOM. SO IF YOU WORRY ABOUT LIKE NOT TREATING THE PREGNANT -- NO, OF COURSE YOU TREAT. HOW DO YOU TAKE CARE OF THE FEET US? YOU TREAT THE WOMAN'S ILLNESS! SO SIMILARLY WHEN WE LOOK AT EXAMPLES OF RESEARCH WITH PREGNANT WOMEN AND I'M GOING TO GIVE YOU ONE. ANOTHER EXAMPLE FROM HIV. ONE OF THE ANTI-RETROVIRALS WAS MOVING INTO PHASE III TRIALS, GREAT EVIDENCE COMING FORTH WITH STANDARD POPULATIONS AND THEY WANTED TO INCLUDE A COHORT OF PREGNANT WOMEN. AGAIN BECAUSE OF THE WORRIES ABOUT WILDCARD PK STUFF. AND TO FIND OUT WHETHER THAT ANTI-RETROVIRAL HAD RISKS FOR THE FETUS THAT SMOTHERS DEPENDENT HAVE. SO REALLY IMPORTANT TO DO. SUPER REASSURING EVIDENCE. THEY WANTED TO ENROLL. THEY SAID LOOK, PROSPECT OF DIRECT BENEFIT. IT LOOKS LIKE THIS CAN CONTROL VIRAL LOAD OR DECREASE INFECTION RATES MORE THAN ALTERNATIVE MEDICINES BUT IT HAS SOME RISK TO THE FETUS. WHEN YOU LOOK AT WHAT THE EVIDENCE SAID, IT WASN'T JUST MATERNAL BENEFIT THAT COULD JUSTIFY THE FETAL RISK. IN THE AREAS THAT THESE WOMEN WERE LIVING WHERE THE TRIAL WAS TO TAKE PLACE, THE FETUSES HAD A BASELINE RISK OF INFECTION THAT WAS EXTREMELY HIGH AND SO IF YOU WERE DOING SOMETHING -- IF THE PREGNANT WOMAN ENROLLING WERE TO GET THE ACTIVE ARM, PROSPECT OF DIRECT BENEFIT TO THE THEIR FETUSES TO NOT GETTING INFECTED WITH A LIFE-THREATENING DISEASE. AND WHEN THEY JUST LOOKED AT THE NUMBERS, WHILE THE IMMEDIATE AFFECT WAS THROUGH THE WOMAN, IN FACT THE DOWNSTREAM BENEFIT TO THE FETUS WAS ALSO SIGNIFICANT AND IT COULD DO THE JUSTIFYING WORKS. AND THIS HAPPENS IN CASES THAT ARE LESS OBVIOUS THAN HIV. SO WITH HIV IT MIGHT SOUND WE GET IT BECAUSE THERE IS A VIRUS AND YOU MANUAL IN IT MOVING FROM THE WOMAN TO THE FETUS AND SO WE WANT TO CONTROL THAT VARIETIES. BUT IF WE LOOK AT OTHER SERIOUS MATERNAL DISEASEY WE ARE STARTING TO UNDERSTAND, THEIR AFFECTS ON THE FETUS, THE SAME LOGIC OFTEN APPLIES. SO TO JUST GIVE YOU A FEW EXAMPLES. WE ARE NOW LEARNING THAT SEVERE UNCONTROLLED DEPRESSION, MA TERM DEPRESSION, DURING PREGNANCY, HAS VERY BAD OUTCOMES FOR BABIES. SIGNIFICANT LOW BIRTH WEIGHT TO MENTION ONE. SO IF YOU'RE LOOKING AT A MEDICATION THAT COULD CONTROL SEVERE DEPRESSION DURING PREGNANCY, MIGHT HAVE SOME RISK TO THE FETUS BUT YOU HAVE TO BALANCE THAT AGAINST THE RISK OF LEAVING SEVERE MATERNAL DEPRESSION UNTREATED WHICH BY THE WAY, IF IT'S SEVERE ENOUGH ALSO INCLUDES A 20% MORTALITY RATE ANNUALLY FROM SUICIDE. STRONG RATES IN ANOREXIA. SO AGAIN, DON'T JUST LOOK AT THE WOMAN, LOOK AT HOW A HEALTHIER WOMAN BENEFITS THE FETUS. LET'S TAKE A HARDER CASE. WHAT IF THERE WERE A DRUG THAT WE WANTED TO DO RESEARCH ON AND WHAT IT LOCKS LIKE IS, IT REALLY COULD OFFER SOME STRONG MEDICAL BENEFIT TO THE WOMAN. BUT IT'S A DISEASE THAT DOESN'T HAVE A LOT OF AFFECT ON THE FETUS. AND SO EVEN HELPING HER DISEASE DOESN'T HELP THE FETUS MUCH IN A DIRECT MEDICAL SENSE. CAN THE -- LET'S SAY THE RESEARCH CARRIED MORE THAN MINIMAL RISK TO THE FETUS. IT'S SMALL BUT MORE THAN MINIMAL. CAN THE PROSPECT OF SIGNIFICANT MEDICAL BENEFIT TO THE WOMAN JUSTIFY IMPOSITION OF MORE THAN MINIMAL RISK TO THE FEET FUSS IT'S NOT TOO HIGH? THE REGS SAY YES. AND IT MAKES SENSE. BECAUSE AGAIN, PREGNANCY IS DIFFERENT FROM PEDIATRICS. WHEN I'M PREGNANT, I CAN'T MEDICALLY TREAT MYSELF WITHOUT BRINGING MY FETUS ALONG. IF I COULD, YOU TAKE CARE OF -- BOY WOULDN'T THAT BE NICE OFTENTIMES. JUST A LITTLE BREAK RIGHT THERE IN THE MIDDLE. BUT OF COURSE IF I COULD TREAT MY SIGNIFICANT ILLNESS AND LET SOMEBODY ELSE HOLD THE FETUS FOR A WHILE. OF COURSE I'D DO THAT. ARE YOU KIDDING? BUT PREGNANT WOMEN CAN'T. AND WE SEE IN THE CLINIC WHEN THIS HAPPENS, THAT WE HAVE TO SAY TO THE WOMAN, AND ETHICALLY SO, FIRST OF ALL KEEPING YOU HEALTHY IS PROBABLY GOOD FOR YOUR BABY. BUT SECOND OF ALL, EVEN IF YOU'RE ILLNESS ISN'T HURTING YOUR BABY, YOU GET TO THE TREAT YOUR SIGNIFICANT ILLNESS. EVEN IF IT HAS SOME SMALL RISK TO THE FETUS. BECAUSE WE DON'T MAKE WOMEN FORFEIT THE RIGHT TO ADEQUATE MEDICAL CARE JUST BY AGREEING TO CARRY A CHILD. WE DON'T. SIMILARLY, IF WE ARE LOOKING AT PREGNANT WOMEN AND RESEARCH AND WE HAVE A SCIENTIFIC NECESSITY FOR NEEDING TO DO RESEARCH WITH THE PREGNANT WOMAN. WE CAN'T BORROW THE KNOWLEDGE IN SOMEBODY ELSE BECAUSE OF THIS CRAZY PLACENTAL MATERNAL INFRA STRUCTURE. EXIT IS RESEARCH THAT CARRIES PROSPECT OF DIRECT BENEFIT. PREGNANT WOMEN SHOULDN'T BE DENIED ACCESS TO THAT PROSPECTIVE BENEFIT SIMPLY BECAUSE SHE IS PREGNANT. THERE NEEDS TO BE ADDED REGULATIONS AND ADDED RESTRICTIONS. A POINT AT WHICH RISK TO THE FETUS IS GOING TO MEAN THAT WE ARE NOT COMFORTABLE DOING THE RESEARCH ON HER EVEN WITH HER CONSENT. BECAUSE WE ALSO HAVE TO BE CAREFUL OF THE HEALTH OF THAT FUTURE CHILD. WHAT I AM SAYING IS, THERE IS A DEGREE OF STRONG BENEFIT TO THE PREGNANT WOMAN WITH SOME SMALL RISK BUT MORE THAN MINIMAL TO THE FETUS WHERE WE SHOULD GET TO SAY, AND THE REGULATIONS ALLOW, YOU CAN DO THAT RESEARCH WITH HER. SO SHE MIGHT GET THE BENEFIT THAT IT ALLOWS. AND OF COURSE SO WE ALL GET THE BENEFIT OF THE KNOWLEDGE THAT THE RESEARCH COULD PRODUCE. WITH ALL OF THESE TRIALS, WE STILL ALWAYS WANT TO ENCOURAGE CREATIVITY IN HOW THE TRIAL IS DESIGNED SO THAT WE CAN GET AS MUCH OF GOOD KNOWLEDGE WE NEED AND GIVE WOMEN ACCESS TO THE BENEFITED WHILE REDUCING THE FETAL LIFIC. AND I WANT TO GIVE YOU A EXAMPLE OF A GREAT CREATIVE TRIAL DESIGN FROM THE NIH. THIS HAPPENS TO BE FROM NAIAD. WITH ONE OF THE MICROBICIDE TRIALS. ONE THAT WAS REALLY PROVING TO BE VERY EFFECTIVE AT PREVENTING HETEROSEXUAL TRANSMISSION TO WOMEN. INTERESTINGLY FOR A LONG TIME THE MICROBICIDE TRIALS EXCLUDED PREGNANT WOMEN FROM THE TRIALS AND YOU FELL PREGNANT WHILE ON THE TRIAL YOU WERE BOOTED OFF PROTOCOL. IF YOU JUST THINK ABOUT IT IS VERY STRANGE. BECAUSE PREGNANCY SHARES THIS CAUSAL FACTOR THAT INFECTION DOES. IF YOU'RE PREGNANT IT MEANS YOU'RE HAVING UNPROTECTED SEX AND THAT'S A RISK FACTOR FOR HIV. AND WE KNOW THAT PREGNANCY, THE STATE OF PREGNANCY, MAKES YOU MUCH MORE SUSCEPTIBLE TO INFECTION IF YOU'RE EXPOSED. THE VAGINAL WALL. SO WE REALLY WANT PREGNANT WOMAN F MICROBICIDES ARE SAFE AND EFFECTIVE, WE WANT PREGNANT WOMEN IN PARTICULAR TO USE THEM. PROGRESSIVE VANGUARD SAYS WE NEED TO GET THIS EVIDENCE OUT. IS IT BEING DOSED RIGHT? OR WHO KNOWS? THEY HAD LOTS OF DATA. THE ONE RISK FOR THE FETUS THAT EMERGED AS A SALIENT ONE AS A BIOLOGICALLY PLAUSIBLE RISK, DIDN'T MEAN THERE WAS EVIDENCE IT WAS GOING TO HAPPEN BUT YOU HAVE TO BE ON THE LOOKOUT FOR IT, WAS PRETERM DELIVERY. WHEN IS NOT GOOD FOR A BABY. SO INSTEAD OF SAYING WE CAN'T DO RESEARCH WITH PREGNANT WOMAN, WE SAY HOW DO WE MINIMIZE THAT RISK. SO THEY STARTED WITH WOMEN WHO WERE 37 WEEKS PREGNANT. SO WE GOT TONSE AND TONSE OF DATA. WE COULD LOOK FOR EVIDENCE IN PRETERM LABOR AND GOT INCREDIBLY ENCOURAGING RESULTS. SO THEY MOVED IT BACK TO 32 WEEKS. GOT MORE AND MORE ENCOURAGING DATA AND THEN THEY MOVED IT BACK EARLIER IN PREGNANCY. SO HOW YOU DESIGN THE TRIALS F YOU TO DO RESEARCH WITH PREGNANT WOMEN, TAKES CREATIVITY TO DO IT ETHICALLY WELL OFTENTIMES. HAVING USED THAT EXAMPLE STARTING LATER AND MOVING IT UP, I DON'T WANT TO BE HEARD AS SAYING THAT IS LIKE THE COOKIE CUTTER RECIPE FOR DOING RESEARCH WITH PREGNANT WOMEN. SO THERE WAS ANOTHER INVESTIGATIONAL DRUG, NOT HIV THIS TIME, WHERE THEY LOOKED AT TO THE AND REALIZED THE SAFEST TIME TO DO THE RESEARCH WITH PREGNANT WOMEN WAS IN THE FIRST TRIMESTER BECAUSE IT WAS BEFORE THE FETUS DEVELOPED THE RECEPTOR FOR THE MOLECULE. RIGHT? SO DON'T ASSUME IT'S LATE TO EARLY. IT HAS TO BE EVIDENCE-BASED. WHAT DO WE KNOW ABOUT HOW THIS DRUG MIGHT WORK? I WANT TO END BY JUST GIVING ONE LAST EXAMPLE THAT IS FROM THE HEADLINES RIGHT NOW. SO I HAVE GIVEN A LOT OF HIV EXAMPLES. BUT LET'S TALK ZIKA FOR A SECOND. FOR THOSE OF YOU WHO WORK ON PREGNANT WOMEN'S HEALTH AND RESEARCH WITH PREGNANT WOMEN. THERE IS ONE SILVER LINING OF THE ZIKA CAREERS. AND IT IS A CRISIS. IT'S ONLY A TINY SILVER LINING BUT IT MEANS WE ARE CONFRONTING THE HEALTH NEEDS AND THE RESEARCH NEEDS WITH PREGNANCY IN A WAY WE OFTEN IGNORE. SO, WHAT WE WORRY ABOUT WITH THE ZIKA VIRUS OTHER THAN MODEST RISK OF THE SYNDROME FOR ADULTS, REALLY IS IT TURNS OUT TO BE NEUROTROPEIC, ESPECIALLY TO UNDIFFERENTIATED CELLS. SORRY. LESS DIFFERENTIATED CELLS. SO IN OTHER WORDS THAT IS WHY THE VIRUS IS SO DAMAGING TO FETUSES? FETI? I DON'T KNOW. AS WE DEVELOP A VACCINE TO MAKE SURE -- THE GOAL IS TO MAKE SURE THAT PREGNANT WOMEN ARE VACCINATED AND DON'T EXPOSE THEIR FEES USES TO THIS -- FETUSES TO THIS TERRIBLE VIRUS. HERE IS AN EXAMPLE OF HOW THE WORLD RESEARCH COMMUNITY HAS TO BE THINKING ABOUT THIS. SO REALLY COOL. THE W.H.O. HAS COME OUT WITH ITS PROTOCOL FOR VACCINE DEVELOPMENT AND THERE ARE 16 VACCINE PLATFORMS UNDER ACTIVE DEVELOPMENT AROUND THE WORLD. IT'S BEEN AN AMAZING COORDINATED EFFORT. AND THERE ARE A BUNCH OF DIFFERENT TYPES OF VACCINE PLATFORMS RANGING FROM KILL THE VACCINE -- THERE ARE FOUR KILL VACCINEERTS THEY ARE JUST TESTING. SOME LIVE ATTENUATED ONCE. SOME SUPER NOVEL DNA VACCINES THAT THEY NEVER DONE BEFORE THAT LOOK LIKE REALLY ENCOURAGING. ZAP THE CELL WITH ELECTRICITY IT'S REALLY NEAT. WELL, HERE IS A FACT THAT WE HAVE TO THINK ABOUT FOR WHEN WE DO THE VACCINE ROLL OUT. FOR BETTER OR WORSE, CLINICIANS ARE VERY REN SANT TO GIVE PREGNANT WOMEN LIVE ATTENUATED VACCINES. NETTLER THERE IS EVIDENCE BASE FOR THAT BUT AT ANY RATE IT'S A FACT. PEOPLE FEEL TOO NERVOUS TO GIVE IT. IN CONTRAST, WE HAVE A WEALTH OF DATA ABOUT USING KILL VACCINES IN PREGNANT WOMEN. PREGNANT WOMEN ARE GIVEN MORE VACCINES PARTLY BECAUSE THERE IS SUCH A NICE DELIVERY MECHANISM TO THE FETUS. SO KILL VACCINES IN PREGNANT WOMEN THUMB UP. THAT MIGHT MEAN THAT AS WE ARE DEVELOPING THE RESEARCH AGENDA AMONG THE 16, WE SHOULD PUT SOME SPECIAL PRIORITYO GETTING AT LEAST ONE OF THE VACCINES TO BE A KILL VACCINE. SO THAT IF A PREGNANT WOMAN, ESPECIALLY IN A RESOURCE-POOR AREA OR MAYBE THE FIRST TIME SHE IS ACCESSING HEALTH CARE IS BECAUSE SHE IS PREGNANT SO SHE HASN'T BEEN PREVIOUSLY VAC VACCINATED; HAS AVAILABLE TO HER A VACCINE THAT THE CLINICIAN CAN GIVE WITH CONFIDENCE, BECAUSE OTHERWISE WHAT IS GOING TO HAPPEN IS, THE PREGNANT WOMEN ARE GOING TO FINALLY COME TO THE CLINIC WORRIED BECAUSE THEY ARE IN A ZIKA ENDEMIC AREA AND REALIZE THEY ARE PREGNANT AND HAVEN'T BEEN VACCINATED AND THE CLINICIAN WILL SAY, SORRY, YOU'RE JUST GOING TO HAVE TO WAIT IT OUT. AND THAT WOULD BE UNETHICAL. LET ME STOP THERE AND OPEN UP TO QUESTIONS AND DISCUSSION. [ APPLAUSE ] >> YOU TOUCHED ON THIS IN THE LAST BIT BUT I WAS THINKING ABOUT THAT COMMENT YOU CAN'T BE JUST A LITTLE BIT PREGNANT. THAT IN RESEARCH WHEN YOU'RE APPROVING RESEARCH WITH PREGNANT PEOPLE THE STATE OF THE PREGNANCY, THE TERM OR THE POINT ALONG THE TERM, IS THAT SOMETHING YOU MIGHT BE EVALUATING WHEN YOU'RE -- USUALLY REVIEWING A PROTOCOL WAY BEFORE ANYBODY IS EP ROLLED. BUT BE ABLE TO STIPULATE ONLY PEOPLE WHO ARE AT 20 WEEKS OR 30 WEEKS? >> ABSOLUTELY. ANY PROTOCOL CONTEMPLATING RESEARCH WITH PREGNANT WOMEN SHOULD ABSOLUTELY -- I MEAN MUST, ADDRESS WHERE IN PREGNANCY. NOW SOME THINGS CAN BE DONE AT ANY -- IRRESPECTIVE OF WHEN IN PREGNANCY, OTHERS WOULD BE VERY SPECIFIC. ONLY THIS STAGE OF PREGNANCY. IT'S IMPORTANT NOT JUST ETHICALLY BUT SCIENTIFICALLY. ONCE WE ARE DOING BIOMEDICAL RESEARCH WHAT WE KNOW ABOUT THE -- FOR INSTANCE THE PK VALUE DURING THE FIRST TRIMESTER IS NOT PREDICT EF OF WHAT WE KNOW ABOUT PK FOR THIRD TRIMESTER. >> HI. I HAVE A QUESTION REGARDING THE LGBTQ COMMUNITY AND TRANSGENDER MEN AND THE STATUS OF RESEARCH ETHICS WHEN TRANSGENDER MEN BECOME PREGNANT AND ALSO SPECIFICALLY TALKED ABOUT SEVERE DEPRESSION AND I KNOW THAT IS AN ISSUE IN THE COMMUNITY AND I WAS WONDERING YOUR TAKE ON THAT. >> WHAT A GREAT QUESTION. SO, LET'S SEE. FIRST THE QUESTION ABOUT WHEN TRANSGENDER MALE TO FEMALE BECOMES PREGNANT. ROCK ON. THERE IT'S NOT GOING TO -- IS THAT THE DIRECTION YOU'RE TALKING ABOUT? FEMALE TO MALE. EITHER ONE? I'LL SAY EITHER ONE. SO, IT'S A BORING ANSWER. WHILE THERE WILL BE MANY, MANY INTERESTING ISSUES AROUND TRANSGENDER, THE ISSUES ABOUT THE REGULATIONS WITH RESEARCH FOR THE STATE OF PREGNANCY WON'T MATTER AT ALL. BECAUSE WHAT THE REGULATIONS ARE CONCERNED ABOUT IS FETAL PROTECTION. SO IF THERE IS A FETUS IN THERE, HOWEVER IT GOT IN THERE, AND HOWEVER THE WOMB GOT IN THERE, YOU KNOW WHAT I'M SAYING? THE REGS SAY I DON'T NEED TO KNOW. HERE ARE THE ADDED REGULATIONS WE NEED. I DO THINK YOU'RE POINTING TO -- YOU'RE SECOND QUESTION ABOUT DEPRESSION AND THE TRANSCOMMUNITY, INCREDIBLY HELPFUL AND IMPORTANT POINT THAT WE NEED TO REALLY PAY ATTENTION IN RESEARCH ETHICS TO UNDERSERVED POPULATIONS WHOSE EITHER PHYSIOLOGY OR SOCIAL CONTEXT MAY CHANGE WHAT IS BEST PRACTICE WITH RESPECT TO THEM. SO, FOR INSTANCE WITH TRANS-FOLKS ON HORMONE THERAPY. WE'LL HAVE VERY INTERESTING QUESTIONS ABOUT PHARMACO-- PSYCHOPHARM CLOG CALL INTERVENTIONS IF YOU'RE ON OR HONES. THAT MEANS A DEDICATED STUDY AND WE NEED AN EVIDENCE BASE TO OFFER YOU. EVEN IF IT DOESN'T CHANGE THE BIOLOGY OF IT, WHEN YOU'RE TALKING ABOUT DEPRESSION INTERVENTIONS, OFTEN THEY ARE COMBINATIONS OF A BIOLOGICAL INTERVENTION AND SOME KIND OF TALK THERAPY OR WHATEVER. YOU CAN'T JUST SAY TO THAT COMMUNITY, SO GO TALK TO YOUR NEIGHBORHOOD COUNSELOR OR PASTOR. YOU WANT TO INDICATE SOME UNDERSTANDING. HERE IS A RESOURCE FOR PEOPLE WHO ARE FAMILIAR WITH ISSUES WITH YOUR POPULATION. >> SO, MY QUESTION IS ABOUT BALANCING THE ETHICS OF DOING TRIALS AND NOT DOING TRIALS. AS SOMEONE WHO IS A PHYSICIAN AND HAS BEEN A PREGNANT WOMAN, THERE IS THIS ISSUE THAT THERE IS NO KNOWLEDGE OF WHAT MEDICINES ARE SAFE OR UNSAFE IN PREGNANCY BECAUSE NOBODY WANTS TO STUDY THEM. AND THAT ISSUE OF LIKE IF PREGNANT WOMEN ARE ALREADY TAKING THEM FOR X OR Y OR Z REASONS OR PLAN TO TAKE THEM, THEN YOU CAN STUDY THE OUTCOMES BUT IT'S DIFFICULT AS A PHYSICIAN AND PATIENT TO THINK HOW DO I WEIGH THE RISKS AND BENEFITS OF TRYING THIS IF THERE IS NO EVIDENCE BECAUSE IT'S NEVER BEEN STUDIED? I WAS WONDERING IF YOU COULD COMMENT ON THAT. >> EXACTLY. SO WHAT YOU DESCRIBE IS THE IDEA OF DEFAULTING PREGNANT -- RESEARCH WITH PREGNANT WOMEN TO PHASE 4 WHICH MEANS IN THE CLINIC POST MARKETING WHERE WE DON'T HAVE AN EVIDENCE BASE FOR THE USE OF A MEDICINE IN YOUR PARTICULAR SITUATION BUT WE HAVE TO PRESCRIBE STUFF FOR SERIOUS CONDITIONS. SO HERE YOU GO. BUT BY THE WAY, HERE IS THE REGISTRY INFORMATION SO SOMETHING HORRIBLE HAPPENS, CALL THIS 800 NUMBER. BY THE WAY, IF NOTHING HORRIBLE HAPPENS, ARE YOU GOING TO CALL THE 800 NUMBER? NO. WE KNOW THE PROBLEM WITH REGISTRIES AND SELF SELECTION BIAS AND THE LIKE. HERE IS A DIFFERENT PROBLEM. NOT TO BE DEPRESSING. BUT ANOTHER PROBLEM, SO SOMEBODY SAYS LET'S JUST DO COHORT STUDIES, POTENTIALLY THE PROSPECTIVE COHORT STUDIES SO BETTER CONTROLLED. AND LET'S GET A HUGE COHORT AND THEN MINE FOR THE DATA. ONE OF THE THINGS WE KNOW ABOUT THE -- ON THE ONE HAND THAT'S GREAT. FOR GETTING SOME PRELIMINARY EVIDENCE AND GENERATING HYPOTHESES. BUT COHORT STUDIES WE RECENTLY SAW THIS WITH STUDY PUBLISHED ABOUT ACETAMINOPHEN USAGE DURING PREGNANCY WHICH GOT A LOT OF PRESS AND MY AMAZING COLLEAGUE DID A GREAT ANALYSIS OF JUST TERRIBLE TERRIBLE STUDY. IN PART BECAUSE WITH LARGE COHORTS, BIG END, I FIND ANY TWO VARIABLES AND YOU CAN OFTEN FIND POSITIVE CORRELATIONS AND YOU CHIRY PICK THEM. IT DOESN'T MEAN ANYTHING. OTHER THAN POTENTIALLY SHOULD BE LOOKED AT AS A HYPOTHESES BUT INSTEAD WE ARE BASING CLINICAL RECOMMENDATIONS ON COOKIE STUFF. SO ALL OF THAT IS TO SAY WE REALLY, REALLY DO NEED TO DO INTENTIONAL, PROSPECTIVE, CLINICAL RESEARCH WITH PREGNANT WOMEN. AND THE REGS AGREE, WE NEED TO DO THAT. AND THEY ARE PRETTY DARN SENSIBLE. REGS AREN'T ALWAYS. I LIKE THESE. IT'S LIKE THAT MAKES SENSE. WOULD I CHANGE THEM? SURE. BUT THE BASIS OF THEM MAKE A LOSS OF LOT OF SENSE. SO MOVING FROM UNSTRUCTURED EXPERIMENTATION OF POST MARKETING INTO HIGHLY REVIEWED AND CAREFUL RESEARCH WITH PREGNANT WOMEN, OUR GROUP CLAIMS IT'S A MORAL IMPERATIVE. YES? >> JUST WONDERING IF YOU HAVE SITUATIONS FOR INSTANCE WITH PREGNANT WOMAN WHO ARE GOING TO ABORT BUT THEY DECIDED THAT I'M GOING TO ABORT THIS FETUS BUT THERE IS SOMETHING THAT CAN BE GAINED MEDICALLY FOR OTHER PERSONS AND THEY WANT TO ENROLL IN -- YOU MAY HAVE SHORT TRIALS JUST LOOKING AT MATERNAL FETAL TRANSMISSION FOR WHATEVER. ARE THESE PEOPLE CONSIDERED FOR ENROLLMENT IN CLINICAL TRIALS? I'M NOT SURE WHAT YOUR REGULATIONS ARE HERE. >> SO THE REGULATIONS -- THERE ARE REGULATIONS THAT APPLY EVEN TO PREGNANCIES THAT ARE NOT GOING TO BE CONTINUED, WHICH IF YOU THINK ABOUT IT, DOESN'T NECESSARILY MAKE SENSE. I'M JUST IN TERMS OF TELLING YOU WHAT THE REGS ARE SAYING. THAT SAID, SOME HAVE PROPOSED REALLY INTERESTING RESEARCH THAT WOULD BE DONE, AGAIN VERY CAREFULLY AND WITH CONCEPT AND NOT ASKING AT THE MOMENT THAT YOU'RE GETTING THE ABORTION. THAT'S NOT -- A VERY EMOTIONAL TIME FOR MANY WOMEN BUT DOING IT REALLY SUPER PROPERLY. ARGUING THAT IT DOES MEET THE REGULATIONS EVEN WITH RESEARCH WITH PREGNANT WOMEN SHOULD THE PREGNANCY CONTINUE BECAUSE THERE WILL BE NO ILL AFFECTS TO THE FETUS OF THE BIOMEDICAL RESEARCH BECAUSE THERE WILL BE NOT BE A CHILD SUBSEQUENT TO THE PREGNANCY. SO IT IS PERMISSIBLE UNDER THE REGS. THAT SAID, YOU WILL NOT BE SURPRISED TO HEAR THAT VERY LITTLE OF THIS RESEARCH HAPPENS BECAUSE IT'S AN EXPLOSIVE ISSUE. SO IF WE LIVED IN A COUNTRY THAT HAD MORE OF A CONSENSUS AND MORE CLARITY CULTURALLY AROUND HOW TO BE A GOOD SOCIETY WITH RESPECT TO ABORTION, THEN THE IDEA OF ONE THING YOU COULD DO IS TO REALLY HELP THE HEALTH OF FUTURE FETUSES AND CHILDREN AND WOMEN BY DOING THIS. AGAIN LIKE TO SEE JUST DOES IT CROSS THE PLA SEPTAL BARRIER? THAT IS A LOT OF GREAT DATA. THAT IS ONE CONTEXT. IN THE CURRENT CONTEXT IN THE UNITED STATES, IT WOULD BE -- I WOULDN'T EVEN ADVOCATE. IT WOULD BE SO WORRISOME THAT PEOPLE WOULD BE CONCERNED GIVEN OUR STATE OF THE CONVERSATION HERE THAT PREGNANT WOMEN MIGHT BE THINKING IT'S OKAY, I WOULDN'T ABORT OTHERWISE BUT IT'S WHAT IS GOING TO MAKE ME SLEEP BETTER AT NIGHT ABOUT IT. SO WE ARE JUST NOT READY FOR THAT, I WOULD SAY. >> THANK YOU, MAGGIE. THIS IS A QUESTION FROM TWITTER. CHRISTOPHER LEE WAS WONDERING -- >> OH, MY GOD, WAIT! I WAS SUPPOSED TO SAY FOLLOW OUR GRANT ON TWITTER. @PREGNANCY ETHICS. GO AHEAD. >> THERE YOU GO. GOOD REMINDER. SO FOR A CHILD -- >> YOU SAID THIS IS GOING OUT TO PEOPLE ALL OVER THE WORLD. >> SEVERAL HUNDRED PEOPLE ARE STREAMING LIVE. FOR A WHILED WHO HAS BEEN THE FETUS OF A PRACTICINGINANT WOMAN IN A CLINICAL TRIAL TAKING EXPERIMENTAL MEDICATION, ARE THERE -- PREGNANT WOMAN -- ARE THERE IMPLICATIONS OR DO PEOPLE DISCUSS THE IMPLICATIONS OF COMPOUNDS OR EXPERIMENTAL MEDICATIONS THAT THEY MIGHT BE OR MIGHT NOT BE THEN ELIGIBLE FOR LATER IN LIFE? >> ELIGIBLE? YOU MEAN DO WE THINK THIS PERSON MEANS LIKE GETTING -- >> SO -- CONTINUED ACCESS TO THE MEDICINE -- >> SO IF YOU'RE THE FETUS OF A MOTHER WHO ENROLLS IN A TRIAL AND TAKES A EXPERIMENTAL MEDICATION, COULD THERE BE -- COULD LATER IN THAT FETUS'S LIFE MAY NOT BE ELIGIBLE FOR A TRIAL FOR AN EXPERIMENTAL MEDICATION THEMSELVES IS THE QUESTION? >> I DON'T THINK SO. >> SORT OF A NARROW CASE. >> BUT IT'S SUPER INTERESTING. I DON'T THINK SO. SUMMERY NOT IN PRINCIPLE IT'S NOT THAT IT MEANS YOU GOT ONE SHOT AND YOU HAD IT WHILE YOU WERE IN THE WOMB. ALWAYS THE CAVEAT IS ALWAYS THAT YOU HAVE TO BE SCIENTIFICALLY OF INTEREST AND ELIGIBLE TO BE IN A TRIAL AND IT'S POSSIBLE THAT SOMETHING HAPPENED. THE FACT YOU WERE IN A MOTHER WHO WAS ILL MEANS HAVE YOU SOME CONDITION SUCH THAT YOU CAN'T BE IN A TRIAL. IT WOULD BE SOMETHING SPECIFIC ABOUT WHO YOU ARE NOW AS A RESEARCH SUBJECT AND NOT YOUR HISTORY. THAT'S HOW I SEE IT. >> I HAVE A QUESTION ON PSYCHOLOGICAL BENEFITS AND RISKS BECAUSE NORMALLY WHEN YOU THAT YOU CAN ABOUT BENEFITS AND RISKS YOU TALK ABOUT PHYSIOLOGICAL. LET'S SAY IN A SITUATION OF A PREGNANT WOMAN WHO HAS A CHILD WITH A CONDITION WHICH IS NOW POSSIBLY TREATED BY INVASIVE PROCEDURE BUT YOU HAVE A DRUG COMING UP THAT CAN POSSIBLY ADDRESS THE ISSUE -- IN THE UTERUS. SO YOU TRY THAT DRUG BUT THEN THERE IS POSSIBLE HARM TO THE WOMAN WHEN THAT DRUG FAILS. AND SO, WE KNOW THAT POSTPARTUM DEPRESSION IS VERY REAL AND CAN COME VERY HOMICIDEAL. SO IF THERE IS A RISK -- SUICIDAL AS WELL. SO THEN TO WHAT EXTENT -- >> FETAL HOLDS HOMICIDE IS VERY RARE. >> IN THAT CASE, PSYCHOLOGICAL BENEFITS SHOULD IT NOT POSSIBLY BE WRITE EN IN THE PROTOO COL? >> GOOD. I DO THINK WHEN WE ARE CONSIDERING RISKS AND BENEFITS, THINGS THAT PSYCHOLOGICAL RISKS AND BENEFITS ARE ABSOLUTELY PART OF IT WHEN THEY FALL INTO AN UMBRELLA OF MEDICAL PSYCHOLOGICAL HARMS AND BENEFITS. SO, DEPRESSION IS PSYCHOLOGICAL BUT IT'S ALSO MEDICAL. THE REASON I MAKE THAT CAVEAT IS BECAUSE SOME PEOPLE HAVE PROPOSED THAT THE BENEFITS OF ENROLLING, THE PROSPECT OF BENEFIT COULD INCLUDE THE PSYCHOLOGICAL FEELING OF HAPPINESS THAT VOLUNTEERING TO HELP HUMANKIND AND THAT IS A REAL PSYCHOLOGICAL STATE. I THINK IT'S A REAL BENEFIT TOO. BUT IT'S NOT ONE AS SKIP SAID TOO, THAT'S NOT ONE WE WOULD US TO OFFSET MEDICAL RISKS. FOR NON COMPETENT PATIENT. THAT COULD BE THE BASIS OF YOUR CONSENTING TO UNDERTAKE RISKS AS A COMPETENT PERSON THEN WE DON'T NEED TO TALK ABOUT RISKS AND BENEFITS. WE ARE JUST SAYING WOULD YOU AGREE TO DO THIS AND YOU SAY YES AND IT'S GOING TO MAKE MY DAY. WE ARE THRILLED. WHATEVER, MOVE ALONG. BUT IF IT WERE A PERSON WHO OR CREATURE THAT CAN'T CONSENT, LATE STAGE ALZHEIMER'S, CHILD, FETUS, WE DON'T SAY SOMEBODY'S HAPPINESS THAT PARTICIPATING IN THIS RESEARCH OR A DIFFERENT PERSON'S HAPPINESS AT THEM PARTICIPATING IN THIS RESEARCH I MEAN IS ANY PART OF THE EQUATION THAT WOULD JUSTIFY DIRECT MEDICAL RISK. >> HI. I HAVE A QUESTION ABOUT HARMS THAT MIGHT NOT BECOME APPARENT FOR MANY, MANY YEARS. SO, IF WE FORESEE THAT TYPE OF RISK DID WE NEED TO MONITOR THE WOMAN AND THE FETUS FOR DECADES IF WE THINK THAT THAT THERE IS A HARM THAT MIGHT NOT BECOME APPARENT UNTIL THE CHILD IS AN ADOLESCENT OR SOMETHING LIKE THAT? >> VERY, VERY IMPORTANT QUESTION. SO, A COUPLE OF THINGS. FIRST OF ALL, LATENT HARMS OF AN INTERVENTION TAKEN CLINICALLY OR IN THE RESEARCH CONTEXT, ARE ALWAYS OF CONCERN. CLINICAL RESEARCH TRIALS EVEN THE REALLY LONG ONES AND VERY FEW ONES ARE LANGUAGITUDEINAL. WHEN THEY SAY THIS DRUG IS PROVEN SAFE FOR USE IN THIS -- LONGITUDINAL -- IT MEANS WE WATCHED IT AT BEST A YEAR. WHICH IS GOOD, BUT NOT LATENT EFFECTS H IS WHY WHEN THEY TALK ABOUT PHASE 1-4 RESEARCH FOR MOST MARKETING, IT REALLY IS AN INHERENTLY CRITICAL PIECE OF RESEARCH. THAT IS WHERE WE ARE GOING TO FIND OUT LOTS OF ISSUES ABOUT LATENCY. AND IT DOESN'T MEAN YOU CAN'T DO GOOD CLIP CALL RESEARCH NOW. IT MEANS YOU DO WANT TO OF WA. SO FIRST OF ALL BASELINE, WE ALWAYS WANT AND SHOULD HAVE BETTER SURVEILLANCE IN TERMS OF LANESY. SECOND, IT IS TRUE THAT FOR SOME CONDITIONS, SOME EFFECTS ON A FETUS, THERE COULD BE LATENT ONES THAT ARE CONGENITAL. SO CONGENITAL NOW BUT LATENT LEHMANN FESTED. AND SO, AS OPPOSED TO YOU'RE ALL FORMED AND SO YES YOU COULD HAVE AN EFFECT LATE BUT IT WON'T BE ABOUT YOUR ORGAN SYSTEMS OR SOMETHING. SO WITH THE FETUS BECAUSE SOME OF THE DANGERS COULD BE ABOUT HOW IT GETS DEVELOPED, WE ALREADY WANT TO HAVE ADDED PROTECTIONS AND INCLUDING THAT WE MAY NOT ALWAYS HAVE REASSURANCE WHEN IF COMES AT BIRTH. SO THAT IS WHY EVIDENCE AND DATA FROM ANIMAL MODELS OR OFTEN THERE MAY BE A DRUG ITSELF OR A COUSIN TO THE DRUG, HAS BEEN USED CLINICALLY AS OPPOSED TO NEW INVESTIGATIONAL COMPOUNDS. WE NEVER SEEN THAT SO THAT'S SOME REASSURANCE. WHEN -- BUT THE BOTTOM LINE IS, IF THERE IS BIOLOGICAL PLAUSIBLE RISK, EVEN WITHOUT EVIDENCE, THAT THERE COULD BE DEVELOPMENTAL PROBLEMS THAT ARE LATENT AND THEN ABSOLUTELY THE STUDY SHOULD HAVE INCLUDED, HERE IS HOW LONG YOU WILL HAVE TO DO SURVEILLANCE BEFORE WE CLAIM RESULTED. REALLY HELPFUL. >> I KNOW THERE IS ONE MORE QUESTION BUT IT IS ALREADY PAST 11:30 SO ANYONE WHO NEEDS TO LEAVE SHOULD LEAVE. IF YOU WANT TO THE STAY, IF YOU CAN STAY, TO ANSWER ANOTHER QUESTION THAT IS WONDERFUL. >> OKAY. >> THIS QUESTION WILL BE SHORT. SO, IT'S ABOUT INFORMED CONSENT FOR WHEN A PREGNANT WOMAN IN GROW ENROLLINGA I TRIAL, OBVIOUSLY THE WOMAN HAD TO CONSENT BUT SINCE THERE IS GOING TO BE ANTICIPATED BENEFITS AND RISKS TO THE FETUS IS THERE NEED FOR THE FATHER TO CONSENT AS WELL? >> YES! I'M SO GLAD I STAYED FOR THIS ONE LAST THING. THE REGULATIONS DO INCLUDE A PARENTAL CONSENT REQUIREMENT THAT IS VERY NARROW AND SPECIFIC. IF STILL SUPER CONTROVERSIAL. I THINK THAT CONSENSUS RIGHT NOW ON PROGRESSIVE RESEARCH ETHICS IS IT SHOULD BE DONE AWAY WITH. LET ME TELL YOU WHAT IT IS. IF THE RESEARCH INVOLVES PROSPECT OF DIRECT BENEFIT TO THE WOMAN OR THE FETUS, THE WOMAN'S CONSENT ALONE IS SUFFICIENT. SHE SHOULDN'T GET OR NEED TO HAVE A PARTNER YES YOU GOAT HAVE ACCESS TO THIS BENEFIT OR THIS WOULD BE GOOD FOR THE CHILD. IF IT IS NO PROSPECT OF DIRECT BENEFIT, SO THE PREGNANT WOMAN IS SAYING I'D LIKE TO VOLUNTEER MYSELF AND MY FETUS FOR THIS MINIMAL RISK TRIAL AS A ALL TRUISTIC VOLUNTEERING FOR SCIENTIFIC UNDERSTANDING, THEN THE FATHER'S CONSENT IS ALSO REQUIRED. ASSUMING WITH PROVISIONS THAT HE'S NOT HARD TO FIND, OR IT'S NOT -- I DON'T REMEMBER THE LANGUAGE, CHRIS. >> UNAVAILABLE. >> UNAVAILABLE OR TERRIBLE WHATEVER. ANYWAY YOU KNOW WHAT I'M SAYING. BUT THIS MIMICS WHAT IS TRUE OF PEDIATRICS. IF YOU'RE GOING TO VOLUNTEER YOUR CHILD WITH NO PROSPECT OF DIRECT BENEFIT, IF THERE ARE TWO PARENTS AROUND BOTH SHOULD CONSENT. >> THANK YOU. >> THANK YOU FOR THAT. THANK YOU EVERYBODY. [ APPLAUSE ] >> THANK YOU MAGGIE AND EVERYONE. SEE YOU NEXT WEEK. PLEASE STAND BY. PLEASE STAND BY. PLEASE STAND BY. TEST TEST. TEST TEST. TEST TEST. >> WELCOME GRAND ROUNDS. THIS IS A GREAT TEACHER'S LECT SERIES. I'M PLEASED TO ANNOUNCE THAT A LECTURE FOR TODAY IS DR. KARIN MURASZKO, THE CHAIRMAN OF NEUROSURGERY AT THE UNIVERSITY OF MICHIGAN. AND DR. MURASZKO IS A GRADUATE OF YALE UNIVERSITY, AND SHE WENT ON TO COLUMBIA UNIVERSITY WITH SHE DID HER MEDICAL SCHOOL. AND HER NEUROSURGERY RESIDENCY AND HER PAEDIATRIC NEUROSURGERY TRAINING. AFTER THAT, SHE CAME HERE FOR TWO YEARS. AND SHE WAS A SENIOR STAFF FELLOW UNDER EDWARD OLD FIELD, THE CHIEF AT THAT TIME. AND FOLLOWING A 2 YEAR FELLOWSHIP, SHE DID WHAT WE LIKE TO SEE WHICH WAS SHE MOVED ON, IN THIS CASE, SHE DIDN'T STAY HERE BUT MOVED ON TO THE UNIVERSITY OF MICHIGAN AND SHE BECAME AN -- AFTER FIVE YEARS, BECAME CHIEF OF THE PAEDIATRIC NEUROSURGERY SERVICE AT THE UNIVERSITY OF MICHIGAN. TEN YEARS LATER SHE BECAME CHAIR OF THE DEPARTMENT. AND SHE BECAME THE FIRST FEMALE CHAIR OF AN ACADEMIC NEUROSURGICAL DEPARTMENT IN THE UNITED STATES. AND SHE SERVED ON NUMEROUS COMMITTEES AND ORGANIZED NEUROSURGERY. SHE WAS THE FIRST FEMALE DIRECTOR OF THE AMERICAN BOARD OF NEUROLOGIC SURGEONS, APPOINTED IN 2008. ALSO HAD MANY RESPONSIBILITIES AT THE MEDICAL SCHOOL. HER RESEARCH INVOLVES PAEDIATRIC BRAIN TUMORS AND THE TREATMENT OF KEY ARRA 1 MALFORMATION. AND SHE ALSO TREATS CHILDREN WITH COMPLEX CRANIOFACIAL DISORDERS. SHE'S A HUMANITARIAN, SHE LEADS A GROUP TO GUATEMALA EVERY YEAR TO TREAT INDIGENT PATIENTS, INCLUDING NEUROSURGEONS, ANESTHESIOLOGISTS, NEURO SURGAL RESIDENTS AND NURSING STAFF FROM THE UNIVERSITY OF MICHIGAN. SHE WAS BORN WITH SPINA BIFIDA AND ON THE ADVISORY COMMITTEE OF THE SPINA BIFIDA ASSOCIATION AND MARCH OF DIMES. SHE HAS A JOINED APPOINTMENT IN PLASTIC SURGERY BECAUSE OF HER CRANIAL FACIAL WORK. IN 2007, SHE WAS NAMED THE JULIAN HOFF PROFESSOR OF NEURO SURGERY AT THE UNIVERSITY OF MICHIGAN T CONGRESS OF NEURALLOGICAL SURGEONS GAVE HER AN AWARD AND WON A HUMANITARIAN AWARD IN 2016. SHE PUBLISHED OVER 120 PEER REVIEWED PUBLICATIONS AND CHAPTERS, AND THE EDITOR OF SEVERAL BOOKS. AND SHE STILL HAS TIME LEFT OVER FOR HER HUSBAND AND TWO BEAUTIFUL CHILDREN. AND SHE ALSO LIKES TRAVELING, FISHING, AND ARCHITECTURAL CONSERVATION. SO IT'S MY PLEASURE TO WELCOME DR. KARIN MURASZKO AS ONE OF OUR GREAT TEACHES. THANK YOU. [APPLAUSE] >> THE TITLE PLAYS WELL INTO THE EGO OF MOST NEUROSURGEONS. GREAT TEACHERS. I'M GOING TO TALK ABOUT SOMETHING WHICH IS NOT SCIENTIFIC. IT'S A LOT MORE TO DO WITH MY ROLE IN THE LAST 12 YEARS AS A CHAIR OF NEUROSURGERY. AND I SORT OF THOUGHT THAT BRINGING SCIENCE TO YOU ALL WAS A LITTLE BIT LIKE BRINGING COALS TO NEW CASTLE. THIS IS A WONDERFUL PLACE FOR LEARNING THE SCIENTIFIC METHODS. I PERSONALLY THOUGHT MY TWO YEARS HERE WAS AMONG THE MOST ENRICHING OF MY LIFE. I HOPE THE PRINCIPLES AND A LOT OF THINGS I WAS TAUGHT, I MAKE USE OF IN A REGULAR BASIS IN MY OWN ACADEMIC CAREERS AS A NEUROSURGEON. WHEN I BECAME THE CHAIR OF NEUROSURGERY IT WAS APPARENT TO ME THAT ONE OF THE THINGS I THOUGHT WAS IMPORTANT WAS TRYING TO UNDERSTAND PROFESSIONALISM IN THE CONTEXT OF BEING A PHYSICIAN, AND SPECIFICALLY, BEING A NEUROSURGEON. I'LL USE NEUROSURGERY AS THE REFERENCE POINT HERE BUT WHAT I'M REALLY TALKING ABOUT IS LEADERSHIP ON THE PART OF INDIVIDUALS AS THEY'RE BEING TRAINED BECOMING A PHYSICIAN. AND THERE IS A CHALLENGE. THE CHALLENGE CHANGES US ALL. THE FACT THAT WE'RE NOW DEALING WITH RESTRICTED WORK HOURS. I THINK THE UNDERSTANDING OF QUALITY, ALL THESE THINGS PLAY INTO IT. SO AS WE LOOK AT -- OKAY. I THOUGHT WE WERE GOING TO LOOK. I HAVE NO DISCLOSURES, NOTHING I'M GOING TO TAKE ABOUT IS OFF-LABEL. I'M NOT GOING TO BE SPEAKING ABOUT DRUGS EXCEPT IN THE MOST LONGITUDINAL OF WAYS. SOME OF THE TAKE AWAYS. THIS IS SOMETHING WHICH I THINK IS IMPORTANT. LEADERSHIP DEVELOPMENT IS AN IMPORTANT PART OF TRAINING PHYSICIANS. I THINK IT HELPS THEM UNDERSTAND THEIR ROLE WITHIN THE ORGANIZATION OF A CARE OF A PATIENT. THERE ARE PRINCIPALS OF LEADERSHIP THAT CAN BE TAUGHT. I THINK IT'S NOT SOMETHING THAT EVERY ONE IS BORN WITH, BUT I THINK IT'S SOMETHING PEOPLE CAN LEARN FROM AND BE TAUGHT, CERTAINLY, THE MILITARY HAS GIVEN US GOOD EXAMPLES OF THAT. THE ABILITY TO COMMUNICATE IS OBVIOUSLY AN IMPORTANT PART OF LEADERSHIP TRAINING. AND IF YOU'RE GOING TO BE A PHYSICIAN, YOU HAVE TO RECOGNIZE THAT YOU'RE TREATING AMONG THE MOST VULNERABLE POPULATIONS, AND THAT YOU HAVE TO HAVE A HEIGHTENED AWARENESS OF WHERE CONFLICT ARRAYS AND MORE IMPORTANTLY, WHERE YOUR OWN BIASES NECESSARILY INFLUENCE THE OUTCOME OF YOUR PATIENTS. THIS WAS ONE OF THE BEST IDEAS REGARDING THIS, A TRUE LEADER IS SOMEONE WHO DEALS IN HOPE. ABLE TO INSPIRE INDIVIDUALS TO GO BEYOND THAT WHICH THEY WOULD NECESSARILY ASSUME THEY CAN DO TO DO SOMETHING EVEN MORE. AND I HOPE AS WE LOOK AT OUR UPCOMING ELECTION, AND I'LL KEEP MY OPINIONS ABOUT WHO AND WHICH TO MYSELF IN THIS HIGHLY POLITICAL ENVIRONMENT OF WASHINGTON, D.C. BUT I WOULD HOPE THAT WE WILL KEEP A PERSPECTIVE ABOUT THAT AS WE AIM TO BE THE BEST THAT WE CAN BE, NOT THE WORST. LEADERSHIP ALSO HAS A VISION. THERE NEEDS TO BE AN ASPECT OF IT IN WHICH YOU ARE THINKING ABOUT WHAT YOU WANT TO ACCOMPLISH, AND IN THE CASE OF PHYSICIANS, WHAT THEY HOPE THEIR PATIENTS WILL BE ABLE TO DO. AND YOU HAVE TO ADVANCE THAT DECISION AND YOU NEED TO HAVE THE SKILL SET, AND THEREFORE, THE SUPPORTING STRUCTURE TO DO IT. OBVIOUSLY, I'M A BIT PREJUDICED WHEN IT COMES TO THIS STATEMENT. I DON'T THINK IT'S GENDER SPECIFIC. AND I THINK THAT MANY OF THE ROLE THAT WE ASSUME ARE ONES THAT ARE TOLD TO US, NOT THOSE THAT WE HAVE CHOSEN FOR OURSELVES. IT BECOMES IMPORTANT TO ASK THAT QUESTION OF YOURSELF. SO WHY CONSIDER LEADERSHIP TRAINING AT ALL IN THE CONTEXT OF SOMETHING LIKE BE A NEUROSURGICAL RESIDENCY. I BELIEVE ALL PHYSICIANS NOT JUST SURGEONS ARE LEADERS BY VIRTUE OF THEIR JOBS. THEY HAVE OFFICES THAT THEY MUST RUN. IN OUR CASE WE HAVE OPERATING ROOMS, CLINICS LABORATORY, CLASSROOMS, AND FRANKLY WE'RE STILL FORTUNATE OR UNFORTUNATE THAT WITHIN OUR GREATER COMMUNITIES, PHYSICIANS ARE STILL VIEWED AS IMPORTANT TO THE COMMUNITY. I CAN STATE IN MY OWN CASE, WHEN I WAS LOOKING AT JOBS AND WHAT I WANTED TO BE WHEN I GREW UP, ONE OF THE THINGS THAT WAS EXTREMELY IMPORTANT TO ME, HAVING BEEN RAISED BY CHILDREN OF THE GREAT DEPRESSION, WAS TO HAVE A JOB EVEN IN THE WORST OFF TIMES. AND SO AS A WOMAN WITH A DISABILITY, ONE OF THE THINGS I LOOKED AT WAS WHERE WAS THERE GOING TO BE A NEED. I LOVE SCIENCE. AND I LIKE PEOPLE, AND I KNEW THAT EVEN IF THEY PAID ME IN CHICKENS, THEY WOULD PROBABLY PAY ME IF I WAS A GOOD DOCTOR. THAT WAS IMPORTANT TO ME. BUT THERE ARE ALSO LAWS OF PHYSICS. ALL OF US BELIEVE IN THE HEIGHT THAT WE CAN DO EVENING. EVERYTHING. I THINK WE ALL KNOW THAT'S NOT TRI. YOU CAN'T BE IN TWO PLACES IN ONE TIME AND THERE ARE 24 HOURS IN A DAY. THE CHALLENGES OF THE NEW AGE, WE'RE WORKING WITH WORK HOUR RESTRICTIONS. THEY'RE GOT GOING TO GO AWAY. IF WE LOOK AT THE INSTITUTE OF MEDICINE AND SOME OF THE NEW STUDIES THAT ARE COMING FORWARD, THEY'RE GOING TO BE IMPORTANT RESTRICTIONS. THEY'RE GOING TO BE PLACED ON ALL OF US. AND THEREFORE, WE HAVE TO LEARN IN THIS NEW WORLD, HOW WE'RE GOING TO PROVIDE THE CARE THAT WE WANT TO FOR OUR PATIENTS. AND THE ASSUMPTION FOR THE PAST ARE NO LONGER TRUE. ONE OF THE THINGS THAT WE USED TO THINK ABOUT, IF YOU FOLLOWED A DOCTOR LONG ENOUGH YOU WOULD BECOME LIKE THEM. I THINK WE HAVE BECOME WAY MORE AWARE OF THE FACT THAT IT IS SHOULD BE METHODICAL, TESTED AND UNDERSTOOD. IF WE LOOK AT THE MATRIX AND THE CURRICULUM THAT ARE OUT THIS, IF WE LOOK AT THE ANALYSIS THAT ARE BEING DONE OF PHYSICIANS GOING THROUGH THEIR TRAINING PROGRAMS, I THINK WE'RE GETTING TO A BETTER UNDERSTANDING OF THE FACT THAT THERE IS VARIATION WITHIN INDIVIDUALS AS TO HOW FAST THEY LEARN. SO OBVIOUSLY GENERATIONAL DIFFERENCES, ALL OF US RECOGNIZE THAT. SO DEFINING THE GOALS OF A RESIDENCY BECOME IMPORTANT AND MORE IMPORTANTLY, INDIVIDUALS HEED TO KNOW HOW THEY'RE SUCCEEDING WITHIN THAT RESIDENCY. RESIDENCY TRAINING IS VERY HIERARCHICAL. THERE ARE GRADUATED LEVELS OF RESPONSIBILITY. THEREFORE, THERE IS ALMOST A COMPRESSION OF A LEARNING CURVE GOING THROUGH THE RESIDENCY. BECAUSE OF THEIR RESTRICTION OF WORK HOURS, AND FRANKLY BECAUSE OF SOME OF THE GENERAL RATIONAL CHANGES, THE FACE TIME SPIND WITH ANY GIVEN RESIDENT CHANGES. THE TIME YOU DO HAVE HAS TO BE VERY FOCUSED, ORGANIZED, AND HAS TO BE ABLE TO ACHIEVE THE GOALS OF THAT TIME IN A STRAIGHT FORWARD FASHION. IN DEVELOPING A PROGRAM, YOU WANT TO ACCELERATE THE TRANSFER OF LEARNING. I THINK THAT LEADERSHIP HELPS INDIVIDUALS ACCOMPLISH THAT. SO WHY CARE ABOUT LEADERSHIP DEVELOPMENT? I THINK IT HELPS CREATE THAT FRAMEWORK THAT ACCELERATES THE LEARNING PROCESS. IT HELPS DEFINE JOBS. RESPONSIBILITIES, AND MORE IMPORTANTLY THE GOALS OF THOSE JOBS. IT'S ALSO RECOGNITION OF THE ULTIMATE JOB THAT EACH RESIDENT WILL HAVE IN THEIR OWN PRACTICES. HOPEFULLY IT PROVIDES THEM WITH A SKILL SET THAT THEY CAN BE RELIED UPON IN THE MOST DIFFICULT OF TIMES. THERE IS A REASON WHY CHECKLISTS WORK, A REASON WHY MANY OF THESE TRIED AND TRUE THINGS THAT ARE BORROWED FROM ONE SPECIALTY APPLY TO ANOTHER, ARE BENEFICIAL. SKILLS REQUIRED TO CONCUR ADVERSITY AND EMERGE STRONGER ARE VERY IMPORTANT. I WAS ASKED BY MANY OF THE STUDENTS EARLIER THIS MORNING THAT I MET WITH ABOUT HOW DO YOU GO BEYOND THE COMPLICATIONS THAT YOU MIGHT CREATE. HOW DO YOU MAKE YOURSELF CAPABLE OF NOT FEELING THE PAIN OF EVERY PATIENT THAT YOU HAVE THAT DOESN'T DO WELL, OR THAT HAS A COMPLICATION. AND I THINK THAT REQUIRES A HEARTINESS OF SPIRIT WHICH ALLOWS ONE TO RECOGNIZE THE FAULTS THAT WE HAVE AND TO IMPROVE UPON THEM, BUT ALSO, ALLOWS US TO GET UP IN THE MORNING AND COME TO WORK THE NEXT DAY. SO HARDINESS AND THE ABILITY TO GRASP THE CONTEXT OF A GIVEN PROBLEM ALLOWS ONE TO SURVIVE, THEREFORE, LEARN FROM DIFFICULT TIMES. HOPEFULLY IT MAKES YOU CONTINUE TO BE ENGAGED AND COMMITTED, NOT HARDENED AND ISOLATED. AT THE UNIVERSITY OF MICHIGAN, I HAVE BEEN THERE FOR 25 YEARS, AND WE DECIDED WE WERE GOING TO TRY TO DEVELOP A LEADERSHIP AND CURRICULUM SPECIFICALLY FOR OUR RESIDENTS THAT HELP THEM RECOGNIZE THEIR VARIOUS ROLES GOING THROUGH THEIR RESIDENCY. MOST OF ALL PREPARE THEM FOR THEIR FUTURE CAREERS AS PHYSICIANS AND NEUROSURGEONS. WE ASSIGNED A NEUROSURGEON AT THE COORDINATOR OF THE COURSE. WE BORROWED HEAVILY FROM KNOWN LEADERSHIP DEVELOPMENT PROCESSES WAMC, AMERICAN COLLEGE OF SURGEONS, ALSO THE MILITARY. IF WE LOOK AT THE DEVELOPMENT OF LEADERS WITHIN THE MILITARY, THEY NEED TO DO THIS ON A REGULAR BASIS AND QUICKLY. THERE WERE IMPORTANT READING LISTS AVAILABLE FROM THAT AS WELL AS COURSES. WE DID CREATE A READING LIST. ONE OF THE FIRST BOOKS THAT I READ THAT I THOUGHT WAS REALLY INTERESTING, THAT DISCUSSED THE MAKING OF A MARINE CORPS OFFICER WAS ONE BULLET AWAY. FOR THOSE INTERESTED IN ANY READING MATERIAL I WOULD CERTAINLY SUGGEST THIS. IT DOES TALK ABOUT HOW THE PROCESS ALLOWS ONE TO CREATE A YOUNG FIELD OFFICER. I THINK THERE ARE LEADERSHIP PRINCIPALS IMPORTANT. YOU NEED TO KNOW IRS AND WORK TO IMPROVE YOURSELF. TECHNICAL HEY NEUROSURGEONS HAVE TO BE COMPETENT BUT ALSO HAVE TO BE INTELLIGENTLY PROFICIENT. CAPABLE OF LOOKING AT COMPLEX PROBLEM, INCOMPLETE INFORMATION, AND MAKING ASSESSMENTS AND DECISIONS. THERE IS NO SUBSTITUTE FOR KNOWING YOUR STUFF. IT REALLY DOESN'T MATTER THAT THERE IS A 40 HOUR OR 80 HOUR WORK WEEK WE STRIKES. YOU NEED TO BE ABLE TO KNOW YOUR MATERIAL TO BE ABLE TO BE THE BEST ADVOCATE FOR YOUR PATIENTS. IF YOU HAVE TO DEVELOP A SENSE OF RESPONSIBILITY SO THAT IT'S NOT JUST ABOUT YOU, IT'S ALSO ABOUT YOUR SUBODDNATES, ABOUT THE OTHERS THAT YOU WORK WITH. AND CREATING THAT TEAM ENVIRONMENT BECOMES CRUCIAL. ONE OF THE THINGS I HAVE FOUND THAT'S IMPORTANT ALSO IS TO BE ABLE TO ALLOW RESIDENTS THE TINT TO FIGURE OUT THE IMPORTANT QUESTIONS. WHAT'S THE TIMEFRAME IN WHICH THEY IMMEDIATE TO COME TO A DECISION? COMING TO A DECISION WHICH CAN OFTEN BE VERY DIFFICULT IS AN IMPORTANT PART OF TRAINING FOR RESIDENTS. LEADERSHIP, YOU NEED TO SET ABEXAMPLE. YOU CAN'T COMMUNICATE ENOUGH. YOU HAVE TO BE ABLE TO LET INDIVIDUALS KNOW WHAT YOU'RE THINKING AND MORE THAN IMPORTANTLY, ONE OF THE THINGS I REALIZED IS THAT SOMETIMES YOU MENTOR PEOPLE WITHOUT EVEN KNOWING IT. THEREFORE, IT DOES MATTER WHAT YOU SAY AT GIVEN TIMES IN YOUR LIFE. YOU HAVE TO KNOW YOUR TEAM. YOU HAVE TO LOOK OUT FOR THEIR WELFARE AND SUPPORT THEM. AND PARTICULARLY, WE WORK IN AN OPERATING SETTING, OF A VERY DEFINED CADRE OF PEOPLE YOU'RE WORKING WITH. YOU NEED TO WATCH OUT FOR THEM, NEED TO HELP THEM THROUGH THE DIFFICULTIES THAT THEY HAVE IN THEIR LIFE. THEY'LL GOING TO HELP YOU THROUGH DIFFICULTIES YOU MAY BE HAVING DURING ANY GIVEN CASE. I DO THINK IT'S IMPORTANT THAT YOU SEEK THE RESPONSIBILITIES THAT ARE APPROPRIATE FOR YOUR JOB, AND THAT I TAKE RESPONSIBILITY FOR THE ACTIONS ASSOCIATED WITH THE THINGS THAT YOU'RE DOING. AND YOU ALSO HAVE TO MAKE SURE THAT YOU ARE NOT ASSIGNING TASKS OR ASKING INDIVIDUALS TO DO SOMETHING WHICH IS BEYOND WHAT THEN. I THINK IT'S IMPORTANT THAT I RECOGNIZE THE INDIVIDUALS WITHIN YOUR TEAM. THIS IS A NATURAL TENDENCY, I THINK, TO WANT TO PUSH EVERYONE TO THE MAX BY I THINK YOU HAVE TO ALSO RECOGNIZE THOSE FOR THOSE INDIVIDUALS, WHAT'S IMPORTANT TO THEM AND WHAT THEY HAVE IN THE WAY OF TRAINING AND KNOWLEDGE BASE. THERE ARE CERTAIN BASIC MARINE CORPS LEADERSHIP PRINCIPALS WHICH HAVE BEEN STATED IN LITERATURE THROUGHOUT THE MILITARY. AND I'M JUST GOING TO MENTION THEM. I DO THINK THAT THEY HAVE SOME MEANING WITHIN THE CONTEXT OF PHYSICIAN TRAINING AS WELL. BEARING -- HOW YOU CARRY YOURSELF. WHETHER YOU'RE ENGAGED, INVOLVED, SOME OF IT HAS TO DO WITH NECESSARILY WHAT YOU'RE WEARING BUT MORE IMPORTANTLY, A LOT MORE TO DO WITH THE ATTITUDE YOU BRING FORWARD. COURAGE. THAT'S THE ABILITY TO ACCEPT CRITICISM, RECOGNIZE YOUR OWN FEARS, AND MORE IMPORTANTLY, MOVE AND MAKE DECISIONS. DECISIVENESS. THE ABILITY TO MAKE PROMPT DECISIONS. DEPENDABILITY. THAT'S ONE OF THE THINGS THAT PHYSICIANS BECOME KNOWN FOR, THEIR ABILITY TO COME FORWARD, PROVIDE INFORMATION, BE THIS. IT'S NEVER CHANGED. APPLICABLE, AVAILABLE AND KNOWLEDGEABLE ARE THE CHARACTERISTICS THAT MAKE A GREAT PHYSICIAN. ENDURANCE. THAT'S ONE THAT EACH INDIVIDUAL HAS TO DECIDE FOR THEMSELVES. NEUROSURGERY IS A LONG RESIDENCY, AND YOU NEED TO HAVE A MENTAL AND PHYSICAL STAMINA TO WITHSTAND THE STRESSES AND FATIGUES. AND ENTHUSIASM. IF THERE IS PROBABLY ONE OF MY MAJOR FAULTS IS THAT I'M INTERNALLY OPTIMISTIC. YOU PROVIDE 2 DROPS OF WATER IN A GLASS, WE'RE WELL ON THE WAY TO A GLASS HALF FULL. I THINK THAT FEEDS TO BE TEMPERED BY THE CIRCUMSTANCES I'M WORKING WITH AND HONESTY WITH THE PATIENTS THAT I'M DEALING WITH. INITIATIVES. TAKING ORDERS OR ACTION IN THE ABSENCE OF ORDERS. WE'RE INTO THE SEASON OF RESIDENT APPLICANTS RIGHT NOW. AND I SEE MANY OF THEM COMING FORWARD TO LOOK FOR RESIDENCY POSITIONS. I HAVE ABOUT 275 APPLICANTS FOR 2 PHYSICIANS THIS YEAR. ONE OF THE THINGS I CAN TELL YOU THAT I WILL LOOK AT IS HOW THE INDIVIDUALS WITH WHOM I'M INTERVIEWING TREAT THE PEOPLE AROUND ME. HOW THEY TREAT THE NURSES. THAT PIECE OF PAPER THAT IT'S IN FRONT OF THE GARBAGE CAN PECKED UP, PUT INTO THE GARBAGE CAN WHEN NO ONE IS WATCHING. INTEGRITY OCCURS IN THE DARK HOURS WITHOUT A LOT OF FAN FAIR AND LIMELIGHT, BUT DOES REFLECT THE FACT THAT YOU HAVE GOOD JUDGMENT AND MORE IMPORTANTLY, THE CHARACTER TO DO IT CORRECTLY. THERE IS NO SUBSTITUTION FOR THAT CHARACTER. JUDGMENT, OBVIOUSLY, MEANS THE ABILITY TO WEIGH FACTS AND POSSIBLE COURSES OF ACTION AND THEREFORE MAKE SOUND DECISIONS. ONE OF THE MOST UNCOMFORTABLE ASPECTS OF BEING A PHYSICIAN IS TO MAKE DECISIONS THAT ARE LIFE ALTERING, BUT WITH LESS THAN PERFECT KNOWLEDGE. WE DO THIS REALLY. AND JUSTICE GIVING REWARD AND CRITICISM ACCORDING TO THE MERITS OF THE SITUATION. KNOWLEDGE AGAIN, NO SUBSTITUTE FOR THAT IN MEDICINE. YOU HAVE TO HAVE THE KNOWLEDGE BASE OR ABILITY TO FIND THE KNOWLEDGE TO HELP THOSE INDIVIDUALS THAT YOU'RE WORKING WITH. LOYALTY, FAITHFULNESS TO ONE UNIT, PEERS AND PATIENTS. A SENSE OF PRIDE IN THE PLACES YOU WORK WITH. I'VE ALWAYS SAID THAT IF YOU CHOOSE TO WORK WITH THOSE THAT ARE STELLAR, THEY WILL IMPRESS YOU AND MORE IMPORTANTLY, PUSH YOU TO YOUR BEST. I ALWAYS TRY TO AIM FOR THE FOLKS THAT MAKE ME FEEL THE MOST UNCOMFORTABLE BECAUSE OF THEIR OWN BRILLIANCE AND CAPABILITY. TACT, THE ABILITY TO DEAL WITH OTHERS WITHOUT HOSTILITY. THERE ARE MANY WAYS TO SAY THINGS. SOME CAN BE SAID DREADFULLY. UNSELFISHNESS. ONE OF THE COMMENTS IS LEADERS EAT LAST. I DON'T KNOW IF THAT'S EXACTLY TRUE, BUT I THINK IT IS IMPORTANT TO RECOGNIZE THAT EVERY ONE CONTRIBUTES TO THE WELFARE OF YOUR GIVEN PATIENT AND IT'S NOT JUST ABOUT YOU. MENTORING BECOMES AN IMPORTANT PART OF IT. DIFFERENT MEMBERS ARE IMPORTANT FOR DIFFERENT ASPECTS OF YOUR CAREER. AND DIFFERENT TIMES. RIGHT NOW, I HAVE A GOOD OLD GIRLS NETWORK WITH SOME OF MY FRIENDS IN NEUROSURGERY THAT I WILL MEET WITH ON A REGULAR BASIS AND TALK TO ABOUT IDEAS THAT I HAVE, ABOUT PROBLEMS I'M HAVING, ABOUT TROUBLESHOOTING. I THINK THAT'S ONE OF THE AREAS THAT EVERY ONE NEEDS TO DEVELOP THAT CADRE OF FRIENDS, COLLEAGUES, MENTORS THAT ARE HONEST AND HELP YOU FIND YOUR WAY. THE SUPPORT GROUPS ARE REALLY IMPORTANT FOR YOU TO BOUNCE IDEAS OFF OF. MENTORS MUST RECOGNIZE THAT IT'S AN INCREASINGLY DIVERSE WORKPLACE. AND OUR PATIENTS, THIS IS A BROAD SPECTRUM OF THEM. UNDERSTANDING THAT, UNDERSTANDING OUR UNCONSCIOUS BIASES. WE'RE DOING SOME OF THAT TRAINING AT THE UNIVERSITY OF MICHIGAN, PARTICULARLY WITHIN THE DEPARTMENT OF NEUROSURGERY. IT'S REALLY SHOCKING HOW THEY COME WITH US AS PART AND PARCEL OF OUR UPBRINGING AND BACKGROUND, BUT THAT YOU CAN INFLUENCE THEM BY POINTING OUT THOSE DIFFERENCES, AND MORE IMPORTANTLY, ALLOWING INDIVIDUALS TO STUDY THE PROBLEM. OFTEN STUDYING THE PROBLEM FINANCES IT, HELPS PEOPLE UNDERSTAND IT. RECOGNIZE THE SKILL SET NEEDED TO BE SUCCESSFUL. FOR ME, AS A NEUROSURGEON AND THE PEOPLE I'M TRAINING, THEY REQUIRE TECHNICAL EXPERT EASE, UNDERSTANDING OF THE RULES AND REGULATIONS. SURGEONS MAY THINK THEY'RE ULTIMATELY IN CHARGE, IN THE END IT'S LAWYERS AND LEGISLATORS THAT DICTATE WHAT WE DO. FINANCIAL. RECOGNIZE WHERE THE BIAS COMES FOR FINANCIAL INCENTIVES. RECOGNIZE WHAT IS FEASIBLE AND NOT FEASIBLE WITHIN THE CONTEXT OF FINANCES. AS AN ADMINISTRATOR, I RECOGNIZE THAT I'M IN CHARGE OF A LARGE GROUP OF INDIVIDUALS, ALL OF WHOM I MUST HAVE RESPONSIBILITY FOR. I CAN ASSURE YOU RIGHT NOW IF SOMEONE AT THE UNIVERSITY OF MICHIGAN IN THE DEPARTMENT OF NEURO SURGERY DOING SOMETHING HORRIBLE, THAT THEY'RE HAVING A TREMENDOUSLY BAD OUTCOME, IF THEY HAVE DONE SOMETHING WHERE THEY'VE OPERATED ON THE WRONG SIDE OF THE PATIENT, TRUST ME, IT BECOMES MY PROBLEM. MY PROBLEM BECAUSE I'M RESPONSIBLE FOR THE DEVELOPMENT OF THE CULTURE WHICH WILL ALWAYS, ALWAYS TRUMP THINGS. IF YOU CAN HAVE A GOOD CULTURE THAT TAKES RESPONSIBILITY AND AIMS TOWARD PROFESSIONALISM AND EXPERTISE, AND HONESTY, THAT GOES A LONG WAY. AND YOU ALSO HAVE TO RECOGNIZE THAT THIS IS AN ASPECT OF BEING A PHYSICIAN NOW WHICH IS -- YOU'RE NOT COMPLETE EVER. YOU'RE CONSTANTLY LEARNING, CONSTANTLY GROWING, CONSTANTLY CHANGING. IF YOU DON'T LIKE CONTINUOUSLY LEARNING, I THINK IT'S VERY HARD TO BE A PHYSICIAN IN THIS DAY AND AGE. YOU ALSO HAVE TO RECOGNIZE THAT THE LEARNING CURVE SEEMS TO BE STEEPER, WITH THE ABILITY TO HAVE INFORMATION IN 24/7 ENVIRONMENT. THERE WAS A TIME WHEN PEOPLE TALKED ABOUT TEN TO 15 YEARS FOR SOMETHING COMING FROM THE BENCH, IF YOU WILL, OUT INTO THE GENERAL COMMUNITY. NOW IT'S PROBABLY ON THE ORDER OF 1-2 YEARS. SO THERE IS JUST A CHANGING REALITY. ONE HAS TO ACCEPT AND RECOGNIZE THAT. AND THAT THE QUALITY OF PATIENT CARE IS DICTATED BY A WIDE VARIETY OF ASPECTS THAT SOME OF WHICH CAN BE TRAINED, SOME OF WHICH ARE INSTINCTIVE. THE MAJORITY OF WHICH REQUIRE WORK AND EFFORT ON THE PART OF THOSE THAT ARE PROVIDING THE EDUCATION. MENTORS ALSO REMAIN ACTIVE. THEY SAVE PART OF THEIR MENIES LIVES. THEY'RE READY TO CHANGE AND ADAPT WITH THE INDIVIDUALS THEY'RE MENTORING. THEY RECOGNIZE THEIR OWN STRENGTHED AND WEAKNESSES, WHEN IT'S TIME TO SAY I THINK YOU SHOULD SEEK ADVICE FROM SO AND SO. THEY DO SEEK CHALLENGES. THEY'RE NOT AFRAID TO BE CONFRONTED WITH THEIR OWN FOIBLES. IT'S IMPORTANT WHEN YOU LOOK AT THAT MENTOR ROLE TO ESTABLISH A RELATIONSHIP OF MUTUAL RESPECT, PROVIDE INTEGRAL AND PROFESSIONAL ASPECT OF BEING A ROLE MODEL. AND YOU NEED TO PROVIDE SUPPORTED FOR THE GOOD AND BAD TIMES. PERHAPS THE MOST DIFFICULT AND MOST IMPORTANT TIMES ARE WHEN INDIVIDUALS ARE GOING THROUGH EITHER COMPLEX PROBLEMS, OR HAVING THEIR OWN PERSONAL PROBLEMS IN WHICH THEY NEED TO HAVE ASSISTANCE. YOU NEED TO UNDERSTAND THE DIFFERENCE BETWEEN BEING A MENTORING PROTEGE AND SUPERVISOR TRAINING. A MENTOR PROTEIN ANGELA NEEDS TO BE HONESTLY HONEST. YOU NEED TO BE ABLE TO PROVIDE CRITICISM IN A WAY WHICH IS DIRECT, BUT ALSO SUPPORTIVE. THE SUPERVISOR TRAINING IS A LITTLE BIT DIFFERENT, WHERE YOU ACTUALLY HAVE TO MAKE JUDGMENTS IN WHICH SOMEONE IS MOVING FORWARD OR NOT, CAPABLE OF MOVING FORWARD. AND THERE HAS TO BE SOME ASPECT OF LIFE -- WORK LIFE BALANCE AND UNDERSTANDING THE GENERATIONAL, THROUGH BECOMES EXTREMELY IMPORTANT TO INDIVIDUALS. ONE OF THE STRONGEST INFLUENCES AS TO WHY SOMEONE GOES INTO A GIVEN SUBSPECIALTY HAS TO DO WITH MENTORS. I'M ALWAYS SURPRISED THAT IT'S THE INDIVIDUAL THAT FOUND SOMEONE WHEN THEY WERE DOING, I DON'T KNOW, SOME ODD PROJECT AND THEY FOUND THIS REALLY INTERESTING INDIVIDUAL THAT LED THEM DOWN THE CAREER OF THEIR LIFETIME. SO IT DOES BECOME IMPORTANT TO BE ABLE TO PROVIDE INDIVIDUALS WITH A BROAD SPECTRUM OF THOSE KINDS OF INTERACTIONS THAT THEY CAN MOVE ON TO SEE THE VARIETY THAT'S OUT THERE, PARTICULARLY WITHIN MEDICINE. IT'S CRUCIAL ON THE FORMATIVE YEARS TO HAVE THAT KIND OF ROLE MODEL. IT'S VERY IMPORTANT, I THINK, FOR CAREER DEVELOPMENT. IF YOU ASK ME, AS A WOMAN HAVING TRAINED IN A PERIOD OF TIME WHEN THE LOCKER ROOMS, DOCTOR'S AND NURSES, I HAVE UNDERSTOOD FULLY THAT DEVELOPING THOSE FRIEND SHIPS, THOSE MENTORING RELATIONSHIPS WITH OTHER WOMEN CAN SOMETIMES BE DIFFICULT. THERE ARE A NOT A LOT OF THEM IN NEUROSURGEON TO SPEAK OF. THE MEN AND WOMEN WHO HAVE ACTED AS MENTORS FOR ME AND SOURCES OF INFORMATION, BUT ALSO, SOURCES OF KNOWLEDGE. FINDING SUPPORT, IMPORTANT THAT YOU HAVE HONEST MENTORS. YOU NEED TO HAVE THAT CRIMP. SOMEONE HAS TO TELL YOU, THAT IS AN UGLY SHIRT. JUST NOT WORKING. YOU NEED TO HAVE PEOPLE SAY TO YOU THAT IS AN INTERESTING CONCEPT, BUT REALLY, ILL ADVISED FOR YOU TO PROCEED WITH THAT. OR IS THIS THE STORE YOU REALLY GO DOWN ON. THE ONE WHERE YOU REALLY WANT TO CHANGE JOBS OVER THIS. IS IT THAT TERRIBLE? YOU ALSO HAVE TO RECOGNIZE THAT THERE ARE DIFFERENCES, AT LEAST FOR ME, IN REACH RESIDENT. HOW I APPROACH. THIS I'VE LEARNED AND THIS SOUNDS GENERAL LISTIC AND APOLOGIZE, BUT OFTEN FOR SOME OF THE RESIDENTS, THIS TENDS TO BE PARTICULARLY TRUE FOR SOME OF THE FEMALE RESIDENTS, A CRITICISM ABOUT A GIVEN CASE AND THEIR TECHNIQUE IN IT IS SUBSTANTIVELY DIFFERENT FOR THEM. THEY TAKE IT AS A CRITICISM OF A GLOBAL SET OF PRINCIPALS THAT THEY HOLD, OR PERFORMANCE, ALL OF WHICH IS NOT TRUE. SO I'VE LEARNED HOW TO BE MORE SPECIFIC WITH CERTAIN RESIDENTS AND MORE GENERALISTIC WITH OTHERS, BECAUSE IT'S IMPORTANT TO RECOGNIZE THAT EACH PERSON IS OFTEN HEARING THINGS THROUGH A VERY DIFFERENT SET OF YEARS THAN YOU ARE NECESSARILY THINKING OR SPEAKING. IT'S ALSO IMPORTANT TO FIND ADVISORS THAT YOU CAN NETWORK WITH. NETWORKING CANNOT BE UNDERESTIMATED. IT ALLOWS YOU TO UNDERSTAND WHAT'S HAPPENING GLOBALLY WITHIN YOUR FIELD, AND MORE IMPORTANTLY, WHAT MAY HELP YOUR PATIENTS. ALSO, HAVE TO -- WHEN YOU FIND THAT SUPPORT, IT HELPS GET THE INDIVIDUALS TO MOVE IN ONE DIRECTION. A GOOD MENTOR WILL FOSTER AN ENVIRONMENT IN WHICH HONEST MISTAKES ARE SEEN AS OPPORTUNITIES TO LEARN. IN WHICH PEOPLE CAN FREELY RECEIVE SUPPORT AND INFORMATION FROM OTHERS. I HAVE [INDISCERNIBLE] -- TOM RUSSEL ONE OF THE BETTER -- HE SAID THIS, FIGURELY IN THE AREA OF SURGERY, THAT'S QUITE TRUE. MENTORS MOTIVATE, EMPOWER, NURTURE, TEACH BY EXAMPLE, OFFER COUNSEL, RAISE THE PERFORMANCE BAR AND A GOOD MENTOR IS REFLECTED LIGHT. ONE OF THE THINGS THAT I ALWAYS SAY ABOUT THE FACT, WHEN I BECAME CHAIR OF NEUROSURGEON, MY CAREER -- NORMING, MY CAREER STOPPED. MY GOALS WERE TO MAKE OTHER PEOPLE SHINE. I AM ALWAYS THE MOON. I SHOULD NEVER BE THE SUN. IT'S ABOUT REFLECTED LIGHT. IT'S ABOUT THE FACT THAT I'M EMPOWERING OTHER INDIVIDUALS WITHIN MY GROUP THAT I'M TAKING CARE OF, TO MAKE SURE THEY CAN BECOME THE BEST NEUROSURGEON, THE BEST SCIENTISTS, THE BEST ADVOCATES FOR THEIR PATIENTS THEY CANBO IT'S ALSO CREATING A CULTURE OF MENTORING. EVEN THE MOST JUNIOR INDIVIDUALS HAVE THE ABILITY TO MENTOR. YOU NEED TO DISCUSS THIS WITH -- WE DISCUSS THIS OPENLY. I THINK SOMETIMES PEOPLE PERHAPS HAVE A NATURAL TENDENCY TO WANT TO DO IT. OTHERS DON'T. YOU NEED TO HELP THEM UNDERSTAND THAT IT'S PART OF THEIR ROLE AS PHYSICIANS, BECAUSE FRANKLY, THAT'S WHAT THEY'RE DOING WHEN THEY WORK WITH PATIENTS. YOU NEED TO PROVIDE FEEDBACK AND EDUCATION AS TO BEST PRACTICES. WE TALK ABOUT THAT. WE LOOK AT ARTICLES. WE LOOK AT ARTICLES FROM OTHER AREAS OF BOTH -- WITHIN MEDICINE AND OUTSIDE OF MEDICINE. AND WE HAVE TO RECOGNIZE THAT THIS MENTORING, AS MUCH AS YOU THINK YOU'RE MENTORING SOMEONE, THEY'RE ALWAYS MENTORING YOU IN THE PROCESS. THAT DIALOGUE BETWEEN TWO INDIVIDUALS OR TWO GROUPS IS IMPORTANT. NEUROSURGEON -- THIS IS VERY SPECIFIC TO NEUROSURGERY. THEY HAVE TO BE LEADERS IN THE OPERATING ROOM. THEY HAVE TO BE MENTORS TO MEMBERS OF THE TEAM, CONSIDER HOW TO PROMOTE ALL PARTS OF THE TEAM. THEY HAVE TO ENCOURAGE AND RECOGNIZE THE STRENGTH OF THEIR TEAM BECAUSE IN THE END, THE TEAM IS WHAT IS WORKING TO TAKE CARE OF THE PATIENT. NOW, MANY OF THE TEAM MAY BE -- IF YOU WILL, TEMPORARY PLAYERS THAT HAVE DEFINED TIMES OF WORK, ET CETERA. BUT THE ABILITY TO BRING THEM TOGETHER IN A COHESIVE FASHION BECOMES IMPORTANT. YOU ALSO HAVE TO RECOGNIZE, AND