FOR TODAY WE HAVE ETHICAL ISSUES AND INTERNATIONAL RESEARCH AND WE HAVE TWO SPEAKERS WHO ARE GOING TO FOLLOW EACH OTHER AND THEN AFTER THE BREAK WALK THROUGH A CASE WITH EVERYBODY. AND BOTH OF THESE WONDERFUL SPEAKERS WORK FOR US IN THE DEPARTMENT OF BIOETHICS. I'LL START WITH DR. ANNETTE RID. SHE'S IN THE DEPARTMENT OF BIOETHICS AT THE NIH AND ALSO WORKS FOR THE KENNEDY INSTITUTE OF ETHICS AT GEORGETOWN UNIVERSITY AND WILL START BY INTRODUCING SOME OF THE ISSUES AND INTERNATIONAL RESEARCH AND TALKING A LITTLE BIT ABOUT SOMETHING CALLED STANDARD OF CARE. SO ANNETTE. >> THANK YOU. GOOD MORNING, EVERYONE. AND A VERY WARM WELCOME TO THIS SESSION THAT I'M VERY HAPPY TO CO-LEAD WITH JOE MILLUM AND MY COLLEAGUE AT THE DEPARTMENT. AS ALWAYS, WHAT I SAY DOESN'T REPRESENT THE VIEWS OF THE NIH OR U.S. GOVERNMENT BUT I THINK MOST OF YOU WELL KNOW THAT. THE QUESTION WE WANT TO POSE FOR TODAY IS WHAT RESEARCHERS AND SPONSORS'OBLIGATIONS ARE IN INTERNATIONAL REASON AND IN THE CON TEXT OF AND WHEN WE TALK ABOUT INTERNATIONAL COLLABORATIVE RESEARCH THIS MORNING WE'LL TALK ABOUT RESEARCH THAT IS SPONSORED BY HIGH-INCOME COUNTRY INSTITUTIONS TYPICALLY CONDUCTED FROM RESEARCHERS FROM HIGH-INCOME AND LOW AND MIDDLE-INCOME COUNTRIES AND CARRIED OUT IN LOW AND MIDDLE-INCOME COUNTRIES AND THE QUESTION THAT ARISES AND THAT WE WANT TO POSE TODAY IS WHAT ARE THE CHALLENGES INVESTIGATORS FACE IN INTERNATIONAL COLLABORATIVE AND LOW AND MIDDLE-INCOME COUNTRIES AND WHAT ARE THE ETHICAL CHALLENGES THAT ARISE. TO GET US THINKING ABOUT THE QUESTION I WANT TO BRIEFLY INTRODUCE A SMALL VIGNETTE OF A STUDY. MOTHER OFFSPRING MALARIA STUDY. THIS WAS A STUDY CONDUCTED IN THE EARLY 2000s IN TANZANIA SPONSORED BY THE NIH AND GATES FOUNDATION AND PART OF THE MALARIA GENOMIC NETWORK AND LOOKING AT THE BIOLOGY AND GENETICS OF THE MALARIA PARASITES AN THE MOSQUITO HOSTS FOR STRATEGY AND TREATMENT. THEY WANTED IN THE STUDY LEARN ABOUT MALARIA INFECTION IN EARLY LIFE AND ENROLLED PREGNANT WOMEN IN THE PREGNANCY AND FOLLOWED THE CHILDREN THROUGH THE FIRST FIVE YEARS OF THEIR LIFE OR ENROLLED AT BIRTH. FOR THE CHILDREN THAT WERE INVOLVED IT INCLUDED FREQUENT CLINICAL VISITS AND BLOOD DRAW. EVERY TWO WEEKS CAPILLARY AND THEN VENOUS BLOOD DRAWS AND THEN DRAWN OUT MORE. AS PART OF THE STUDY THE PARTICIPANTS AND CHILDREN WERE TREATED FOR MALARIA WHENEVER THERE WAS AN EPISODE OF MALARIA AND RECEIVED PROPHYLAXIS FOR HIV INFECTIONS AN REFERRED TO HOSPICE CARE IN THE CASE OF SERIOUS HIV ILLNESS. THIS WAS IN THE EARLY 2000s SO ANTIRETROVIRAL TREATMENT WERE STILL NOT COMMON AND WHAT DO YOU THINK THE CHALLENGES THAT RESEARCHERS CONDUCTING THIS KIND OF RESEARCH IN THIS INTERNATIONAL COLLABORATIVE CONTEXT FACE AND WHAT ARE THE ETHICAL ISSUES THAT ARE RAISED FROM THOSE? I SAW SOME PEOPLE WHO SPEAK IN AN INTERNATIONAL CONTEXT SPEAK. >> I THINK ONE ISSUE MAYBE NOT IN THIS STUDY IN PARTICULAR BUT MANY OF THESE INTERNATIONAL STUDIES IS THIS INTERVENTION OR THE STUDY GOING TO BENEFIT THAT POPULATION OR ARE WE JUST DOING IT THERE TO THEN BRING IT ELSEWHERE WHERE ULTIMATELY THESE PEOPLE WILL NOT HAVE ACCESS. >> EXCELLENT. THAT'S ONE ISSUE THAT DR. MILLUM IS GOING TO TALK ABOUT LATER. >> I THINK THE METHOD OF THE STANDARDIZATION OF EACH COUNTRY WOULD BE DIFFICULT TO COORDINATE AND SUSTAINABILITY. AFTER THE RESEARCH WHETHER PARTICIPANTS WILL GET BENEFIT AFTER STUDY ENDED BECAUSE THEY DON'T HAVE RESOURCES NO LONGER. >> EXCELLENT. PERFECT. ANY QUESTIONS OR IDEAS ABOUT THIS? THAT'S ALREADY SOMETHING TO GET US GOING. I'M GOING TO BRIEFLY OUTLINE THE WAY WE SEE THIS AND INCLUDE SOME OF YOUR COMMENTS INTO HOW I SEE THE CHALLENGES THERE'S DIFFERENT HABITS AND SHAPING IDEAS ON WHAT RESEARCH SHOULD BE CONDUCT AND HOW. AND WHERE RESEARCH IS BEING CONDUCT AND POWER DIFFERENTIALS WHERE THERE ARE DIFFERENCES IN BEING ABLE TO NEGOTIATE THE COLLABORATIVE PROJECTS DUE TO THE DIFFERENCES IN EDUCATION, FINANCE AND SO ON. AND BACKGROUND RESEARCHES OVER NON-IDEAL CIRCUMSTANCES. SO THEY FIND THEMSELVES IN CONTEXT WHERE THE PARTICIPANTS RECRUITING DO NOT HAVE ACCESS OR SOMETIMES DO NOT HAVE ACCESS TO SAN ITATION -- SANITATION AND VULNERABLE AND THOUGH THEY'RE NOT PERSONALLY RESPONSIBLE FOR THE BACKGROUND INJUSTICES AND THE PRIMARY ROLE IS TO CONDUCT RESEARCH AND THE NEEDS THAT THEY CAUSE HAVE RELEVANCE FOR THINKING ABOUT THE OBLIGATIONS OF RESEARCHERS. SO IF YOU LOOK TO THE THREE KEY CHALLENGES AN ETHICAL QUESTIONS I THINK THE CULTURAL DIFFERENCES PRIMARILY ARE RELEVANT DURING THE INFORMED CONSENT PROCESS AND THE COMMUNITY ENGAGEMENT PROCESS. SO WHAT FOR EXAMPLE SHOULD INFORMED CONSENT LOOK LIKE WHEN THE SOCIAL NORMS AROUND DECISION MAKING ARE DIFFERENT AND LESS INDIVIDUALISTIC THAN IN WESTERN CONTEXT AND POWER DIFFERENTIALS ARE COLLABORATIVE FOR DIFFERENT PARTNERSHIP WHEN ONE ACTOR HAS ALL THE MONEY AND HAS MORE EDUCATION AND SO ON IN TYPICAL CASES AN HOW CAN YOU REALLY ACHIEVE THAT EQUALLY INDEPENDENT REVIEW. HOW CAN YOU ENSURE INDEPENDENT ETHICAL REVIEW WHEN A STUDY WITH A LOT OF MONEY IS ABOUT TO BE PROPOSED IN A COMMUNITY AND SO ON. AND THE BACKGROUND UNJUST -- INJUSTICES HAVE TO DO WITH QUESTIONS AROUND SHOULD THE RESEARCH ALWAYS BE RESPONSIVE TO THE LOCAL HEALTH NEEDS GIVEN PEOPLE DON'T HAVE ACCESS NORMALLY TO HEALTH CARE OR IS THERE A PROBLEM WHEN THEY CONDUCT THE RESEARCH IN ORDER TO DEVELOP PRODUCTS THAT ARE ONLY AVAILABLE IN HIGH-INCOME COUNTRIES AND WHAT SHOULD STANDARD OF CARE LOOK LIKE WHEN IT'S DIFFERENT BETWEEN HIGH-INCOME AND LOW AND MIDDLE-INCOME COUNTRIES. ONE STUDY WAS FOR MALARIA BUT THERE WAS STUDY OF OTHER INFECTIOUS DISEASE AND SO ON AND DO THEY HAVE AN OBLIGATION TO ADDRESS THOSE HEALTH NEEDS GIVEN PEOPLE DON'T HAVE ACCESS TO HEALTH CARE THE WAY THEY WOULD NORMALLY POST-STUDY OBLIGATIONS IS SOMETHING YOU BOTH TOUCHED ON. WHEN THE RESEARCH IS OVER WHAT SHOULD HAPPEN? DO YOU HAVE AN OBLIGATION TO MAKE ANY PRODUCTS DEVELOPED REASONABLY AVAILABLE TO COMMUNITIES OR INDIVIDUAL PARTICIPANTS AND WHAT HAPPENS TO THEIR CARE YOU CAN'T IN A HIGH-INCOME COUNTRY TRANSITION PEOPLE TO A REGULAR HEALTH SYSTEM. I HIGHLIGHTED STUDY OF CARE AND POSTSTUDY OBLIGATIONS BECAUSE THIS IS WHAT WE PICKED FOR DISCUSSION. I'LL SPEAK ABOUT STANDARD OF CARE AND JOE WILL TALK ABOUT POST-STUDY OBLIGATIONS. TO THINK WITH THE STANDARD OF CARE I WANT TO KICK US OFF WITH A CASE THAT SPARK THIS DEBATE AND SOME MAY BE FAMILIAR WITH. IN THE EARLY 1990s THERE WAS A PLACEBO CONTROLLED STUDY THAT SHOWED THE 076 PLACEBO REDUCED TRANSMISSION TO CHILDREN BY TWO-THIRDS WHERE CHILDREN OF HIV-POSITIVE MOTHERS WOULD BE POSITIVE 15% TO 45% BUT THE RENIMENT REDUCED THIS TO LESS THN 5%. BECAUSE OF THE DRAMATIC REDUCTION IN INFECTION DURING BIRTH IT QUICKLY BECAME THE STANDARD OF CARE IN THE U.S. AND OTHER HIGH-INCOME COUNTRIES BUT THE 076 REGIMENT WAS COMPLEX AND EXPENSIVE. IT INVOLVED ORAL AND ANTIVET ROW VIRALS DURING THE TRIMESTER AND FOR THE INFANT AFTER BIRTH AND BOTTLE FEEDING. YOU SEE AN AGGRESSIVE INTERVENTION AND WAS ALSO EXPENSIVE AT THE TIME. AND THIS IS WHEN MANY COUNTIES WERE SPENDING LESS THAN $50 PER PERSON A YEAR AND IT COULDN'T BE IMPLEMENTED AND THERE WAS AN INTERNATIONAL EFFORT TO DEVELOP A SHORT COURSE ANTIRETROVIRAL MEDICINE. THIS WAS EXPECTED TO BE INFERIOR IN STANDARD OF CARE AND THE COMPARISON AND IT WAS NOT EXPECTED TO PROVIDE MEANINGFUL RESULTS. SO A PLACEBO-CONTROL DESIGN WAS CHOSEN IN THE VAST MAJORITIES OF STUDIES. OF THEM WERE ALL CONDUCTED 15 - PLACEBO-CONTROLLED TRIALS FOLLOWING DEBATE AT THE WORLD HEALTH THESE TRIALS, AS SOME MAY KNOW, BECAME THE SUBJECT OF A VERY INTENSE ETHICAL CONTROVERSY. HEY WERE HEAVILY CRITICIZED IN A SOUNDING BOARD ARTICLE YOU SEE BELOW IN THE NEW ENGLAND JOURNAL OF MEDICINE WHERE SOME FROM A PUBLIC CONSUMER ADVOCACY GROUP WERE SAYING IT WAS UNACCEPTABLE THE STANDARD OF CARE IN THIS TRIAL WAS BASICALLY NO INTERVENTION OR PLACEBO AND THE TRIALS COULD HAVE BEEN CONDUCTED IN COMPARISON TO THE 076 REGIMENT. AND IT LED TO THE THIRD PAPER YOU SEE UP THERE TO A RESPONSE BY THE DIRECTORS OF THE CDC. THIS WAS ON ETHICAL GUIDELINES AND HOW THEY WERE WRITTEN. THERE ARE A NUMBER OF ETHICAL CONCERNS THAT LAURI ANDIAN -- AND ANGEL VOICED IN THEIR WORK BUT THE KEY ONE WAS THE RESEARCH SHOULD PROVIDE THE CONTROL GROUP WITH THE GLOBAL BEST STANDARD OF CARE. THEY MADE A SLIGHT QUALIFICATION THAT UNLESS THIS IS REALLY EXPENSIVE AND KIND OF NOT FEASIBLE. THE EXAMPLE THEY GIVE IS IF YOU HAD TO BUILD A CORONARY CARE UNIT, THAT'S KIND OF ASKING TOO MUCH. OTHERWISE IT REALLY SHOULD BE THE BEST STANDARD OF CARE. THE JUSTIFICATION FOR THIS IS SORT OF VARIOUS. ANGEL PRIMARILY APPEALS TO ARGUMENTS THAT SAYS THERE'S AVOIDABLE HARM AND WE CAN AVOID IT AT REASONABLE COST AND IT'S NOT EXPENSIVE TO GIVE EVERYBODY AZT IN THE TRIALS AND RESEARCHERS HAVE OBLIGATIONS TO THE BENNIVE -- TO THE BENEFICIARIES AND THEY APPEAL TO THE DECLARATION OF HELSINKI AND S SAYING THEY SHOULD BE PART OF THE BEST DIAGNOSTIC METHOD AND THEY SAY LOOK, THE TRIALS ARE INCOMPATIBLE WITH THIS STANDARD. I WANT TO HIGHLIGHT AND THE DECLARATION OF HELSINKI AND THE GUIDELINES AND THE CURRENT VERSION LOOKS SIMILAR. THERE'S A SMALL EXCEPTION ON WHEN YOU CAN USELESS THAN THE BEST GLOBAL STANDARD OF CARE WHEN THERE'S METHODOLOGICAL REASONS. SO HOW CAN THE PEOPLE WHO CONDUCT THE AZT TRIALS COULD HAVE DEFENDED THE TRIALS? ONE WAY OF RESPONDING TO THE CHALLENGES OF WHY NOT THE BEST GLOBAL STANDARD OF CARE WAS POVIDED IS TO TAKE SOMETHING LIKE THE NO-LOSS VIEW. THAT IS TO SAY IT'S PERMISSIBLE TO PROVIDE LESS THAN THE GLOBAL BEST STANDARD OF CARE IF PARTICIPANTS ARE NOT DEPRIVED OF TREATMENT THEY WOULD HAVE OTHERWISE HAVE RECEIVED AND THE THOUGHT IS THE PEOPLE WOULD NOT HAVE OTHERWISE RECEIVED TREATMENT BECAUSE CARE WAS LIMITED AT THE TIME. AND SO IT'S OKAY FOR THEM TO GET THE PLACEBO BECAUSE THEY WOULD NOT HAVE GOTTEN ANYTHING OTHERWISE AND THIS IMPLIES RESEARCHERS SHOULD PROVIDE THE LOCALIZED STANDARD OF CARE BUT THE LOCAL STANDARD OF CARE IN THE SENSE OF WHAT IS CURRENTLY BEING PROVIDED SO SOME PEOPLE HAVE CALLED THIS THE DE FACTO STANDARD OF CARE. THIS ARGUMENT I THINK IS PRETTY VULNERABLE AND PEOPLE HAVE QUICKLY POINTED OUT THAT THE DE FACTO LOCAL STANDARD OF CARE MAY NOT BE ACCEPTABLE. IT MAY NOT BE ACCEPTABLE PEOPLE ARE NOT GETTING CARE FOR TRANSMISSION OF HIV DURING BIRTH. ONE WAY THIS IS BEING PUT AND YOU CAN SEE HERE, LAURI AND WOLF CITE AND COMMENT ON THE CHARACTERIZATION OF PLACEBOS AS A STANDARD OF CARE. NOTHING IS A DESCRIPTION OF WHAT HAPPENS. STANDARD OF CARE IS ENORMATIVE STANDARD OF EFFECTIVE MEDICAL TREATMENT WHETHER OR NOT IT'S PROVIDED TO A PARTICULAR COMMUNITY. I THINK THAT'S ACTUALLY RIGHT ON. SOMETIMES IT'S JUST NOT OKAY TO SAY OKAY, PEOPLE WOULDN'T HAVE GOTTEN IT ANYTHING OUTSIDE THE TRIAL, THEREFORE IT'S OKAY TO TEST AGAINST NO INTERVENTION OR AGAINST THE PLACEBO. BUT A SLIGHT MODIFICATION OF THIS RESPONSE YOU COULD TAKE A SLIGHTLY DIFFERENT ARGUMENT AND TAKE SOMETHING LIKE THE APPROPRIATE LOCAL CARE VIEW WHICH WOULD ARGUE THAT IT'S PERMISSIBLE TO PROVIDE LESS THAN THE GLOBAL BEST STANDARD OF CARE IF PARTICIPANTS ARE NOT DEPRIVED OF TREATMENT THAT THEY SHOULD OTHERWISE RECEIVE. NOTE THE DIFFERENCE BEFORE WAS THEY WOULD OTHERWISE RECEIVE. SO THIS SAY SHOULD. BASICALLY THIS IS ARGUING IT'S OKAY TO PROVIDE THE LOCAL STANDARD OF CARE BUT IT SHOULD BE ONE THAT'S ENOR -- ENORMATIVE STANDARD OF CARE. THE QUESTION IS THEN HOW DO YOU DEFINE WHAT PEOPLE SHOULD RECEIVE LOCALLY? THERE'S HELPFUL ATTEMPTS AROUND THE TIME WHEN THE DEBATE WAS HEATING UP. THE COUNCIL ON THE BIOETHICS IN THE U.K. HAD A LONG REPORT ON THE ETHICS OF RESEARCH RELATED TO HEALTH CARE IN DEVELOPING COUNTRIES. AND THEY SAY THE STANDARD OF CARE THAT SHOULD BE PROVIDED LOCALLY IS THE STANDARD THE COUNTRY ENDEAVORS TO PROVIDE NATIONALLY. SO THEY SAY AT A MINIMUM, THAT'S WHAT YOU SHOULD PROVIDE. THEY ALSO SAY IN MANY CIRCUMSTANCES IT'S APPROPRIATE TO OFFER HIGHER LEVEL OF CARE THAN THIS AND SAY EXCEPTIONALLY COULD BE APPROPRIATE TO PROVIDE CARE BELOW THE NATIONAL STANDARD BUT THIS IS THE MINIMUM THEY SET OUT. IT'S SIMILAR TO GUIDANCE BY U.N. AIDS WITH PREVENTIVE AIDS MEDICINE AND SAID PARTICIPANTS SHOULD GET THE HIGHEST LEVEL OF CARE IN THE HOST COUNTRY AND THE IDEAL IS TO PROVIDE THE GLOBAL BEST STANDARD OF CARE AND THEY MAKE SOME HELPFUL COMMENTS ABOUT WHAT ATTAINABLE MEANS. IT DEPENDS ON WHAT THE HIGHEST LEVEL OF CARE AVAILABLE IS IN THE SPONSOR AND HOST COUNTRY. THE AVAILABILITY OF INFRASTRUCTURE TO PROVIDE CARE AND TREATMENT INCLUDING NECESSARY STOPPING AND SO ON AND THE POTENTIAL DURATION AND SUSTAINABILITY OF CARE AND TREATMENT. THESE ARE HELPFUL DEFINITIONS AN FROM AN ETHICAL PERSPECTIVE THE RIGHT APPROACH WOULD BE TO TIE THE DEFINITION OF THE APPROPRIATE LOCAL STANDARD OF CARE TO WHAT COUNTRIES DO ON THE PATH TOWARDS UNIVERSAL HEDGE -- HEALTH COVERAGE THIS IS WHERE YOU SET A NATIONAL LEVEL SHOULD DEFINE APPROPRIATE LOCAL CARE AS THEY'RE TRYING TO ACHIEVE UNIVERSAL HEALTH COVERAGE. THE IDEA IS THERE'S A COMMITMENT TO UNIVERSAL HEALTH COVERAGE AND ALL PEOPLE SHOULD RECEIVE SERVICES THAT MEET THEIR NEEDS WITHOUT REACHING FINANCIAL HARDSHIP IN PAYING FOR THE SERVICES AN LOW AND MIDDLE-INCOME COUNTRIES SHOULD STRIVE TO PROGRESSIVELY REALIZE UNIVERSAL HEALTH COVERAGE. EVERYBODY WORKS TOWARDS THE SAME GOAL BUT IT'S ACCEPT AND JUSTIFIABLY GIVEN WHERE THEY'RE AT IN AVAILABILITY OF RESOURCES AND BECAUSE OF WHAT IS THE LOCAL STANDARD OF CARE AND WHAT SHOULD BE INCLUDED IN THE BENEFITS PACKAGE ON THE PATH TOWARDS UNIVERSAL HEALTH COVERAGE IS GOING TO BE CONTESTED IDEALLY. THIS SHOULD HAPPEN IN A FAIR PROCESS THESE KINDS OF DECISIONS. I THINK THAT WOULD BE IDEAL. I'M AWARE OF THE FACT THAT IN MANY COUNTRIES THIS DOES NOT EXIST. AND I STILL THINK AS THE HELPFUL TO THINK ABOUT IN TERMS OF TRYING TO WORK OUT WHAT THE LOCAL STANDARD OF CARE IS IN COLLABORATION AND COMMUNICATION INTERNATIONAL AIRPORT THIS IS ARGUING FROM THE PARTICIPANTS PERSPECTIVE ENSURING THEIR RIGHTS AND INTERESTS ARE MET IN THE RESEARCH. ONE COULD BROADEN AND STRENGTHEN THE ARGUMENT BY TAKE POPULATION LEVEL PERSPECTIVE AND ADDING THAT ON TOP OF THIS AND TAKE SOMETHING LIKE THE RESPONSIVENESS WHERE IT'S PERMISSIBLE TO PROVIDE LESS THAN THE STANDARD OF CARE IF NECESSARY TO TEST AGAINST A LOWER STANDARD OF CARE. THIS WOULD BE COMBINED WITH THE NO-LOSS OR APPROPRIATE LOCAL CARE USE OR LOCAL STANDARD OF CARE THAT'S A DE FACTO ONE WHICH I HAVE RESERVATIONS ABOUT OR A NORMATIVE ONE ON WHAT PEOPLE SHOULD RECEIVE. THE ARGUMENT BEHIND THIS, IF YOU LOOK AT THE AZT TRIALS THEY LOOKED TO GET A SIMPLER AND CHEAPER INTERVENTION THAT WAS IMPLEMENTABLE BUT IT WAS EXPECTED IT WOULD BE INFERIOR SO WITH THE SIMPLER AND SHORTER AZT REGIMENT TO THE 076 REGIMENT WOULD ADDRESS THE QUESTION OF HOW MUCH WORSE IS THE SHORTER AND SIMPLER TREATMENT. THAT DOESN'T SEEM TO BE QUITE THE RELEVANT QUESTION IF ONE LOOKS AT COUNTRIES WHO ARE TRYING TO DECIDE GIVEN THEY HAVE LIMITED RESOURCES TO INVEST IN. THEY WOULD RATHER WANT TO KNOW -- THEY DON'T WANT TO KNOW HOW MUCH WORSE IS THIS THAN THE IDEAL THING WE COULD DO BUT THEY WANT TO KNOW POLICY MAKERS WOULD WANT TO KNOW HOW MUCH BETTER IS IT NOTHING AND HOW'S IT COMPARE TO OTHER CHOICE ON THE PATH TO UNIVERSAL HEALTH CONFERENCE WE COULD BE MAKING. -- HEALTH COVERAGE WE COULD BE MAKE. AND TO KNOW WHETHER IT'S BETTER THAN NOTHING OR NOTHING IN THE SENSE -- SORRY, I SHOULD HAVE SAID THE QUALIFICATION IS NOTHING REFLECTS IS AT THE TIME THE AZT TRIALS WERE CONDUCTED WHAT PEOPLE SHOULD HAVE RECEIVED LOCALLY WAS NO INTERVENTION BECAUSE THE 076 REGIMENT WAS JUST TOO EXPENSIVE. IT WAS $800 AND SOME COUNTRIES WERE WORKING WITH $20 TO $30 PER PERSON A YEAR. SO THE REAL QUESTION IS LIKE, SOMETIMES IT'S WHAT SHOULD BE -- IS THIS SIMPLER AND CHEAPER INTERVENTION BETTER THAN NOTHING OR THE GENERAL QUESTION IS IS IT BETTER THAN WHAT WE SHOULD BE OFFERING. AND IT MUST BE MEDICALLY NESS AGAINST THE STANDARD OF CARE -- NECESSARY AGAINST THE STANDARD OF CARE AND HOW MUCH BETTER SIT THAN WE CURRENTLY SHOULD BE PROVIDING IS THE SIMPLER TREATMENT THEN IT SHOULD BE THE CASE YOU CAN'T ANSWER THAT QUESTION IN OTHER WAYS AND THERE WAS A VARIABILITY IN THE RATE AND IT RANGED IN DIFFERENT SETTINGS. YOU CAN SEE THE RESPONSIVENESS VIEW DEFENSE SHOW UP IN THE DEBATE ABOUT THE AZT TRIALS. THESE ARE THE NIH AND CDC DIRECTORS AT THE TIME AND WRITING AND SAYING THE MOST COMPELLING REASON TO USE A PLACEBO-CONTROLLED STUDY IS IT PROVIDES DEFINITIVE ANSWERS ABOUT THE SAFETY AND VALUE OF THE STUDY IN WHICH IT'S PERFORMED AND WITHOUT CLEAR AND FIRM ANSWERS TO WHETHER AND IF SO HOW WELL AN INTERVENTION WORKS IT'S IMPOSSIBLE FOR A COUNTRY TO MAKE SOUND JUDGMENT WITH THE APPROPRIATENESS OF FINANCIAL FEASIBILITY ABOUT JUDGING THE INTERVENTION. THE DEBATE THEN SHIFTS TO IS THIS VIEW ITSELF CONVINCING. I WANT TO WALK THROUGH POINTS OF THIS VIEW. ONE IS BASICALLY PEOPLE WHO ACCEPT THE RELEVANT QUESTION IS WHETHER THE SIMPLER AND CHEAPER VERSION IS BETTER THAN WHAT PEOPLE SHOULD PROVIDE OR SHOULD BE PROVIDED IN THE LOCAL CIRCUMSTANCES BUT THEY SAY IT'S NOT ACTUALLY SCIENTIFICALLY NECESSARY IN ALMOST ALL CASES. SO THEY BASICALLY SAY WHAT RESEARCHERS REALLY SHOULD DO IS TO TEST THE STUDY INTERVENTIONS AGAINST THE GLOBAL BEST STANDARD OF CARE AND THEREBY AVOID PREVENTIBLE DEATH WITHIN THE STUDY AND USE HISTORICAL DATA TO ESTABLISH SUPERIORITY TO THE STANDARD OF CARE. THEY ACCEPT WHAT WE WANT TO WORK OUT IS HOW MUCH BETTER IS THIS THAN WHAT PEOPLE SHOULD RECEIVE OR DO RECEIVE LOCALLY. BUT THEY SAY IT'S NOT REALLY SCIENTIFICALLY NECESSARY BECAUSE YOU CAN WORK WITH HISTORICAL DATA. I THINK THAT IDEA IS VERY APPEALING. AND IF METHODOLOGICALLY APPROPRIATE. AND THE DATA QUALITY IN A COUNTRY IS OFTEN LIMITED SO THE DATA OFTEN HAVE CONFOUNDERS IN THEM. I THINK THERE'S NO BLANKET JUDGMENT TO BE MADE. OFTEN IT'S NOT THE CASE BUT THE KIND OF JUDGMENT NEEDS TO BE MADE ON A CASE-BY-CASE BASIS. IT'S A VALID CRITICISM TO THE EXTENT THAT IT APPLIES. AND THAT'S SOMETHING TO LOOK AT WHEN YOU'RE LOOKING AT A PARTICULAR STUDY. OTHER CRIT TEAK -- CRITIQUE OF THIS VIEW IS NOT CHALLENGING THE SCIENTIFIC NECESSARILY BUT WHAT THE BACKGROUND ASSUMPTION IS ON THE LOCAL STANDARD OF CARE AND WHAT THE RELATIVE WAYS OF IMPROVING IT ARE. SO THEY REJECT BASICALLY THE RELEVANT QUESTION IS WHETHER THE SIMPLER OR CHEAPER INTERVENTION IS BETTER THAN WHAT'S CURRENTLY PROVIDED OR SHOULD BE PROVIDED. INSTEAD THEY SAY RESEARCHERS SHOULD LOOK AT THE STANDARD -- BECHTD BEST STANDARD OF CARE YOU SHOULD ALWAYS STRIVE FOR INTERVENTIONS THAT ARE CHEAPER AND SIMPLER AND EQUALLY GOOD IN TEMS OF SAFETY ANDE AND EFFICACY. THIS A THEY -- THIS IS AN ARGUMENT IMPLYING THEY ANSWER THE QUESTION IS THE SHORTER REGIMENT BETTER THAN NOTHING. WE TAKE THE MOVE OPTIMISTIC VIEW GIVEN THE FINDINGS OF T THE 076 TRIAL RESEARCHERS CAN COME UP WITH A SHORTER REGIMENT APPROXIMATELY AS EFFECTIVE AS THE 076 REGIMENT. THES STUDY THAT USED -- THE ONE STUDY THAT USED THE GLOBAL BEST STANDARD AS A COMPARATOR STATES CLEARLY REDUCES THE DURATION OF PROPHYLACTIC TREATMENT WITHOUT INCREASING THE RISK OF PERINATAL RISK OF HIV AND WITHOUT THE DEMONSTRATED EFFICACY OF THE 076 REGIMENT. WE BELIEVE SUCH EQUIVALENCY STUDIES OF ALTERNATIVE REGIMENTS WILL PROVIDE MORE USEFUL RESULTS THAN PLACEBO-CONTROLLED TRIALS. YOU CAN SEE THIS. AGAIN, THIS IS A VALID ARGUMENT TO MAKE IN THE SENSE THAT WE SHOULD ALWAYS STRIVE TO DEVELOP SIMPLER AND CHEAPER INTERVENTIONS THAT ARE NOT INFERIOR. I THINK THAT'S SOMETHING WE SHOULD BE DOING THE QUESTION IS IS IT REALISTIC AND SOME COMPROMISES WILL HAVE TO BE MADE IN TERMS OF ACCESSIBILITY AND FEASIBILITY OF IMPLEMENTING THEM AND HOW SIGH OF AND EFFECTIVE -- HOW SAFE AND EFFECTIVE THEY ARE AND THERE KOUD BE AVOID -- COULD BE AVOIDABLE DEATHS THAT RESULT FROM THIS POSITION AND THAT'S A REAL PROBLEM BECAUSE YOU'RE NOT DEVELOPING ADMITTEDLY NON-IDEAL INTERVENTIONS BUT IT CAN MAKE DO A LOT OF GOOD ON THE PATH TO UNE UNIVERSAL HEALTH LEVEL. THE THIRD CRITICISM IS RESEARCH THE RIGHT WAY OF ADDRESSING THE QUESTION AND THE QUESTION ON SIMPLER, INFERIOR AND CHEAPER IS NOT THE RIGHT APPROACH TO IMPROVING HEALTH BUT WE SHOULD MAKE AVAILABLE WHAT WE ALREADY HAVE AND INVEST IN HEALTH INFRASTRUCTURE IN LOW AND MIDDLE-INCOME COUNTRIES AND DEVELOP MORE WAYS OF INCENTIVIZING INTERVENTION. WE SHOULDN'T JUST ACCEPT THE STATUS QUO BUT WORK TO IMPROVE THE BACKGROUND INJUSTICES AN THE NEED FOR RESEARCH WILL VANISH AND IT MIGHT REDUCE THE PRESSURE FOR FUNDAMENTAL REFORMS AND LOOKING AT ECONOMIC REASONS SO HE'S BASICALLY SAYING THE SAME THING HE SAID BEFORE THIS IS ABOUT SIMPLICITY AND SAYING THESE ARE ECONOMIC REASONS. I REMAIN SKEPTICAL THE APPROACH TO SUCH PROBLEMS SHOULD LIE IN MORE RESEARCH AND THE ECONOMIC YEG WITTIES ARE -- INEQUITIES ARE AFFECTING TRIALS AND IF WE WANT TO EFFECT FOR THE WORLD'S POOR, THIS IS THE OTHER PAPER THAT YOU MAY HAVE READ, PERHAPS, WE SHOULD SPENT MORE TIME THINKING ABOUT ENSURING ACCESS TO EXISTING DRUGS OPPOSED TO USING THIS AS A RATIONALE FOR ADDITIONAL DRUGS AND ADDITIONAL DRUGS INFERIOR TO WHAT WE ALREADY HAVE. I'M SYMPATHETIC TO WORK TO REDUCE BACKGROUND INJUSTICES AND IMPROVE IT AS THE FUNDAMENTAL LEVEL AND THE CRIT TEAK OF THE RESPONSIVENESS VIEW WHICH ARGUED THAT WE SHOULD ALWAYS BE DEVELOPING INTERVENTIONS AS LEAST AS GOOD AS WHAT'S CURRENTLY AVAILABLE. IF YOU'RE NOT CONDUCTING RESEARCH A LOT OF PEOPLE WILL DIE AND THAT COULD HAVE BEEN AVOIDABLE. IT'S A NON-IDEAL SOLUTION BUT THE PERFECT CAN BE THE ENEMY OF THE GOOD. IN CONCLUSION, I THINK AS YOU WILL HAVE SEEN THE STANDARD OF CARE DEBATE REVEALS FUNDAMENTAL DISAGREEMENTS RESEARCHERS AND TO THE SPECIFIC VALUE OF THE RESEARCH. I'D LIKE TO NOTE THE AGREEMENTS ERROR FOR RESEARCH EVERYWHERE. YOU COULD EASILY IMAGINE IN HIGH-INCOME COUNTRY SETTING WHERE THERE'S QUITE A BIT OF INEQUALITY. YOU CAN IMAGINE SOME PLACES LIKE THAT. FOR EXAMPLE BETWEEN THE PUBLIC AND PRIVATE HEALTH CARE SYSTEM AND AS THERE'S INCREASING PRESSURE YOU CAN IMAGINE DEVELOPING CHEAPER INTERVENTIONS IS AN ATTRACTION FOR HEALTH CARE COUNTRIES WHERE RESOURCES COULD BE LIMITED. MY OWN VIEW IS THAT IT'S PERMISSIBLE TO PROVIDE LESS THAN THE GLOBAL STANDARD OF CARE WHEN THE RESEARCH IS RESPONSIVE TO LOCAL HEALTH NEED AND NECESSARY TO TEST AGAINST THE LOWER STANDARD OF CARE AND PARTICIPANTS RECEIVE WHAT THEY SHOULD LOCALLY AND IT'S RESPONSIVENESS COMBINED WITH THE APPROPRIATE CARE VIEW AND PARTICIPANTS RECEIVE THE STANDARD OF CARE THEY SHOULD RECEIVE. THERE'S EXCEPTIONS AND THAT'S WHEN IT'S SCIENTIFICALLY TO TEST AGAINST A PLACEBO AS IN HIGH RATES AND YOU COULDN'T WORK OUT HOW IT WORKS. THERE CANNON SCIENTIFIC REASONS IN A NARROW NUMBER OF CASES AND FOR THOSE IN THE COURSE FOR A LONGER PERIOD OF TIME TIES BACK TO THE CLINICAL EQUIPORBS AND TO ME THERE'S NOT MUCH OF A DIFFERENCE IN DOING INTERVENTIONS LIKE RESEARCH BIOPSIES THAT IMPOSE RISK ACTIVITY VERSUS WITH HOLDING BENEFITS FOR THE LEVEL OF RISK. THAT'S FOR THE COMPLETE VIEW SO A FOOT NOTE TOWARDS THE END. I'D ALSO LIKE TO SAY THIS MAY NOT BE THE ONLY WAY OF COULD BE BE -- CONDUCTING RESEARCH WITH THE GLOBAL BEST STANDARD OF CARE. TO TRANSITION INTO THAT I WANT TO BRIEFLY CLOSE WITH A VERY ANOTHER VIN YET -- VIGNETTE WHERE YOU CAN SEE WHERE WE CAN MAKE RESEARCH ACCEPTABLE IN LOW AND MIDDLE-INCOME COUNTRY SETTINGS. THIS IS ANOTHER TRIAL YOU MAY HAVE HEARD ABOUT. THIS WAS WORKING WITH PREMATURE INFANTS WHO DEVELOPED AS RESPIRATORY SYNDROME A FLUID THAT ALLOWS THEM TO OPEN ONCE BORNE AND PREMATURE INFANTS DON'T HAVE THIS SO THE LUNGS CANNOT OPEN UP AND THEY CANNOT BREATHE. IN HEALTH CARE COUNTRIES THIS IS TREATED WITH SURFACTANT REPLACEMENT THERAPY AND INTERVENTION AND AT THE TIME THE TRIAL WAS PROPOSED AND AT THE TIME SEVERAL SURFACTANTS WERE ALREADY AVAILABLE AND THE TRIAL WAS PROPOSED IN BOLIVIA WHERE SURFACTANTS WERE NOT AVAILABLE AND THE IDEA WAS TO PROVIDE THEM TO ALL PARTICIPANTS AND TEST IT AGAINST THE PLACEBO. THERE WAS NO INTENTION TO LICENSE SURFACTANT AND THIS GOES BACK TO THE COMMENTS FROM YOU WE HEARD EARLIER, THE TRIAL WAS INTENDED TO PROVIDE DATA FORLY CENSURE IN HIGH-INCOME COUNTRY SETTINGS. LEVEL PERSPECTIVE, IT'S A GOOD TRIAL TO BE IN BECAUSE MECHANICAL VENTILATION EXCEEDS WHAT PEOPLE ARE RECEIVING LOCALLY SO EVEN IF YOU JUST LOOK AT THE CONTROL GROUP AND GIVEN WHERE BOLIVIA WAS ON THEIR PATH TO UNIVERSAL HEALTH COVERAGE AND WHAT THEY SHOULD RECEIVE LOCALLY IT SEEDS WHAT PEOPLE SHOULD HAVE RECEIVED LOCALLY AT THE TIME. SO THIS SAY REALLY GOOD DEAL FOR ANYONE ENROLLING IN THE STUDY BECAUSE THEY'RE ASSURED OF MECHANICAL VENTILATION THEY OTHERWISE SHOULDN'T AND WOULDN'T RECEIVE AND THEY HAVE A CHANCE OF GETTING -- A 1 IN 50 CHANCE GETTING A SURFACTANT THAT IS REASONABLY LIKELY TO WORK. WHAT THE TRIAL HIGHLIGHTS IS THE POPULATION LEVEL CONCERN ABOUT THE RESPONSIVENESS I SPOKE ABOUT BECAUSE ON THE RESPONSIVENESS VIEW THERE'S NO INTENTION TO LICENSE THE DRUG AND THE INFRASTRUCTURE IS NOT AVAILABLE IN NONE OF THE INFANT CARE UNITS SO SURFACTANT COULDN'T BE IMPLEMENTED. IT RAISES CONCERNS ABOUT THE PLOITATION AT THE COMMUNITY AND -- EXPLOITATION AND NOT THE PARTICIPANT LEVEL AND ARE THERE OTHER WAYS OF MAKING AND MAKING THE BENEFITS OF THE SORT OF THERE ONE WAY IS IN TERMS OF RESPONDING TO LOCAL HEALTH NEEDS AND IDEALLY MAKING INTERVENTIONS AVAILABLE. IT COULD BE YOU OFFER BENEFITS. THIS IS A SKETCH AND TEASER FOR DR. MILLUM'S PRESENTATION IN THE NEXT PART. I WANT TO CLOSE WITH THAT BUT MAKE A COMMENT ABOUT THE DEBATES JOE WILL BE ADDRESSING MER IN THE DETAIL. -- MORE IN THE DETAIL. THIS IS WHAT I HAD FOR THE MORNING AND I LOOK FORWARD TO YOUR QUESTIONS. THANK YOU VERY MUCH. [APPLAUSE] >> HOW MUCH IS FOR THE INSTITUTE VERSUS NON FORPROFIT INSTITUTIONS AND WHETHER THIS RESEARCH SHOULD BE INCLUDED OR WHETHER IT'S TOO PROBLEMATIC AND MAY BE SEEN WITH SUSPICION. >> I DON'T KNOW AND MAYBE CHRISTINE AND JOE KNOW THE DATA BETTER THAN I DO. I DON'T KNOW EXACTLY THE PROPORTION OF RESEARCH THAT'S BEING CONDUCTED WITH PRIVATE FUNDING AND PUBLIC FUNDING INTERNATIONALLY. I THINK THAT THE PROPORTION -- IF YOU JUST LOOK IN AGGREGATE, THERE'S A LOT OF PRIVATELY FUNDED RESEARCH BUT THAT COULD BE ALSO FROM WITHIN THE COUNTRY. SO COUNTRIES LIKE INDIA HAVE A THRIVING PHARMACEUTICAL INDUSTRY. AND LOCAL ACTORS GO TO LOW AND MIDDLE-INCOME COUNTRIES BECAUSE THERE'S TREATMENT NAIVE PATIENTS THEY CAN QUICKLY RECRUIT. PEOPLE DON'T HAVE ACCESS TO HEALTH CARE OUTSIDE THE TRIAL SO IT COULD BE ATTRACTIVE FOR THEM TO GET IN THE TRIAL. POTENTIALLY LESS REGULATION AND AN EASIER FRAMEWORK ENVIRONMENT TO WORK IN AND SO ON. BECAUSE IT'S OFTEN HARDER TO GET THE RESEARCH DONE, THIS HAS NOT BECOME THE BIG TREND A LOT OF PEOPLE WERE CONCERNED ABOUT. THE BIG WAVE OF OFF-SHORING HASN'T HAPPENED BUT IT DOES HAPPEN. I THINK THOSE ARE PROBLEMATIC TRIALS ESPECIALLY WHEN THE BIN FITS FOR THE HOST COMMUNITIES ARE NOT FAIR AND THEY'RE ALSO THERE'S OTHER ISSUES BORDERS OR CAN BORDER ON THE MISCONDUCT WHERE INFORMED CONSENT MAY BE SLOPPY AND ENGAGEMENT WITH HOST COMMUNITIES MAY BE SLOPPY AND SO ON. >> THERE'S BEEN A SUBSTANTIAL AMOUNT OF RESEARCH AND BECAUSE PRIVATE COMPANIES ARE VERY CONCERNED ABOUT DEVELOPING PRODUCT ARE GOING TO GET APPROVED IN HIGH-INCOME COUNTRIES JURISDICTIONS, THEY TEND NOT TO BE CARRYING OUT RESEARCH IN RESOURCE POOR DEVELOPING COUNTRIES. IT'S MIDDLE-INCOME COUNTRIES WHERE THERE'S INFRASTRUCTURE IN PLACE THEY CAN MAKE USE OF CHINA, THAILAND AND INDIA OPPOSED TO VERY POOR PLACES LIKE SUB-SAHARAN AFRICA. >> THANK YOU. WONDERFUL TALK. I WAS JUST MAKING A NOTE TO MYSELF IT SEEMS THE RESPONSIVENESSVIEW SHOULD BE CONCURRENTLY SOUGHT AFTER. IMPROVING DRUG EFFICACY AND FINDING NEW MEDS OBVIOUSLY FANTASTIC AND WORKING TO IMPROVE THE ACCESS AND ECONOMICS. INSTEAD OF DOING EVERYTHING INDIVIDUALLY WE SHOULD COMBINE THEM TOGETHER AS WELL AS USING OUR EXISTING DRUGS BECAUSE MAKE YOU CAN GET A SIMILAR ADVOCACY FROM A SHORTER TIME FRAME. THAT STUCK OUT TO ME AND WE SHOULD IDEALLY COMBINE EVERYTHING TOGETHER TO HOPEFULLY GET THE BEST OUT OF IT. >> THANKS FOR THAT COMMENT. I WOULD AGREE WITH THAT. AND THERE'S TIERED PRICING SYSTEMS AND SO ON AND THERE'S GOING TO BE AN EMPIRICAL QUESTION THAT'S COMPLEX TO ANSWER AND THE EXAMPLE EVERYONE HAS IS THE HIV-AIDS ACADEMIC DUE TO HUGE INTERNATIONAL PRESSURE AND THE DRUG PRICES TUMBLED FROM $10,000 TO $300 WITHIN YEARS. IF YOU DON'T HAVE THE NUMBERS OF SCALE AND SO ON. THERE'S A QUESTION OF WHAT DO YOU NEED IN ORDER TO KEEP UP THE PRESSURE. IF YOU GO ALONG WITH THE ARGUMENT THERE'S A QUESTION THAT BASICALLY YOU'RE ALLOWING DEATHS TO HAPPEN. >> I HAVE A QUESTION ABOUT THE SURFAXIN TRIAL. IT WASN'T RESPONSIVE TO THE NEEDS OF THE COMMUNITY BUT IT WAS TO THE NEEDS OF PARTICULAR INDIVIDUALS BECAUSE IT'S A BENEFICIAL TREATMENT. WHAT WOULD MAKE THAT TRIAL RESPONSIVE AND AT WHAT LEVEL SIT RELEVANT. IS IT IN THE CITY, TOWN, HOSPITAL? >> BOTH GREAT QUESTIONS. JOE WILL SPEAK MORE ABOUT THIS IN HIS TALK. ONE WAY OF THINKING OF RESPONSIVENESS TO THE COMMUNITY IS TO SAY THEY'RE NOT JUST HEALTH-RELATED BENEFITS AND SPECIFICALLY THE HEALTH-RELATED BENEFITS THAT COULD RESULT FROM THE PARTICULAR TRIAL. AND THERE'S ALTERNATIVE THING THAT COULD BE BOUGHT. FOR EXAMPLE, A NEW HOSPITAL. A NEW SCHOOL. FAND YOU'RE FOCUSSING ON RESPONSIVENESS AND AVAILABILITY OF TREATMENTS YOU'RE TESTING TRIALS DON'T ALWAYS USE EVERYTHING BUT YOU'RE USING THE LOCAL INFRASTRUCTURE AND THE BENEFITS AREN'T SHARE SO YOU SHOULD ALWAYS PROVIDE SOMETHING IN ADDITION. THAT'S THE FIRST QUESTION THE QUESTION ON THE SCOPE OF THE COMMUNITY, I'M NOT SURE I HAVE THE ANSWER FOR THAT. MAYBE CHRISTINE OR JOE HAVE A BETTER ONE. >> I COULD SAY SOMETHING ABOUT IT. AT A MINIMUM IT'S GOING TO BE THE NARROW COMMUNITY YOU'RE ENGAGING WITH THAT HAS MIGHT HAVE A BURDEN OF THE TRIAL BEING CONDUCTED SUCH THAT LOCAL INFRASTRUCTURE IS BEING USED OR HEALTH CARE STAFF IS BEING RECRUITED INTO THE TRIAL THAT OTHERWISE WOULD PROVIE CARE AND SO ON. THAT NARROWS THE CONCEPTION AND YOU CAN THINK MORE BROADLY ON A NATIONAL OR NARROWER LEVEL. IF YOU'RE JUST FOCUSSING ON PEOPLE'S NEEDS TO THE HOST POPULATION AND MAYBE EXISTING SOLIDARITY YOU CAN BUILD AN ARGUMENT AND A QUESTION THAT COMES UP IS HOW MUCH CAN YOU REASONABLY ASK FROM RESEARCHERS. 'S IT'S NOT THAT THEY HAVE NO RESPONSIBILITY BUT THEIR PRIMARY ROLE IS TO CONDUCT THE RESEARCH. THEY'RE NOT THERE TO PROVIDE AID. I THINK THAT WILL ALWAYS LIMIT VERY BROAD CONCEPTIONS OF THE COMMUNITY. I DON'T HAVE A BROADER VIEW BUT CHRISTINE CAN MAYBE HELP. >> I DON'T. I HAVE A QUESTION BUT YOU FIRST. >> I'M INVOLVED IN GRAND REVIEWS AND STANDARD OF CARE HAS BECOME MORE OF AN ISSUE AND AN ASPECT WE LOOK AT IS HUMAN SUBJECTS. THERE'S SHIFTING OPINIONS. SOME PEOPLE FEEL IF YOU'LL BE FUNDED BY A U.S. AGENCY AND YOU'RE GOING ABROAD REGARDLESS OF WHAT THEIR STANDARD OF CARE IS AND YOU SHOULD PROVIDE THE SAME STANDARD OF CARE YOU WOULD PROVI PROVIDE AS IF YOU'RE IN THE UNITED STATES BUT OTHERS ARE LIKE MORE IT'S THE STANDARD OF CARE THERE SO IT'S OKAY. I WANT TO GET MORE OF YOUR FEEL AND THOUGHTS ON RESEARCH SUPPORTED BY SAY THE NIH. SHOULD THEY USE THE STANDARD OF CARE THEY WOULD IN THE U.S. OR LEAVE IT UP TO THE INVESTIGATOR TO FOLLOW STANDARD IN THE COUNTRY OR IN THE U.S. IT'S A GRAY AREA >> MAYBE I CAN ASK MY QUESTION BECAUSE I THINK IT'S RELATED IN A CERTAIN WAY. I THINK ONE OF THE CHALLENGES IS WHAT YOU DESCRIBED AS SCIENTIFICALLY NECESSARY. >> SO LET ME JUST ORGANIZE MY THOUGHTS. IN TERMS OF THE FIRST PART OF YOUR QUESTION IS SHOULD THERE BE MORE GUIDANCE. THERE'S SUBSTANTIAL DEBATE IN THE POSITIONS ARE CLEAR. I'M NOT SURE GUIDANCE IS GOING TO BE THAT USEFUL. I RESPECT WHAT OTHERS ARE SAYING AND HOW THEY ARE RESPONDING AND TAKING DIFFERENT POSITIONS. I DO THINK THERE'S SOMETHING INTUITIVE WHEN YOU'RE COMING AS A RESEARCHER FROM A HIGH-INCOME COUNTRY SETTING AND THE COST OF THE STUDY IT'S NOT GOING TO BE EXPENSIVE TO GIVE EVERYBODY THE SAME CARE. EN -- UNLESS YOU HAVE TO MAKE INVESTMENTS IN INFRASTRUCTURE. THERE'S SOMETHING INTUITIVE AND IT GOES BACK TO CHRISTINE'S QUESTION IS WHAT YOU PRESIDE AS THE COMPARATIVE -- PROVIDE CHANGES THE COMPARATIVE YOU'RE ASKING AND NEED TO BE CAREFUL. WE'RE ALL GENEROUS PEOPLE AND RESEARCHERS AND IT WON'T MAKE A DIFFERENCE FOR THE AZT TRIALS IN TERMS OF THE BUDGET THEY WERE EXPENSIVE. FROM THAT PERSPECTIVE IT'S NOT THE CONCERN BUT I THINK WHAT IS THE CONCERN IS THAT IT CHANGES THE QUESTION. THERE'S TWO PARTS. THE ONE IS WHAT ARE YOU TRYING TO ANSWER AND IT DOES CHANGE THE QUESTION SO ARE YOU TRYING TO SHOW THAT SOMETHING IS -- WHERE YOU EXPECT IT WILL BE INFERIOR AND TRYING TO SHOW HOW MUCH MORE INFERIOR IS IT WITH HIGH CONFIDENCE OR ARE YOU TRYING TO SHOW IT'S BETTER THAN WHAT IS BEING PROVIDED ORDER SHOULD BE PROVIDED LOCALLY WITH HIGH CONFIDENCE. I THINK THAT'S A REAL DIFFERENCE AND ONE IMPORTANT TO POINT OUT. BUT THEN THE QUESTION OF COURSE IS HOW MUCH CONFIDENCE DO WE NEED? SOMETIMES WOULDN'T IT BE OKAY TO USE OBSERVATIONAL DATA FROM HISTORICAL DATA. IN ORDER TO ANSWER THAT QUESTION HOW MUCH BETTER IS IT AND I HAVE MORE TOLERANCE FOR GREATER OR WORKING WITH LESS CONFIDENCE. I THINK IT WILL DEPEND ON WHAT YOU'RE LOOKING AT. IF IT'S AN INTERVENTION THAT WILL BE COSTLY YOU WANT HIGHER CONFIDENCE THAN IN INTERVENTIONS THAT ARE RELATIVELY LOW COST. IN MY VIEW IT'S GOING TO BE DEPENDENT ON A CASE BY CASE BASIS WHAT YOU NEED AND WHAT IS THE HEALTH CARE BUDGET AND HOW MUCH OF A STRAIN WOULD IT BE TO IMPLEMENT THIS AND SO ON. I PROBABLY HAVE MORE TOLERANCE THAN SCIENTISTS WOULD HAVE FOR THIS. >> LOGISTIC QUESTION FOR YOU -- WE'RE EATING IN TO YOUR TIME SO DO YOU WANT TO CONTINUE TO HAVE THE CONVERSATION AND ADJUST LATER OR GO AND HAVE THESE PEOPLE QUESTION LATER? >> I THINK IT DEPENDS ON HOW SPECIFIC THE QUESTION TO ANNETTE'S PRESENTATION. >> DO YOU WANT TO ASK YOUR QUESTIO QUESTIONS AND WE'LL SEE BECAUSE PERHAPS THEY'LL BE ANSWER JOE'S PRESENTATION. >> I WAS GOING TO FOLLOW-UP ON THE LAST TWO QUESTION/COMMENTS. MY BACKGROUND IS MOSTLY IN HUMANITARIAN WORK THOUGH I'M NOT WORKING IN A GLOBAL OFFICE HERE. I THINK MOST LOW AND MIDDLE-INCOME COUNTRIES THOUGH THEY DON'T HAVE A LOT OF RESEARCHERS BUT HAVE A LOT OF CLINICIANS AND TO ME THE PURPOSE OF DOING A STUDY IN A GIVEN COUNTRY SHOULD BE TO HELP THAT COUNTRY OTHERWISE WHY WITH WE DOING IT THERE. AND WHETHER OR NOT IT'S A BENEFIT TO THAT POPULATION I THINK HAS TO BE WE HAVE TO INTERACT WITH THE LOCAL DOCTORS. I'M WONDERING IF IT'S PATERNALISTIC TO ASK THE QUESTION SHOULD WE HAVE MORE GUIDANCE? I THINK IT SHOULD COME MORE FROM THEM. >> THANK YOU. I TAKE THAT AS A HELPFUL COMMENT THEY DON'T NEED TO RESPOND TO. >> SO STANDARD OF CARE HAS DEVELOPED FROM LOTS OF EVIDENCE AND SO CAN IT BE CONTEXT UALIZED. CAN IT BE CONTEXTUALIZED AGAINST THE EVIDENCE WHICH HAS BEEN GENERATED AND CREATE THE STANDARD AND IF EVIDENCE IS BEING GENERATE FROM A PARTICULAR TRIAL WHERE THE TREATMENT IS BETTER THAN THE STANDARD OF CARE AND IF YOU LOWER THAT STANDARD OF CARE HOW CAN WE QUANTIFY THE RESULTS GENERATING FROM THAT PARTICULAR CLINICAL TRIAL? YOU HAVE SET A STANDARD IN A HIGH-INCOME COUNTRY AGAINST A BEST PRACTICE BUT IF YOU LOWER THAT STANDARD BY GOING TO LOWER-INCOME COUNTRIES HOW CAN YOU JUSTIFY THAT RESULT? >> I'M NOT SURE I CAUGHT EVERYTHING THERE. I'LL RESPOND AND MAYBE WE CAN CHAT MORE AFTERWARDS BECAUSE WE'RE SHORT ON TIME. I DIDN'T SPEAK ON SCIENTIFIC DIFFERENCES ON WHAT WE KNOW ABOUT DIFFERENT COUNTRIES. SOMETIMES THAT'S A REASON TO MODIFY THE STANDARD OF CARE. WE DON'T KNOW HOW IT WORKS IN LOCAL CIRCUMSTANCES. AND I KNOW FOR SURE I DIDN'T GIVE JUSTICE TO YOUR QUESTION SO LET'S TALK AFTERWARDS. OR YOU CAN ASK AGAIN WHEN JOE SPEAKS. >> THANK YOU SO MUCH. [APPLAUSE] . >> TO CONTINUE THIS DISCUSSION WE HAVE DR. JOE MILLUM WHO WORKS FOR THE FOGARTY CENTER AND WILL TALK ABOUT THE INTERVENTIONS AND AND AFTER THE BREAK WE'LL TALK WITH THE ISSUES SO THEY'LL COME UP AGAIN. >> THANKS AGAIN ANNETTE FOR SETTING THIS UP SO NICELY. ANNETTE DISCUSSED THE ISSUE OF THE STANDARD OF CARE WHICH SHOULD BE USED IN RESEARCH STUDIES IN RESOURCE-LIMITED SETTING. ANOTHER ISSUE THAT CAME UP IN VARIOUS WAYS IN THE QUESTIONS CONCERNS THE TYPES OF TRIALS THAT ONE SHOULD BE DOING IN RESOURCE-POOR SETTINGS AND THE ASSOCIATED ISSUE OF POST-TRIAL ACCESS TO TREATMENTS USED OR THAT ARE TESTED IN THE TRIALS. THAT'S WHAT I'M GOING TO TALK ABOUT TODAY. CAN EVERYONE HEAR ME OKAY? AND I'VE SIMPLIFIED THE DETAILS. THE FIRST ONE IS A CASE THAT CONCERNS ACCESS TO ANTIRETROVIRAL THERAPY FOR PATIENTS WITH HIV. MILLIONS AROUND THE WORLD INCLUDING SUB-SAHARAN AFRICA AND SOUTHEAST ASIA NOW HAVE ACCESS TO ANTIRETROVIRAL AND IT DEVELOPS RESISTANCE. THIS STUDY WAS CARRIED OUT WITH PATIENTS WHO WERE ALREADY ON SECOND LINE ANTIRETROVIRALS AND FAILING THE SECOND-LINE REGIMENT. THE STUDY WAS TRYING TO STUDY OPTIMIZING PATIENTS TO ANOTHER SET OF ANTIRETROVIRALS. THIS ENROLLED 500HIV1 ADULTS WITH A CERTAIN ANTIRETROVIRAL AND THE GOAL WAS TO ASSESS A PERSON'S RESISTANCE TO THE CURRENT REGIMENT AND ASSIGNING HIM OR HER TO ANOTHER REGIMENT WITH ANOTHER COMBINATION OF ANTIRETROVIRAL DRUGS. AND THEY HAD SIGHTS IN THEY -- THAILAND AND UGANDA AND A RANGE OF COUNTRIES AROUND THE WORLD. ALL THE DRUGS USED IN THE TRIAL WERE LICENSE IN THE U.S. THEY WERE NOT ALL LICENSED IN THE COUNTRIES WHERE THE STUDIES WERE TAKING PLACE. THIS MEANT PARTICIPANTS MAY HAVE BEEN PUT ON A LIFE-SAVING REGIMEN BUT AFTER THEY LEFT THEY MAY NOT HAVE OBTAINED THE DRUGS AND TO RESEARCHERS THIS SEEMED UNETHICAL. THE SECOND CASE IS A STUDY ON HUNTINGTON'S DISEASE CAUSED BY A MUTATION. IF SOMEONE HAS HUNTINGTON'S NORMALLY THE CHILDREN HAVE A 50% CHANCE OF INHERITING THE GENE AND SO DEVELOPING THE DISEASE AS WELL. SYMPTOMS START USUALLY BETWEEN 30 AND 50. CAUSES UNCOORDINATED JERKY BODY MOVEMENTS AND A DECLINE OF DEMENTIA AND MOST PATIENTS DIE WITHIN 20 YEARS OF ONSET OF SYMPTOMS. NOW, THERE'S A RURAL COMMUNITY IN VENEZUELA THAT HAS THE HIGHEST CONCENTRATION OF HUNTINGTON'S CARRIERS IN THE WORLD. AND THIS MAKES IT AN IDEAL COMMUNITY IN WHICH TO CARRY OUT RESEARCH IN HUNTINGTON'S. BACK IN '90, '93 U.S.S. U.S. RESEARCHERS USED SAMPLE OF BLOOD AND SEMEN TO IDENTIFY THE GENE RESPONSIBLE FOR CAUSING HUNTINGTON HUNTINGT HUNTINGTON'S AND A GENETIC TEST WAS CREATE AND NOW IT'S AVAILABLE IN MANY HEALTH SYSTEMS AROUND THE WORLD BUT NOT AVAILABLE TO PEOPLE WHO LIVE IN THIS LOCATION. AND ONE PERSON SAID THE PEOPLE IN THE U.S. CAN GET THE TEST AND THE PEOPLE THAT LIVE THERE CAN'T GET THE TEST THOUGH THEY COLLABORATED IN THE RESEARCH. AND THIS LACKED AS ACCESS TO THE CARE AND IT INCLUDES CERTAIN POPULATIONS IN HIGH-INCOME COUNTRIES TOO. FIRST THERE'S THE ISSUE OF POST-TRIAL ACCESS. WHAT SHOULD PARTICIPANTS RECEIVE AFTER A STUDY AND IF THEY HAVE A CHRONIC CONDITION THAT REQUIRES TREATMENT, ARE THEY ENTITLED TO TREATMENT? AND REASONABLE AVAILABILITY. SHOULD HAVE PARTICIPANTS HAVE ACCESS TO INTERVENTION AFTER THE STUDY? I'LL START BY TALKING ABOUT POSTTRIAL ACCESS IN CARE TO PARTICIPANTS. I'LL FOCUS MOSTLY ON THE QUESTION OF POST-TRIAL ACCESS TO THE INTERVENTION STUDIED DURING A TRIAL. THOUGH OF COURSE IT'S NOT THE ONLY SORT OF CARE PARTICIPANTS MAY LEAVE A TRIAL NEEDING. THE DECLARATION OF HELSINKI ANNETTE QUOTE SUNDAY THE ETHICAL PRINCIPLES THEY THINK SHOULD BE USED TO GOVERN MED -- MEDICAL RESEARCH WITH HUMAN PARTICIPANTS AND USED BY IRBs AROUND THE WORLD. IT GETS MENTIONED IN REGULATIONS. THE DECLARATION OF HELSINKI SAYS IN ADVANCE OF A CLINICAL TRIAL, SPONSORS, RESEARCHERS AND HOST COUNTRY GOVERNMENTS SHOULD MAKE PROVISIONS FOR POST-TRIAL ACCESS FOR ALL PARTICIPANTS WHO STILL NEED INTERVENTION IDENTIFIED AS BENEFICIAL IN THE TRIAL. THAT'S RELATIVELY CLEAR. AND OTHERS ARE SILE IN THE ISSUE OF POST-TRIAL ACCESS. IT SAYS NOTHING ABOUT THIS ISSUE. OTHER REGULATIONS MAY ENCOURAGE PROVISION. THEY MAY REQUIRE RESEARCHERS TO MAKE EFFORTS TO TRANSITION PARTICIPANTS TO CARE OR THEY MAY SIMPLY REQUIRE THE PROVISION OF INFORMATION. THERE'S A LEGAL REQUIREMENT TO PROVIDE POST-TRIAL ACCESS TO PARTICIPANTS IN TWO COUNTRIES THAT I'M AWARE OF. ARGENTINA AND BRAZIL. NOT MUCH DATA ON THE IMPLEMENTATION OF THE REGULATION IN ARGENTINA. I BUGGED A FRIEND OF MINE WHO WORKS IN RESEARCH ETHICS THERE AND GOT NOTHING BACK FROM HIM DESPITE MULTIPLE TEXTS AND EXTREMELY PERSUASIVE EMOJIS. IT ENDS UP WITH PHARMACEUTICAL COMPANIES SUING THE GOVERNMENT AND THE GOVERNMENT SUING THE PHARMACEUTICAL COMPANIES. IT'S NOT CLEAR WHO IS SUPPOSED TO PROVIDE POST-TRIAL ACCESS. POST-TRIAL ACCESS IS ALSO RECOMMENDED BY A NUMBER OF INTERNATIONAL GUIDELINE. FOR EXAMPLE, IN INDIA, SOUTH AFRICA AND UGANDA THE RECOMMENDATIONS ARE MADE BUT NOT LEGALLY BINDING BUT LIKE THE DECLARATION OF HELSINKI THEY CAN BE ENFORCED BY COMMITTEES WHO HAVE THE POWER TO APPROVE RESEARCH. VARIOUS SPONSORS OF RESEARCH HAVE ACCESS TO THE POST-TRIAL AND THE NIHs POLICY. IT APPLIES NARROWLY. IT'S A WRITTEN FOR THE PROVISION OF ANTIRETROVIRAL TREATMENT AND PROVIDES ONLY TO THE PROVISION OF ANTIRETROVIRAL TREATMENT TO PARTICIPANTS IN THE TREATMENT TRIALS. FOR EXAMPLE, NOT TO STUDIES OF PREVENTION. AND IT APPLIES ONLY IN DEVELOPING COUNTRIES. SO NOT FOR EXAMPLE TO STUDIES THAT TAKE PLACE IN THE U.S. THE GUIDANCE STATES THE NIH EXPECTS INVESTIGATORS OR CONTRACTORS TO ADDRESS THE PROVISION TO TRIAL PARTICIPANTS AFTER THEIR COMPLETION OF THE TRIAL. THE NIH RECOMMENDS INVESTIGATORS WORK WITH OTHER STAKEHOLDERS TO IDENTIFY AVAILABLE SOURCES OF ANTIRETROVIRAL TREATMENT AND CRUCIALLY PRIORITY MAY BE GIVEN TO SIGHT SITE WHERE'S SOURCE GIVEN FOR THE ANTIRETROVIRAL AFTER THE TRIAL. THAT'S WHAT GUIDANCE AND REGULATIONS SAY ABOUT POST-TRIAL ACCESS. WHAT SHOULD WE MAKE OF IT FROM THE POINT OF VIEW OF ETHICS? LOTS OF RESEARCHERS AND TRIAL PARTICIPANTS AND IRB MEMBERS AN ETHICISTS THINK THERE'S A DUTY TO PROVIDE IT TO TRIAL PARTICIPANTS WHO NEED IT PROVIDE JUSTIFICATION FOR THAT DUTY HAS PROVEN TO BE MORE CHALLENGING. I'LL QUICKLY DISCUSS FOUR IMPORTANT GROUNDS RAISED BY BIOETHICISTS AND USE THEM IN REQUIREMENT TO PROVIDE POST-TRIAL ACCESS TO TREATMENT. THEN I'LL END BY SAYING SOMETHING ABOUT HOW POST-TRIAL ACCESS PLAYS OUT IN PRACTICE. SO THE FIRST JUSTIFICATION WHICH COMES UP QUITE OFTEN IS BASED ON AVOIDING HARM TO PARTICIPANTS. THIS IS BASED ON THE DUTY OF NORMAL ABSENCE. SO COMMON HAS A CHRONIC DISEASE AND BENEFIT FROM THE TREATMENT THEIR ON IN A TRIAL AND THEN TAKING THEM OFF THE TREATMENT WOULD SEEM TO HARM THEM. SO THAT VIOLATES THE DUTY. IF HIV IS CONTROLLED BY THE REGIMEN SHE'S ON TAKING HER OFF WILL LEAD TO RESURGENCE OF HER DISEASE. THIS IS A FAIRLY COMMON JUSTIFICATION. I THINK IT'S USUALLY A MISTAKEN JUSTIFICATION. NO IT'S MISTAKEN IN WHICH POST-STUDY ACCESS WOULD BE DESIRABLE IT BENEFITTED PARTICIPANTS RELATIVE TO HOW THEIR LIFE WOULD HAVE GONE OTHERWISE. SUPPOSE THAT WE'RE LOOKING AT A TRIAL OF A DRUG AND NOT EXPECTED TO BE AVAILABLE ANYTIME SOON AND SUPPOSE THE DRUG TURNED OUT TO BE BENEFICIAL. SUPPOSE THE DRUG TURNS OUT TO BE BENEFICIAL. IN SUCH A STUDY ASSUMING THERE ARE ALTERNATIVES AVAILABLE OUTSIDE THE STUDY AND THE QUESTION OF POST-TRIAL ACCESS WOULDN'T AB -- WOULDN'T BE AN ISSUE AND PARTICIPANTS WOULD LIKELY WHO RECEIVE THE DRUG THEY'LL LIKELY LEAVE THE TRIAL STILL NEEDING THE BENEFITS OF THE DRUG BUT RELATIVE TO WHERE THEY WOULD HAVE BEEN OUTSIDE OF THE TRIAL THEY'RE BETTER OFF. THEY PRECEIVED THE DRUG FOR THE DURATION THE TRIAL HAD TAKEN PLACE. THIS SEEMS TO ME IMPLIES THAT TRIAL PARTICIPATION ITSELF DIDN'T HARM THEM AND SO THE DUTY OF NON-MALEFICENCE, THE DUTY TO DO NO HARM DOESN'T REALLY APPLY. A SECOND MORE PLAUSIBLE JUSTIFICATION GROUNDS PLAUSIBLE RELATIONSHIPS THAT MAY DEVELOP BETWEEN RESEARCHERS AND RESEARCH PARTICIPANTS. THE IDEA IS THIS IS ANALOGOUS TO THE RELATIONSHIP BETWEEN THE DOCTOR AND HER PATIENT. JUST AS A DOCTOR HAS A SPECIAL DUTY WITH REGARD TO THE WELL BEING OF HER PATIENT, THE RESEARCHER HAS A SPECIAL DUTY TO THE WELL BEING OF HER SUBJECT. THIS IS BECAUSE IN ANY CLINICAL RESEARCH PARTICIPANTS ENTRUST ASPECTS OF THEIR HEALTH TO THE RESEARCHERS. SO THEY RECEIVE CLINICAL CARE AND SO ON. CLEARLY, THE DUTY THEN SHOULD BE GREATER WHEN A STUDY HAS BEEN LONG AND INVOLVED A LOT OF CLINICAL CARE AND WHEN THE RELATIONSHIP IS DEEPER. THEN THAT ALSO FITS WITH HOW RESEARCHERS TEND TO THINK THEIR DUTIES TO PARTICIPANTS HAVE DEVELOPED. IN LONG STUDY WHERE THERE'S A LONG STUDY THE FELT OBLIGATION THERE IS OFTEN MUCH STRONGER. THIS IT MORE PLAUSIBLE. THERE'S TWO CHALLENGES IN APPEALING TO THIS RELATIONSHIP IN REGARDS TO A DUTY TO PROVIDE POST-TRIAL CARE. THE ROLE OF MORALITY OF A RESEARCHER MAY BE DIFFERENT THAN THAT OF A CLINICIAN. AFTER ALL, THE PRIMARY GOAL OF RESEARCH IS TO CONDUCT RIGOROUS SCIENCE THAT CAN GENERATE SCIENCE TO BENEFIT FUTURE PATIENTS. THE WELL BEING OF RESEARCH PARTICIPANTS IS NORMALLY A SECONDARY GOAL OR CONSTRAINT ON THE PURSUIT OF SCIENTIFIC KNOWLEDGE. BY CONTRAST, THE PRIMARY GOAL OF CLINICAL CARE IS TO BENEFIT THE PATIENT WHO IS IN FRONT OF THE CLINICIAN. SO INSOFAR AS THE ROLES ARE DIS DISANALOGOUS SHOULD BE DIFFERENT THAN THE RELATIONSHIP PEOPLE NOT CONVINCED THE RESEARCHERS HAVE AN OPEN-ENDED OBLIGATION TO THEIR PATIENT. AT LEAST IN THE U.S. AS I'VE LEARNED IN EXPLORING THE HEALTH INSURANCE SYSTEM AND THE MANY CHOICES I HAVE FOR HEALTH INSURANCE HERE IF SOMEONE LOSES THEIR INSURANCE, THE PRIMARY CARE PHYSICIAN DOESN'T HAVE AN OBLIGATION TO CONTINUE TO PROVIDE CARE. THERE'S A DUTY NOT TO ABANDON ONE'S PATIENT AND ENSURE A TRANSITION TO OTHER SOURCES OF CARE. I THINK THIS RELATIONSHIP IS A POSSIBLE GROUND FOR OBLIGATIONS POST TRIAL. POTENTIALLY QUITE A WEAK GROUND. SOME ETHICISTS CITE A DUTY OF OBLIGATION. RESEARCH PARTICIPANTS CONTRIBUTE TO MEDICAL KNOWLEDGE WHEN THEY TAKE PART IN MEDICAL EXPERIMENTS. IT SEEMS PLAUSIBLE TO THINK IF THEY'VE CONTRIBUTED TO MEDICAL KNOWLEDGE THEN THEY DESERVE SOMETHING IN RETURN. ONE APPROPRIATE WAY MIGHT BE TO PROVIDE ADDITIONAL MEDICAL CARE THE RESEARCH IS COMPLETE. AGAIN, LIKE THE CASE OF THE RELATIONSHIP, I THINK THIS IS A PLAUSIBLE GROUND FOR POST-TRIAL OBLIGATIONS. ONE IMPORTANT CHALLENGE IS IT WON'T GROUND OPEN-ENDED OBLIGATIONS. IT WON'T GROUND THE SAME OBLIGATIONS IN EVERY CASE. IF WHAT WE'RE DOING IS RESIPRY INDICATING FOR THE CONTRIBUTION OF THE PARTICIPANTS THE EXTEND TO OBLIGATE THEM WILL DEPEND ON THE EXTENT OF THEIR CONTRIBUTION AND IT'S ANALYZED IN LOOK AT THE RISK THEY UNDERTOOK AND SO ON. NOW, NOTE ALSO IT'S NOT EVEN MOSTLY RESEARCHERS WHO WOULD HAVE THIS OBLIGATION BECAUSE OTHER PARTIES BENEFIT FROM THE CONTRIBUTION OF RESEARCH PASS TIS -- PARTICIPANTS. AT THE VERY LEAST LIKE PHARMACEUTICAL COMPANIES WOULD SHARE THE OBLIGATION TO RECIPROCATE AND THE COUNTRIES THAT BENEFIT IN THE RESEARCH IN THE HEALTH SYSTEMS. FOURTH, A DUTY TO PROVIDE POST-TRIAL ACCESS MAY BE IN THE DUTY TO RESCUE. THE CLASSIC CASE IS IMAGINE I'M ON MY WAY TO GIVE THIS TALK AND A PASSED A LARGE POND. THE POND BY THE NATIONAL LIBRARY OF MEDICINE. AND IN THE POND I NOTICE A CHILD DROWNING. NO ONE ELSE IS AROUND I WOULD WADE INTO THE POND. I DON'T KNOW IF YOU HAVE SEEN IT BUT IT'S PROBABLY NOT THAT DEEP PROBABLY COME TO MY WAIST. I CAN WADE IN THE POND BUT I'M WEARING A RATHER NICE SUIT AND IT'S GOING TO BE RUINED IF I RESCUE THE CHILD. THIS IS WHAT I NORMALLY WEAR WHEN I'M NOT GIVING A TALK. NOW THAT SUIT WOULD COST SEVERAL HUNDRED DOLLARS. IT'S ACTUALLY NOT THAT NICE A SUIT BUT IT'S GOING TO BE RUINED IF I WADE IN THE POND. HERE'S THE POINT ABOUT THE DUTY TO RESCUE. EVEN IF IT'S GOING TO RUIN MY SUIT, I STILL HAVE A MORAL DUTY TO WADE IN THE POND AND SAVE THE CHILD. I'M LOOKING FOR A NOD OF AGREEMENT. IT'S NOT AN AUDIENCE OF MORAL MONSTERS. SO HERE'S THE SUCCINCT DUTY FROM THE ETHICISTS PETER SINGER, HE SAYS IF IT'S IN OUR POWER TO PREVENT SOMETHING BAD FROM HAPPENING, WE OUGHT MORALLY TO DO IT. APPLY THIS TO THE IN HAND. RESEARCHERS MAY BE IN A POSITION TO GIVE URGENTLY GIVEN TREATMENT AND IT COULD BE LIFE-SAVING AND RESEARCH PARTICIPANTS MAY NOT HAVE ACCESS TO TREATMENT OUTSIDE OF THE TRIAL SO THE DUTY TO RESCUE COULD GROUND POST-TRIAL OBLIGATIONS. NOW, TWO CHALLENGES IN THE DUTY TO RESCUE CONTEXT. IT WILL APPLY IN CASE WHERE'S THE BENEFIT IT PROVIDES IS VERY HIGH. THE COSTS OF PROVIDING THE BENEFIT IS LOW. THE COST IS RUINING MY SUIT AND THAT'S A CASE WHERE YOU HAVE TO RESCUE. IN CASE WHERE'S AN INTERVENTION IS EXTREMELY EXPENSIVE OR ONLY PROVIDES MARGINAL BENEFIT, THOSE ARE NOT GOING TO BE RESCUE CASES AND SO THEY'RE NOT GOING TO PROVIDE OR GENERATE A DUTY TO PROVIDE CARE. SECOND, THIS DUTY APPLIES ANYTIME THAT SOMEONE CAN PROVIDE A GREAT BENEFIT AT LOW COST TO HERSELF. IT'S NOT SPECIFIC TO RESEARCHERS OR TO RESEARCH SUBJECTS. SO SUPPOSE THAT WE HAVE A RESEARCH STUDY IN A PARTICULAR COUNTRY SAY WE'RE DOING A RESEARCH STUDY IN MALI AND WE'RE STUDYING PATIENTS WITH HEART DISEASE. PEOPLE IN THE LOCAL COMMUNITY MAY BE IN DESPERATE NEED OF ANTI-MA ANTI-MALARIAS IN AND IF THE RESEARCHERS HAVE A BUILT TO PROVIDE THE ANTI-MALARIALS MAYBE THEY HAVE A DUTY OF RESCUE TO PROVIDE THE DRUGS THOUGH THEY HAVE NOTHING TO DO WITH THE STUDY. SO THERE'S A DUTY TO RESCUE. THIS TABLE SUGGESTS FOUR AND WHY MIGHT THERE BE A DUTY TO GIVE POST-TRIAL CARE TO PARTICIPANTS THAT MAY NOT HAVE ACCESS OTHERWISE. THE DUTY TO NOT CAUSE HARM DOES NOT NORMALLY APPLY IN THE CASES WE'RE INTERESTED IN. THE SPECIAL RELATIONSHIP BETWEEN RESEARCHERS AND PARTICIPANTS AND THE DUTY OF RECIPROCITY BUT THEY'LL BE LIMITED IN THEIR EXTEND AND DUTY OF RESCUE MAY APPLY IN SOME LIMITED CASES BUT IT'S IMPORTANT TO ACKNOWLEDGE IT DOESN'T JUST APPLY TO HELPING PARTICIPANTS. AND THEY DON'T APPLY AN OPEN-ENDED RESEARCH SO THEY DON'T HAVE AN OBLIGATION TO PROVIDE CARE FOR THE NEXT 30 YEARS, FOR EXAMPLE. NONE OF THE JUSTIFICATIONS IMPLY THE BEST OR ONLY WAY TO DISCHARGE ONE'S ETHICAL OBLIGATION TO PROVIDE THE STUDY INTERVENTION THAT'S BEING TESTED IN A TRIAL. IN OTHER CASES ESPECIALLY WHEN THE STANDARD OF CARE IS HIGHER IT MAY BE THE CARE OTHER THAN THE EXPERIMENTAL INTERVENTION MAY BEST FULFILL THE DUTY. AND FINALLY WE NEED TO CONSIDER THE DUTY OF MULTIPLE PARTIES. RESEARCHERS AND SPONSORS AND NATIONAL GOVERNMENTS AND SO ON. SO SAY SOMETHING ABOUT WHAT HAPPENS IN PRACTICE. CURRENT PRACTICE WITH REGARD TO PROVIDING EFFECTIVE PRODUCT HIGHLY VARIABLE. A LOT OF RESEARCH SITES AROUND THE WORLD THE FOCUS IS TRANSITIONING PARTICIPANTS TO OTHER SOURCES OF CARE. IT COULD BE NATIONAL HEALTH CARE SYSTEMS AND OTHER STUDIES FOR WHICH PARTICIPANTS ARE ELIGIBLE. RESEARCH SITES SOMETIMES PROVIDE SHORT-TERM CARE DURING A TRANSITION PERIOD NOT FOR EXTENDED PERIOD OF TIME. SOME COMPANIES CONTINUE TO ACCESS TO BENEFICIAL TREATMENTS BY RUNNING OPEN-LABEL EXTENSION STUDIES THIS IS NOT A CONSISTENT PRACTICE. IN HIGH-INCOME COUNTRIES IT'S LIKELY PARTICIPANTS WILL GET ACCESS TO CONTINUE TREATMENT THROUGH EXPANDED ACCESS PROGRAMS OR IN THE U.S. THROUGH COMPASSIONATE USE PROGRAMS. AND FINALLY PERCEIVED OBLIGATIONS TO PROVIDE POST-TRIAL CARE HAVE LED PUBLIC AND PRIVATE SPONSORS TO AVOID CARRYING OUT RESEARCH IN CERTAIN ENVIRONMENTS WHERE PEOPLE WON'T HAVE ACCESS THROUGH THE NATIONAL HEALTH CARE SYSTEM TO CARE AFTERWARDS. I WANT TO FLAG THIS BECAUSE IT'S A POTENTIALLY UNFORTUNATE EFFECT OF HAVING A REQUIREMENT IN PLACE THAT POST-TRIAL ACCESS BE AVAILABLE. THERE'S A POTENTIAL FOR PEOPLE WHO ALREADY LACK ACCESS TO CARE TO BE MADE EVEN WORSE OFF BECAUSE THEY WOULDN'T HAVE ACCESS TO CARE AFTER A TRIAL. SO LET ME RETURN TO THE CASE THAT I BEGAN WITH. THE DRUGS IN THIS TRIAL WERE MADE BY MULTIPLE PRIVATE COMPANIES AND THOSE MULTIPLE PRIVATE COMPANIES DID NOT WANT TO GET INVOLVED IN THE DISTRIBUTION OF THE DRUGS AND THE VARIOUS COUNTRIES WHERE THE TRIAL WAS HAPPENING BUT THEY AGREED THEY WOULD PROVIDE THE DRUGS FOR FREE. THE SPONSOR WAS NOT ALOWD -- ALLOWED TO PROVIDE CLINICAL CARE OUTSIDE THE STUDY. AFTER A LOT OF NEGOTIATION THE FOLLOWING ARRANGEMENT WAS REACHED THE RESEARCHER WOULD PROVIDE THE MANUFACTURER'S DRUGS WITH TEST WELL-BEING -- WHETHER THEY REMAIN VIRALLY SUPPRESSED AND THE THOUGHT WAS TWO YEARS IS ENOUGH TIME FOR THE DRUGS TO GET LICENSED IN COUNTRIES WHERE THEY WEREN'T CURRENTLY LICENSED AND PROVIDED TO PATIENTS THROUGH NATIONAL PROGRAMS. I'LL LEAVE TO YOU DECIDE WHETHER THIS IS A SUFFICIENT ARRANGEMENT. TURN TO THE ISSUES OF THE COMMUNITY HOST RESEARCH WHICH ARE NONE OF THE QUESTIONS THAT CAME UP AT THE END OF ANNETTE'S TALK AND THE QUESTIONS. THIS DISCUSSION HAS FOCUSSED ON MAKING STUDY INTERVENTIONS TO HOST COUNTRIES. THIS IS THE QUESTION OF REASONABLE AVAILABILITY. THERE ARE FEWER GUIDELINES AN REGULATIONS. THE DECLARATION OF HELSINKI AND THE NATIONAL COUNCIL OF MEDICAL SCIENCES SPEAK TO IT. THE DECLARATION OF HELSINKI SAYS MEDICAL RESEARCH WITH A VULNERABLE GROUP AND THEY INCLUDE PEOPLE IN RESOURCE-LIMITED SETTINGS IS ONLY JUSTIFIED IF THE RESEARCH IS NOT RESPONSIVE TO THE PRIORITY OF THE GROUP AND THE RESEARCH CANNOT BE CARRIED OUT IN A NON-VULNERABLE GROUP. THIS SHOULD STAND TO BENEFIT FROM THE KNOWLEDGE, PRACTICES OR INTERVENTIONS THAT RESULT FROM THE RESEARCH. AND THEY SAY BEFORE UNDERTAKING RESEARCH IN A POPULATION OR COMMUNITY WITH LIMITED RESOURCES THE SPONSOR AND THE INVESTIGATOR MUST MAKE EVERY EFFORT TO ENSURE THE RESEARCH IS RESPONSIVE TO THE HEALTH NEEDS AND PRIORITY OF THE POPULATION TO THE COMMUNITY WITH WHICH IT'S TO BE CARRIED OUT AND ANY INTERVENTION OR KNOWLEDGE WILL BE MADE AVAILABLE TO THE POPULATION OF THAT COMMUNITY. SO WHAT IS THE ETHICAL REASONING BEHIND THESE RECOMMENDATIONS THAT A GROUP OR POPULATION OR COMMUNITY SHOULD GET ACCESS TO THE PRODUCTS OF RESEARCH? I THINK THE UNDERLYING CONCERN ABOUT CONDUCTING RESEARCH WHERE IT'S NOT EXPECTED THE HOST COMMUNITY WOULD GET ACCESS TO THE PRODUCTS OF RESEARCH IS ABOUT EXPLOITATION. WHAT'S IT MEAN FOR ONE PARTY TO EXPLOIT ANOTHER OR FOR A TRANSACTION TO BE EXPLOITIVE. THE STANDARD ANALYSIS DEFINES EXPLOITATION LIKE THIS. X EXPLOITS Y WHEN X TAKES UNFAIR ADVANTAGE OF Y'S SITUATION. SO THE PARTY DOING THE EXPLOITING TAKES ADVANTAGE OF VULNERABILITY OF THE OTHER PARTY IN ORDER TO GET MORE OUT OF HIM THAN SHE DESERVES. FOR EXAMPLE, SUPPOSE IN ALL THE RAIN HAPPENING OVER THE LAST COUPLE DAYS, SUPPOSE I'M FOOLISHLY OUT DRIVING ON A COUNTRY ROAD. I'M NOT A PARTICULARLY GOOD DRIVER. I'M VERY SAFE. I WANT PEOPLE TO GO THE SPEED LIMIT BUT NOT A PARTICULARLY GOOD DRIVER. INTO A MUD BANK AND GET STUCK. NOW, THIS MIGHT BE A VERY UNFORTUNATE CIRCUMSTANCE IF I'M OUT IN THE MIDDLE OF NOWHERE. MAYBE THEN DESPERATE FOR SOMEONE TO COME AND HELP ME. SUPPOSE THAT AFTER A WHILE OF WAITING IN THE RAIN SOMEONE DOES COME SAY CHRISTINE COMES IN HER DODGE RAM TRUCK AND SHE SAYS, HAPPY TO HELP YOU. I HAPPEN TO HAVE TOW ROPES HERE. I CAN PULL YOU OUT OF THE MUD. I SAY GREAT, THAT'S BRILLIANT. I'LL BE ABLE TO GET TO WORK ON TIME, SHE SAYS, NO, NO, NO. NOT SO FAST. YOU SEEM TO BE IN DESPERATE NEED TO GET OUT OF THE MUD, YOU'LL HAVE TO PAY ME $1,000 FOR ME IT PULL YOU OUT. NOW, LET'S ASSUME I HAVE $1,000 IN CASH WITH ME -- LET'S NOT ASK QUESTIONS ABOUT WHY I HAVE THAT. I PAY MY RENT IN CASH, WHATEVER IT MIGHT BE. SO I MAY BE WILLING TO PAY THAT AND I'M DESPERATE TO GET OUT OF THE MUD AND NO ONE ELSE IS GOING TO COME ALONG AND RESCUE ME. I MAY BE WILLING TO PAY THAT MONEY. NEVERTHELESS, IT SEEMS TO ME I WOULD BE WRONGED IF CHRISTINE INSISTS ON THE $1,000 PAYMENT FOR 10 MINUTES OF WORK PULLING ME OUT OF THE MUD. THE WRONG IS SHE IS EXPLOITING ME. SHE'S TAKING UNFAIR ADVANTAGE OF MY SITUATION TO GET MORE FROM THE TRANSACTION THAN SHE SHOULD. SO NOTICE A COUPLE IMPORTANT POINTS ABOUT EXPLOITATION THAT COME FROM THE EXAMPLE. DOES IT HAVE TO BE HARMFUL TO THE PEOPLE BEING EXPLOITED. NO. I'M NOT HARMED BY CHRISTINE EXPLOITING ME IN THIS CASE. I'M BENEFITTED. THAT'S WHY I AGREED TO PAY THE $1,000 BECAUSE IT'S A GOOD DEAL FOR ME TO GET RESCUED. DOES EXPLOITATION INVOLVE INVALID CONSENT. NO, I UNDERSTAND WHAT I'M AGREEING TO AND DO IT VOLUNTARILY BUT NEVERTHELESS I'M EXPLOITED. THIS IS WHAT IS CALLED MUTUALLY ADVANTAGEOUS EXPLOITATION. RETURN NOW TO THE EXPLOITATION TO COMMUNITIES THAT RECEIVE RESEARCH. IF THEY RECEIVE BENEFITS RELATIVE TO THE BURDENS OF HOSTING THE RESEARCH AND RELATIVE TO THE GAINS OF OTHER PARTIES. GAINS TO OTHER PARTIES MIGHT BE COMPANIES WHO PROFIT FROM A SUCCESSFUL STUDY OR PATIENTS IN OTHER COUNTRIES WHO BENEFIT FROM DRUGS BEING DEVELOPED. WHAT ARE THE BURDENS HOST COMMUNITIES MIGHT FACE OVER AND ABOVE THE RISKS AND BURDENS FACED BY RESEARCH PAR TIS PANTHS PANTHS -- PARTICIPANTS THEMSELVES. IT MAY MAKE USE OF CLINICAL FACILITY ARE SCARCE AND IT MAY ATTRACT THEM AWAY FROM THE PUBLIC HEALTH SYSTEM. IT MAY CONTRIBUTE TO LOCAL BRAIN DRAIN. THERE'S A LIMIT ON HOW MUCH RESEARCH CAN TAKE PLACE AT ANY ONE SITE. SO RESEARCH NOT PARTICULARLY SOCIALLY VALUABLE MAY CROWD OUT OTHER RESEARCH THAT MAY TAKE PLACE AT A SITE. THESE ARE SOME OF THE POSSIBLE BURDENS OVER AND ABOVE THE BURDENS PLACED ON RESEARCH PARTICIPANTS. WHAT ABOUT POSSIBLE BENEFITS? WELL, A RESEARCH STUDY MAY ANSWER QUESTIONS ABOUT LOCAL HEALTH PROBLEMS THAT ARE IMPORTANT TO THAT COMMUNITY. SO FOR EXAMPLE, ANSWERS QUESTIONS ABOUT THE EPIDEMIOLOGY OF A DISEASE MAY HELP WITH LOCAL VECTOR CONTROL EFFORTS. THE RESEARCH MAY BE PART OF THE PROCESS OF DEVELOPING NEW MEDICAL INTERVENTIONS FOR THE POPULATION OR BENEFIT PATIENTS IN THAT COMMUNITY. RATHER THAN TAKING AWAY FROM FACILITIES AN CLINICIANS PROVIDING CARE, THE INFRASTRUCTURE USE FOR THE RESEARCH MIGHT ACTUALLY INCREASE THE CAPACITY OF THE LOCAL HEALTH CARE SYSTEM TO PROVIDE CARE. AND LOCAL HEALTH CARE WORKERS MAY BENEFIT THROUGH TRAINING PROVIDED BY THE RESEARCH. OKAY. SO THERE ARE DIFFERENT WAYS IN WHICH WE MIGHT THINK WITH THE BURDENS AND BENEFITS OF THE RESEARCH. NOW, IF WE REQUIRE THAT RESEARCH ONLY BE CONDUCTED WHEN THE PRODUCTS OF RESEARCH ARE MADE REASONABLY AVAILABLE WHICH IS THE PROPOSAL I STARTED WITH. I THINK THE IDEA IS THAT WILL AVOID EXPLOITATION BY ENSURING THE BENEFIT TO COMMUNITIES ARE FAIR. THE BENEFITS OF GETTING ACCESS TO INTERVENTION FOR PEOPLE IN THE COMMUNITY IS A SUFFICIENT BENEFIT THEN IT WON'T BE AN UNFAIR DISTRIBUTION OF BENEFITS AND BURDENS AND THERE WON'T BE EXPLOITATION TAKING PLACE. THINK THAT'S THE IDEA BEHIND THIS IDEA THAT THE PRODUCTS OF RESEARCH SHOULD BE MADE REASONABLY AVAILABLE. NOW, THE REQUIREMENT OF REASONABLE AVAILABILITY HAS COME TO SOME CRITICISM. FOR ONE, IT'S NOT GOING TO BE APPLICABLE TO CERTAIN TYPES OF RESEARCH. IT'S NOT GOING TO BE APPLICABLE TO PHASE 1 TRIALS BECAUSE THERE WON'T BE A SUCCESSFUL INTERVENTION AVAILABLE SOON AFTER THE TRIALS. IT WON'T BE RELEVANT TO EPIDEMIOLOGICAL STUDIES BECAUSE THEY WON'T BE TESTING A PRODUCT. SOMETIMES THERE'S NO BENEFIT TO PROVIDING A SUCCESSFUL INTERVENTION. SOMETIMES A STUDY SHOWS A NEW TREATMENT IS NOT EFFECT PITCH THE REQUIREMENT HAS BEEN CRITICIZED FOR PUTTING EXCESSIVE PRESSURE ON THE RESEARCHERS. IT'S NOT THEIR JOB TO PROVIDE DRUGS TO EVERYBODY IN THE POPULATION THAT MAY BENEFIT FROM THE DRUGS. AND IT'S NOT THEIR JOB TO ENSURE THE LOCAL HEALTH CARE SYSTEM PROVIDES THE DRUGS. FINALLY, THE REASONABLE AVAILABILITY REQUIREMENT HAS BEEN CRITICIZED FOR TAKE A VIEW OF THE BENEFITS THAT COUNT IT TOO NARROW. ACCORDING THE COUNT OF EXPLOITATION WHAT MATTERS FOR WHETHER OR NOT AN INTERACTION IS EXPLOITIVE IS THE TIME OF THE BENEFITS NOT THE TYPE OF THE BENEFITS. NOTHING OF THAT CONCEPTION PROVIDES THE BENEFITS BE PROVIDED IN THE FORM OF THE EPERIMENTAL INTERVENTIONS. SOME OF THESE OBJECTIONS HAVE BEEN ADDRESSED IN THE RECENT PROVISIONS IN THE GUIDELINES WHICH CLARIFY THE REASONABLE AVAILABILITY REQUIREMENT TO SAY AS PART OF THEIR OBLIGATION SPONSORS AND RESEARCHERS MUST ALSO MAKE EVERY EFFORT IN COORDINATION WITH GOVERNMENT TO MAKE AVAILABLE AS SOON AS POSSIBLE INTERVENTION AND KNOWLEDGE GENERATED FOR THE POPULATIONAL COMMUNITY AND BUILDING LOCAL RESEARCH CAPACITY. THAT'S RESPONDING WITH MORE FLEXIBILITY SOME OF THE OBJECTIONS. IT DOESN'T AS FAR AS I CAN SEE, DEAL WITH THE OBJECTION THAT WHAT MATTERS IS THE AMOUNT, NOT THE TYPE OF BENEFITS. IN ALTERNATIVE DEVELOPED BY MEMBERS OF THE DEPARTMENT OF BIOETHICS IN THE CLINICAL CENTER, A VIEW CALLED THE FAIR BENEFITS FRAMEWORK. THE IDEA BEHIND THE FRAMEWORK IS THAT A WIDE RANGE OF BENEFITS CAN BE COUNTED WHEN WE THINK WITH THE BENEFITS TO HOFT HOST COMMUNITIES. IF THE RESEARCH HAS PROVIDED ADDITIONAL CLINICAL CARE IT WOULD COUNT AND THEY'RE IN A COMMUNITY WITH POTABLE WATER, PAYING FOR A WELL WOULD COUNT PROVIDED THE BENEFIT TO THE COMMUNITY IS LARGE THE RESEARCH WOULDN'T EXPLOIT THE COMMUNITY EVEN IF THE INTERVENTIONS COULD BE TESTED IN THAT COMMUNITY. AS WELL AS THE REQUIREMENT ON THE AMOUNT OF BENEFITS THROUGH THE PROCEDURAL SAFEGUARDS PROPOSED BY THE PROPONENTS OF THE FRAMEWORK THAT AS WELL AS THE AMOUNT BEING FAIR COMMUNITIES HAVE TO AGREE THE LEVEL OF BENEFITS IS FAIR AND THERE BE TRANSPARENCY ABOUT BENEFIT AGREEMENTS TO COMPARE ACROSS DIFFERENT STUDY SECTS. SO IN MAKING THE BENEFITS AVAILABLE TOO NARROW IS ALSO BEING CRITICIZED. ONE CRITICISM IS THAT WE DON'T KNOW WHAT COUNTS AS FAIR. WE DON'T KNOW WHAT AMOUNT OF BENEFITS IS FAIR. WE'RE NOT CERTAIN IN DECIDING HOW MUCH BENEFIT IS SUFFICIENT. THE OTHER IS IT'S POSSIBLE THERE WILL BE A RACE TO THE BOTTOM IN PRACTICE. WHAT WE HAVE IS A SITUATION WHERE THERE'S ENORMOUS POWER IMBALANCES AGAINST HIGH-INCOME COUNTRY SPONSORS OF RESEARCH AND COMMUNITIES IN DEVELOPING COUNTRIES THAT MAY BE HOST OF RESEARCH THE DANGER IS THE IMBALANCE IN NEGOTIATING POWER MEANS THE COMMUNITIES AGREE TO LOW-LEVELS OF BENEFIT IN PRACTICE. IT'S STILL BETTER FOR THEM THAN NOTHING AT ALL. THIS IS CLEAR BENEFITS OF THE FRAMEWORK. THERE'S MIDDLE POSITIONS BETWEEN THE TWO. YOU RECALL THE IDEA OF REASONIVENESS AND RESPONSIVENESS AND THAT WAS ONE HALF OF A TWO-PART REQUIREMENT ORIGINALLY. PRODUCTS OF RESEARCH SHOULD BE MADE AVAILABLE AND TO HOST COUNTRY NEEDS. IF YOU'RE CONVINCED THAT REASONABLE AVAILABILITY IS NOT THE RIGHT ANSWER BUT YOU ALSO THINK WE SHOULDN'T JUST ALLOW ANY BENEFITS TO HOST COMMUNITIES THEN YOU MIGHT TURN TO THE RESPONSIVENESS REQUIREMENT TO HELP OUT HERE. AND YOU MAY THINK IT'S RESPONSIVE TO THE COUNTRY TO WHICH THE REASON -- RESEARCH IS CARRIED OUT AND I PLAN TO TALK UNTIL THE BREAK AND THEN DO QUESTIONS AFTER THE BREAK IF THAT'S OKAY. SO THIS IS HOW I LIKE TO THINK ABOUT RESPONSIVENESS. IT'S NOT THE ONLY WAY IN THINKING ABOUT RESPONSIVENESS. I LIKE TO THINK ABOUT IT IN TERMS OF LOCAL SOCIAL VALUE. TALKED EARLIER ON IN THE COURSE ABOUT THE SOCIAL VALUE REQUIREMENT AND RESEARCH SHOULD BE EXPECT TOD GENERATE VALUABLE KNOWLEDGE. THE IDEA IS THAT WE CAN TALK IN TERMS OF THE LOCAL SOCIAL VALUE, THAT IS THE VALUE OF THE KNOWLEDGE THAT THE RESEARCH GENERATES TO THE COMMUNITY THAT HOSTS RESEARCH. IF WE THINK THAT'S SUFFICIENTLY GREAT, GREAT ENOUGH TO JUSTIFY RESEARCH IN THE SAME PLACE TO DO REASON IN THE FIRST PLACE, THE CLAIM IS THAT WILL PREVENT IT FROM BEING EXPLOITIVE. AND IT MAY BE EASIER TO WORK OUT WHETHER OR NOT A STUDY HAS SUFFICIENT LOCAL SOCIAL VALUE THEN IF THE BENEFITS PROVIDE TOD A COMMUNITY IS FAIR. AND TO THINK IF THE KNOWLEDGE GENERATED WOULD JUSTIFY ASKING PEOPLE TO TAKE ON THE RISKS AN BURDENS OF THE RESEARCH FOR THIS COMMUNITY MAY BE EASIER THAN TO ASK IF THIS IS PROVIDING THIS SUPPLY OF WATER ENOUGH TO JUSTIFY DOING THE RESEARCH. IF SO WE SHOULD THINK OF THIS IN RESPONSIVENESS RATHER THAN THE AMOUNT OF BENEFITS. THERE'S MORE TO BE SET ABOUT THE DEBATE. WE CAN TALK ABOUT IT MORE IN DISCUSSION. LET ME WRAP UP AND TWO TAKE-HOME NOTES ABOUT REASONABLE AVAILABILITY. ONE, IT'S HARD TO JUSTIFY REQUIRING THE RESEARCH AND SPONSORS ENSURE PRODUCTS MUST BE MADE REASONABLY AVAILABLE TO THE COMMUNITIES OR POPULATION HOST RESEARCH. IT'S HARD TO THINK OF RESEARCH THAT'S NOT RELEVANT TO THE HEALTH OF COMMUNITIES IN LOW AND MIDDLE-INCOME COUNTRIES. IN PRACTICE, ASKING THE QUESTION, WHAT'S THE RELEVANCE OF THE POPULATION TO WHICH IT'S BEING CARRIED OUT IS A GOOD WAY TO AVOID EXPLOITIVE RESEARCH AND TO IDENTIFY WAYS A RESEARCH PROJECT SHOULD BE CHANGED TO GIVE IT MORE LOCAL SOCIAL VALUE. WE RETURN TO THE SECOND CASE IN WHICH I START THE TALK. MOST THE PEOPLE IN MARACAIBO DON'T KNOW WITH THE TEST AND IT WAS AVAILABLE FOR $1,000 IN CARACAS. THE ORIGINAL GOAL OF THE RESEARCH WAS IT TO FIND A SECURE FOR HUNTINGTON'S DISEASE HASN'T BEEN ACHIEVED SO THEY DON'T HAVE THE TREATMENT OR THE TEST DEVELOPED FROM THE RESEARCH. ON THE OTHER HAND, THE RESEARCHER WHO LED THE PROJECT IN MARACAIBO RAISED A LARGE AMOUNT OF MONEY, ABOUT $6 MILLION TO FUND A HUNTINGTON'S DISEASE CLINICAL IN THE COMMUNITY. ONE WOULD THINK THE BENEFIT IN THE COMMUNITY IS LARGE ENOUGH WE WOULD NOT CRITICIZE HER ON THE GROUNDS OF EXPLOITING THAT COMMUNITY. SO TO CONCLUDE. WIDESPREAD AGREEMENT THAT PARTICIPANTS IN CLINICAL TRIALS AND THE COMMUNITIES THAT HOST RESEARCH SHOULD BENEFIT FROM RESEARCH PARTICIPATION. I'VE TALKED ABOUT SOME OF THE WAYS IN WHICH PEOPLE SHOULD BENEFIT AND WHY SHOULD THERE BE AN EXTENT OF BENEFIT AND WHO SHOULD PROVIDE THAT BENEFIT. WHETHER IT'S GOVERNMENT OR RESEARCH OR SPONSORS. I WANT TO END ON A CAUTIONARY NOTE ON THE ETHICAL ISSUES WE TALKED ABOUT THIS MORNING. CONDUCTING RESEARCH IN ENVIRONMENTS WHERE MANY PEOPLE LACK ACCESS TO HEALTH CARE I THINK IS ETHICALLY CHALLENGING. I DON'T THINK THAT SHOULD PUT US OFF DOING IT. AS A NUMBER OF THE CASES WE'VE DESCRIBED ILLUSTRATE, CONDUCTING THE RESEARCH IS VITALLY HEALTH OF PEOPLE IN LOW AND MIDDLE-INCOME COUNT RID AND THE ETHICAL -- COUNTRIES SO THE ETHICAL CHALLENGES SHOULD BE MET NOT AVOID. [APPLAUSE] >> DO YOU WANT TO HOLD ALL QUESTIONS UNTIL AFTER? >> I FIGURED WE COULD BREAK AT THE SAME TIME WE'D NORMALLY BREAK AND START WITH QUESTIONS AFTER. >> OKAY. SO TAKE A BREAK, COME BACK AT 10:35, PLEASE. WE'LL HAVE A DISCUSSION AND IF YOU DON'T WANT TO GO TO THE MICROPHONES RAISE YOUR HAND AND I'LL BRING YOU ONE BECAUSE IT'S GOING TO BE INTERACTIVE. >> SO IF PEOPLE HAVE QUESTIONS STILL REMAINING FROM THE LECTURE I JUST GAVE, LET'S DEAL WITH A FEW OF THOSE QUESTIONS FIRST AND THEN LET'S MOVE ON TO DISCUSSING THE CASE. >> THANKS, JOE. I HAVE A QUESTION ABOUT THE FAIR BENEFITS. MANY RELATED TO TRAINING OR INVESTMENT ON THE LOCAL FACILITIES OR ANCILLARY CARE TO THE RESEARCH SUBJECTS OR THE AGREEMENTS THAT HAVE BEEN TAKEN BETWEEN THE RESEARCHERS OR SPONSORS AND THE LOCAL COMMUNITIES, ALL THAT INFORMATION IS OFTEN NOT PUBLICLY AVAILABLE AND THERE ARE NO OFFICIAL WAYS OF REGISTERING IT. PROBLEM IF WE WANT TO MAKE THE BALANCE BETWEEN BENEFITS AND RISKS. >> WE DON'T KNOW WHAT'S GONE ON IN THE NEGOTIATIONS ABOUT WHAT BENEFITS ARE GOING TO BE PROVIDED IN A PARTICULAR STUDY OR TO A PARTICULAR COMMUNITY. AND SO THIS IDEA THAT WE WOULD BE ABLE TO COMPARE WHAT HAPPENED IN DIFFERENT CONTEXTS IS ACTUALLY VERY HARD TO IMPLEMENT. I THINK IT'S RIGHT AND UNFORTUNATE IN A WAY THAT THERE ISN'T CURRENTLY WHAT THE PROPONENTS OF THE FAIR BENEFITS FRAMEWORK HOPED FOR IS THERE WOULD BE A REPOSITORY OF BENEFITS SHARING THAT YOU COULD USE AS A STANDARD FOR WHAT IS AN ACCEPTABLE AGREEMENT. THAT HASN'T ARISEN. IT'S UNFORTUNATE THAT INFORMATION IS HARD TO GET AND FOUND ON A CASE BY CASE BASIS BY QUERYING RESEARCHERS AND SPONSORS. I DON'T THINK PEOPLE ARE DELIBERATELY KEEPING IT SECRET I JUST DON'T THINK THERE'S A NATURAL PLACE FOR IT TO BE PUBLICIZED IN A LOT OF CASES. >> I SAVED THIS QUESTION BECAUSE I THINK IT RELATE TO BOTH TALKS. I WAS WONDERING IF YOU CAN ELABORATE ON WHAT'S THE MORAL STATUS OF A COMMUNITY AND WHAT IS THAT BASED ON AND THEN HOW CAN WE USE THAT TO BALANCE THE RIGHTS OF THE COMMUNITY AGAINST THE RIGHTS OF INDIVIDUALS WHETHER THEY'RE PARTICIPANTS OR OTHER PEOPLE? >> COULD YOU SAY JUST QUICKLY WHAT YOU MEAN WHEN YOU SAY THE MORAL STATUS OF THE COMMUNITY. >> SURE. I THINK THERE'S A PHILOSOPHICAL LITERATURE THAT SUPPORTS THE MORAL STATUS OF A PERSON. FOR EXAMPLE, WHEN YOU START TO TALK ABOUT SOMETHING LIKE EMBRYONIC RESEARCH AND WHAT'S THE STATUS OF AN EMBRYO AND DOES IT HAVE RIGHTS. I HAVEN'T SEEN A LOT OF AND I CERTAINLY DIDN'T SEE ANYTHING AS FAR AS I REMEMBER IN THE READINGS THAT WE HAD FOR THIS SESSION ABOUT WHETHER OR NOT A COMMUNITY EVEN HAS A MORAL STATUS. >> GOOD, THANK YOU. THAT'S HELPFUL. SO I WAS GOING GIVE YOU MY VIEW ON THIS WHICH MAY NOT BE SHARED AND MAYBE ANNETTE CAN WEIGH IN IF I MISS SOMETHING IMPORTANT. I DON'T THINK COMMUNITIES HAVE MORAL STATUS. I THINK THE INDIVIDUAL COMPRISE THEM DO. I THINK AND THERE'S A MISTAKE WE MIGHT MAKE WHICH IS TO IMAGINE THE COMMUNITY IS ONE THING THAT MATTERS AND THEN THE INDIVIDUALS THAT COMPRISE IT ARE A DIFFERENT THING THAT MATTERS. WE SHOULD THINK OF SOCIETIES ARE MADE OF INDIVIDUALS AND WHAT'S HELPFUL IN THINKING ABOUT THE COMMUNITY IS THINGS LIKE THINKING ABOUT ON WHOSE BEHALF IT'S ACCEPTABLE TO ASK RESEARCH PARTICIPANTS TO TAKE ON BENEFITS AND BURDEND. WE MIGHT THINK FOR EXAMPLE THAT IN THE UNITED STATES IT'S ACCEPTABLE TO SAY TO PEOPLE, FOR YOUR FELLOW CITIZENS WE'D LIKE TO YOU TAKE ON THE RISKS AND BURDEN WHERE WE MAY NOT THINK OF IT TO SAY TO PEOPLE IN SOUTH AFRICA FOR THE PEOPLE IN THE UNITED STATES WE WANT YOU TO TAKE ON THE RISKS AN D BURDENS AND THERE'S OFTEN REALLY IMPORTANT ACTUAL CONNECTIONS BETWEEN MEMBERS OF THE COMMUNITY AND IF A HEALTH CARE SYSTEM FOR A COMMUNITY OR CLINIC FOR THAT COMMUNITY THEN PEOPLE WHO USE RESOURCES FROM THAT CLINIC ARE TAKING RESOURCES THAT ARE TAKE FROM OTHERS SO THEN WE HAVE TO THINK WITH THE COMMUNITY THAT EXISTS. THANK YOU FOR THE QUESTION. I THINK IT'S AN IMPORTANT ISSUE. >> I HAVE VERY LITTLE TO ADD. THE ONLY THING I WOULD ADD IS THAT OFTEN INDIVIDUALS CARE ABOUT THE COMMUNITY AND IN A PARTICULAR WAY AND THAT'S REALLY IMPORTANT IN ORDER TO RESPECT THEM AS INDIVIDUALS. ALSO FOR THAT REASON IT'S IMPORTANT TO ENGAGE AT THE LEVEL OF THE COMMUNITY AND TAKE COMMUNITY CONSIDERATION SERIOUSLY. AND IN BOTH OF OUR TALKS WE HAVEN'T TALKED MUCH ABOUT COMMUNITY ENGAGEMENT BUT AS YOU MAY KNOW FROM IF YOU ATTENDED ALL THE COURSE IN THE FIRST SESSION ESPECIALLY FOR RESEARCH IN LOW AND MIDDLE-INCOME COUNTRIES AND ARGUMENTS COULD BE LAID OUT AND WE KNOW WHAT ARE FOR OR AGAINST POSITIONS PEOPLE HAVE TAKEN, THEY'RE STILL CONTESTED AND REASONABLE PEOPLE WILL DISAGREE ABOUT THEM WHICH MAKES PROCESS ABOUT MAKING ULTIMATE VERY IMPORTANT AND MAKES IT IMPORTANT IN ORDER TO MAKE DECISIONS SUCH AS HOST. STUDY BENEFITS OR A STANDARD OF CARE QUESTION INSOFAR WITHIN THE CONSTRAINTS OF THE SCIENTIFIC PURPO PURPOSES OF THE STUDY. >> I HAVE A QUESTION ON THE DUTY TO RESCUE AND WHETHER IT'S SUFFICIENT TO GROUND OBLIGATION TO PARTICIPANTS POST-TRIAL. I I HAVE THE SENSE THERE ARE WHY THE DUTY TO RESCUE WOULD PROVIDE GROUNDS TO THEM OTHER THAN TO OTHER PEOPLE AND THE DUTY TO RESCUE SAYS IF I CAN PROVIDE A SUFFICIENT BENEFIT AT A SUFFICIENTLY LOW COST I OUGHT TO DO SO. HOW CAN THAT GO TO THE THE PARTICIPANTS OF THE TRIAL. >> SO BASICALLY I THINK THAT'S QUITE RIGHT AND I'VE TRIED TO ACKNOWLEDGE THAT. THE REASON THAT UP CERTAIN CIRCUMSTANCES THERE'S LIKELY TO BE A DUTY TO RESCUE PARTICIPANTS THAN OTHERS IS BECAUSE AS A RESULT OF CONDUCTING THE RESEARCH IN LOCATION WHERE'S THEY'RE WELL SITUATED TO PROVIDE RESCUE AND MAY PROVIDE OR HAVE CONTACT WITH PEOPLE WHO NEED RESCUE AS A RESULT OF THE RESEARCH. IF YOU'RE DEALING WITH A CONDITION LIKE HIV, FOR THE MOST PART FOR MOST PEOPLE IN THE ROOM WE DON'T HAVE AN OPPORTUNITY TO RESCUE SOMEONE WHO MIGHT NOT OTHERWISE HAVE TREATMENT FOR HIV. BUT IF YOU'RE DOING RESEARCH ON IT YOU'RE LIKELY TO BECAUSE YOU'LL HAVE PEOPLE COMING TO THE CLINICAL WHO HAVE HIV. IT COULD BE THERE ARE OTHER PEOPLE IN THE COMMUNITY THEN NOT JUST RESEARCH PARTICIPANTS BUT OTHERS YOU COULD RESCUE. THE COST OF IDENTIFY WHO THOSE PEOPLE ARE IS MUCH LOWER WHEN IT COMES TO THE PEOPLE WHO ARE PARTICIPANTS IN YOUR TRIAL THAN OTHER PEOPLE IN THE COMMUNITY. TO SAY THERE'S A 5% REF LENS RATE -- PREVALENCE RATE IN THE COMMUNITY THE COST WILL BE HIGHER. IT'S ALL CONTINGENT ON FACTS ON THE GROUND. SOMETIMES IT'S GOING TO BE CLEAR THERE ARE PEOPLE COMING WHO HAVE NOTHING TO DO WITH THE TRIAL. AND RESEARCH SITES FUNCTION AS RESEARCH SITESES AND WHERE PEOPLE GET -- SITES AND WHERE PEOPLE GET CARE AND IT'S NOT ETHICAL TO MAKE THE DISTINCTIONS ON WHAT THE RESEARCH IS DOING AND WHERE CARE IS BE PROVIDED. YOUR POINT IS WELL TAKEN. SOMETIME THE VIEW OF RESCUE WILL APPLY SPECIFICALLY TO RESEARCH AND PARTICIPANTS BUT NOT ALWAYS. >> NOW, I WOULD SUGGEST WE MOVE ON TO A CASE DISCUSSION. SO WHAT I'M GOING TO DO IS I'M GOING TO INTRODUCE THIS CASE. I MIGHT WANDER A BIT. IS THAT OKAY OR SHOULD I STAY STILL? >> I'M GOING DESCRIBE THIS CASE IN A SUCCINCT WAY AND I'LL OPEN IT UP FOR PEOPLE TO ASK QUESTIONS ABOUT THE FACTS OF THE MATTER AND THEN I'M GOING TO GIVE YOU A MOMENT TO THINK ABOUT SOME OF THE ETHICAL QUESTIONS THAT MIGHT ARISE AND FOR US TO DISCUSS THE ETHICAL ISSUES WHERE IT'S OPEN TO YOU TO SUGGEST CHANGES TO THE RESEARCH STUDY I'LL DESCRIBE OR TO ARGUE THAT THE RESEARCH STUDY IS FINE AS DESCRIBED OR INDEED TO ARGUE NO STUDY LIKE THE ONE I'M DESCRIBING COULD BE ETHICALLY OPEN. OKAY, SO THIS IS GOING TO BE A STUDY OF MALARIA AND FOR THOSE NOT FAMILIAR, IT'S A MOSQUITO-BORN DISEASE CAUSED BY ONE OR FOUR SPECIES OF PARASITES. IT'S ENDEMIC IN TROPICAL AND SUBTROPICAL REGIONS. THE MAP IS SHOWING WHERE MALARIA'S ENDEMIC LOOKING AT THE ORANGE AND RED. AND THERE'S MILLIONS OF CASES OF MALARIA EVERY YEAR AND SOMEWHERE BETWEEN 400,000 AND 700,000 DEATHS CAUSED BY MALARIA EVERY YEAR. SO SYMPTOMS OF MALARIA INCLUDE FEVER, VOMITING, HEADACHE AND COULD LEAD TO SEIZURES, COMA AND DEATH AND THEY'RE NOT EXCLUSIVELY IN CHILDREN AND PREGNANT WOMEN. >> THERE ARE EFFECTIVE ANTI-MALARIA DRUGS BUT RESISTANT IS A GROWING PROBLEMS AND THERE'S MEASURE AS IN VECTOR CONTROL. SPRAYING OR REMOVING OF BREEDING SITES FOR MOSQUITOS. REPELLENTS AN INSECTICIDES. THINK BED NETS AND CHEMICAL APPROVAL PROPHYLAXIS AND THAT IS USING SMALL DOSES OF THE DRUGS THAT WOULD BE USED TO TREAT MALARIA ITSELF. AND YOU TAKE THE DRUG AND YOU HAVE IT IN YOUR BLOOD SO IF YOU GET INFECTED WITH MALARIA YOU'RE ALREADY PRIMED TO FIGHT THE PARASITE. NOW, PEOPLE LIVING IN MALARIA-ENDEM MALARIA-ENDEMIC REGIONS DEVELOP PARTIAL IMMUNITY. THEY WON'T HAVE MALARIA SYMPTOMS WITH SMALL AMOUNTS IN THEIR BLOOD YET PEOPLE CAN GET A LEVEL THAT COULD KILL YOU OR I BUT THE IMMUNITY COMES OVER TIME. IN CASE ANYBODY LOOKS UP THE STUDY AND SAYS THIS NOT QUITE ACCURATE I HAVE CHANGED SOME CRUCIAL DETAILS. THE STUDY WAS RANDOMIZED FOR PROPHYLAXIS FOR P5X AND THE OTHER SPECIES OF MALARIA. THE DRUG HAD BEEN APPROVED FOR TREATMENT SO THE INTEREST HERE WAS IN WHETHER OR NOT IT WAS ALSO EFFECTIVE FOR PREVENTION OF MALARIA. THE STUDY WAS FOR 3,000 ADULTS ON AN ISLAND IN INDONESIA. IT WAS MOVING FROM A MALARIA-FREE REGION ON THE LEFT HAND OF JAVA TO A MALARIA-ENDEMIC REGION. THEY WERE MOSTLY MALARIA NAIVE. THIS IS IMPORTANT BECAUSE IT MADE IT A GOOD POPULATION FOR THE STUDY. TYPICALLY THE PEOPLE DEVELOP PARTIAL COMMUNITY TO THE MALARIA ENDEMIC REGIONS AND IT'S NOT USUAL USUALLY THE PEOPLE IN THE AREA WOULD USE PROPHYLAXIS. THEY WOULD USE BED NETS AND BEHAVIORAL MEASURES AND SO ON BUT TYPICALLY IF YOU'RE LIVING IN A MALARI ENDEMIC REGION YOU DON'T TAKE ANTI-MALARIA DRUGS FOR PROPHYLAXIS. THAT'S IS NOT WHAT THE POPULATION WOULD TYPICALLY USE. THERE'S LOTS OF PEOPLE THAT WOULD BENEFIT FROM AN ANTIMALL AERI AERIAL -- ANTI-MALARIAL DRUG AND THERE WAS INTEREST IN USING THIS FOR THE U.S. MILITARY IS BECAUSE OF THE DANGERS OF SOLDIERS CONTRACTING MALARIA WHEN IN TROPICAL REGIONS. SO THAT'S THE STUDY POPULATION. THIS IS THE TIME LINE FOR WHAT WOULD HAPPEN DURING THE STUDY. ALL PARTICIPANTS WOULD RECEIVE A TWO-WEEK READY -- RADICAL CURE. EVERYONE WHO IS GOING TO BE IN THE STUDY THEY TREATMENT THEM WITH THIS DRUG AS THOUGH THEY HAVE MALARIA SO THEY CAN BE SURE THE BEGINNING OF THE STUDY THAT NO ONE HAS MALARIA INFECTION. THEN RANDOMIZED ONE TO ONE TO DRUG OR PLACEBO FOR 20 WEEKS AND THIS IS PEOPLE TAKE DAILY TABLET FOR 20 WEEKS. AND THE BLOOD AND CEREBRAL SPINAL FLUID COLLECTED IS GOING TO BE STORED FOR FUTURE RESEARCH PURPOSE. VARIOUS PROCEDURES AND DAILY HOME VISITS BY STAFF TO SEE IF THE PARTICIPANT HAS DEVELOPED SYMPTOMS OR LIVER PUNCTURE AT WEEKS FOUR AND 24 AND THE TREATMENT MADE AVAILABLE IN CLINICS AT ANY TIME FOR PEOPLE WHO REPORT SYMPTOMS. IF ANYONE THINK THEY DEVELOP A FEVER THEY CAN GO AND A BLOOD SMEAR WILL BE USED TO PROVIDE TREATMENT. SO THAT'S THE STUDY. DOES ANYONE HAVE ANY QUESTIONS JUST FACTUAL QUESTIONS HOW THE STUDY DESIGNED? THAT'S BEFORE WE GET IN THE ETHICS OF THE STUDY? EXCELLENT. >> YOU CAN STILL TRY TO GO TO THE MICROPHONES. I'LL TRY TO DO SOME RUNNING WHICH IS NICE. >> I HEARD AT HOME VISIT AND THERE WAS THE LUMBER PURNCTURE. WAS THAT PERFORMED AT HOME? IN THE CLINIC.G TO BE PERFORMED THEY COME IN FOR THE WEEKLY CLINIC VISITS THEN LUNG PUNCTURE WILL BE PERFORMED THEN. >> I WAS WONDERING WHAT THE PARTICIPANTS WERE INSTRUCTED TO DO IN TERMS OF NON-MEDICAL PROPHYLAXIS. WERE THEY ALLOWED TO USE MOSQUITO REPELLANT? >> THE PROPOSAL IS FOR NO MODIFICATION IN WHAT THEY'D NORMALLY DO EXCEPT THEY'RE BEING MONITORED MORE CAREFULLY THAN THEY WOULD OTHERWISE BE FOR SYMPTOMS OF MALARIA INFECTION. NOTHING IS BEING WITHHELD BUT THEY'RE NOT BEING TOLD TO DO ANYTHING IN ADDITION. >> YOU WERE TALKING ABOUT HOW THE PARTICIPANTS HAD TO COME AND IDENTIFY THEIR OWN SYMPTOMS IN ORDER TO RECEIVE TREATMENT, IS THAT CORRECT? OR DO THE BLOOD TESTS HELP INDICATE WHETHER THEY HAVE MALARIA? >> IF THEY THINK THEY'RE EXPERIENCING SYMPTOMS THEY CAN ALWAYS GO TO THE CLINICAL BUT THERE'S ALSO A DAILY VISIT FROM STUDY STAFF TO ASK ABOUT SYMPTOMS PLUS EVERY WEEK THEY GO TO THE CLINICAL ANYWAY IN ORDER TO GET BLOOD DRAWN AND TO HAVE A CLINICAL EVALUATION. SO IT'S NOT JUST SELF-REFERRAL FOR THAT. >> DOES THE DRUG THAT WILL BE USED FOR PROPHYLAXIS HAVE SIDE EFFECTS? >> IT DOES HAVE SIDE EFFECTS AS FAR AS WE KNOW. THEY'RE RELATIVELY MILD. POTENTIAL FOR NAUSEA, FATIGUE, MAYBE SOME BAD DREAMS. THAT'S AS FAR AS WE KNOW IT'S NOT BEING USED YET TO CAUSE SIDE EFFECTS. IS IT BLINDED OR DOUBLE-BLINDED. >> IT'S DOUBLE-BLINDED. SORRY, I DIDN'T MENTION THAT. >> ARE PEOPLE BEING TREATED FOR OTHER THINGS OTHER THAN MALARIA. >> THAT HAS NOT BEEN PROPOSED BUT OF COURSE I CAN LEAVE IT UP TO THE WISDOM OF THE GROUP TO SAY WHAT SHOULD BE DONE. YOU MENTIONED THERE ARE MEDICATIONS AS A PREVENTIVE FOR MALARIA SO WHY WOULD THEY PICK A PLACEBO RATHER THAN A DRUG THAT CAN BE EFFECTIVE AS A CONTROL. >> THE SCIENTIFIC REASON FOR THAT IS THAT IS THEY WANT TO KNOW WHETHER OR NOT THE DRUG IS EFFECTIVE AS PROPHYLAXIS. IT COULD BE AN ALTERNATIVE FOR AN EXISTING DRUG TO A PROPHYLAXIS. >> YOU MISUNDERSTAND MY QUESTION. AS A CONTROL, I DON'T UNDERSTAND WHY THEY USED A PLACEBO RATHER THAN A DRUG THEY KNOW IS EFFECT PITCH I -- EFFECTIVE. AS A CONTROL THEY USE A PLACEBO AND NOT A DRUG THEY KNOW IS EFFECTIVE. >> SO THE BASELINE LEVELS ARE NOT STABLE ENOUGH TO KNOW WHETHER THE DRUG THEY WERE TESTING IS HAVING AN EFFECT IN THE CASE WHERE NAY -- THEY DISCOVER IT'S NOT WORKING AS WELL AS THE TREATMENT. THEIR CONCERN IS THE DATA THEY GET FROM THE TRIAL IS NOT GOING TO BE USEFUL FOR WHETHER IT'S EFFECTIVE IN PREVENTING MALARIA IN THE CASE IN PATIENTS THAT ARE PRESUMABLY AND BLOOD SMEARS AREN'T HEALTHY WHAT'S THE LP SHOWING YOU? >> A NUMBER OF THE BLOOD DRAWS AND LP TOGETHER OF SAMPLES IN THE POPULATION THEY THINK COULD BE OF INTEREST TO RESEARCHERS LATER ON AND THEY HAVE AN INTERESTING POPULATION OF PEOPLE WHO ARE MALARIA NAIVE MOVING TO A MALARIA REGION AND WILL GET ALL THE BLOOD SAMPLES OF THE 24 WEEKS AND THE SAMPLES OF CSF FOR POTENTIAL FUTURE RESEARCH. THEY'RE GOING TO BE STORED. THEY'RE NOT REQUIRED FOR TESTING THE EFFECTIVENESS OF THIS INTERVENTION. >> HOW DOES THAT PROVIDE ANYTHING FOR THIS STUDY? IT SEEMS LIKE A LOT TO PUT SOMETHING THROUGH TO PUT SOMEONE THROUGH THAT DOESN'T HAVE ANYTHING TO DO WITH THE STUDY IF IT'S NOT CONTRIBUTING TO ZIENGS DIAGNOSIS OR IF THERE'S NOT A SIGN OF ENCEPHALITIS. >> WHETHER YOU WOULD APPROVE THE STUDY AS I'VE DESCRIBED IT AND IF NOT, WHAT FURTHER JUSTIFICATION WOULD YOU ASK FOR FROM THE RESEARCHERS? AND WHAT CHANGES WOULD YOU REQUIRE FOR THE STUDY. WE HAVE ABOUT 20 MINUTES. LET ME SUGGEST PEOPLE TAKE TWO MINUTES AND SAY HI TO YOUR NEIGHBOR AND DISCUSS WITH THEM WHAT YOU'RE THINKING. WE'LL GIVE IT TWO MINUTES. QUICK DISCUSSION AMONG YOURSELVES AND THEN LET'S COME BACK TO THE MIKE MICROPHONES AN ANSWER THESE QUESTIONS. >> NOW THAT YOU'VE HAD TWO MINUTES TO SOLVE THE ETHICAL PROBLEMS WITH THE CASE, WHO WOULD LIKE TO RAISE SOMETHING THEY THINK THIS REALLY REQUIRES THINK IT RAISES AN ETHICAL JUST FISSION -- JUSTIFICATION OR SOMETHING THAT SHOULD BE REQUIRED. LET'S START WITH WHETHER WE CAN JUST APPROVE IT BECAUSE WE CAN ALL LEAVE NOW. SO MAYBE JUST A SHOW OF HANDS, WHO WOULD APPROVE THE STUDY AS I HAVE DESCRIBED IT? >> ONE PERSON, GREAT. I'D LIKE TO HEAR THE ETHICAL CONCERNS AND IF THAT WOULD BE ENOUGH TO DISCREDIT THE STUDY. FOR ALL THE REST WHO THINK NO, WHAT CHANGE WOULD YOU REQUIRE AND WHY? >> SO I WAS THINKING AT FIRST AND WHEN YOU READ A PROTOCOL I FEEL THERE'S USUALLY MORE INFORMATION TO DETERMINE IF A STUDY SHOULD BE APPROVED. FROM THE STANDPOINT OF BASELINE OF THE INFORMATION WE'RE GIVEN I DON'T THINK IT WOULD BE EFFICIENT FOR ANYBODY TO SAY, YES, LET'S DO THIS 100%. ALSO, IN TERMS OF LIKE WHAT THE POPULATION IS LIKE AND THE DISTRIBUTION OF AGE AND WHO WILL BE ENROLLED AND THE FACT WOMEN ARE MORE SUSCEPTIBLE TO DEATH BY MALARIA AND MAYBE ADMINISTERING PREGNANCY TESTS AN THE RISK TO BENEFIT RATIO FOR LUMBAR PUNCTURE SEEMS CONCERNING BECAUSE OF THE AMOUNT OF DISCOMFORT OR PAIN FOR SOMETHING THAT MAY NOT DIRECTLY BENEFIT THEM. >> THANK YOU. THE DEVIL IS ALWAYS IN THE DETAILS. THE STUDY POPULATION IS SUPPOSED TO BE BETWEEN 18 AND 65. I'D LIKE TO HEAR THE CONCERN ON PREGNANT WOMEN. DO WE WANT TO EXCLUDE THEM OR INCLUDE THEM? WHAT'S THE THOUGHT? >> KNOWING ALL THE RISKS POSSIBLE LIKE BEING ABLE TO UP FRONT BE LIKE OH, THIS PERSON IS PREGNANT I THINK IS IMPORTANT TO TAKE THE NECESSARY MEASURES TO MAKE SURE THEIR SAFETY IS MAXIMIZED. AND A QUESTION ON THE LUM PAR -- LUMBAR PUNCTURE AND NO PROTECTIVE EFFECT BUT NEVERTHELESS GOING THROUGH RISKY PROCEDURES. >> SO WHAT WE DISCUSSED WAS THERE IS A CONTROL GROUP AND WHAT WE DON'T UNDERSTAND IS THAT THE RISK BENEFIT ANALYSIS FOR WILL GROW BECAUSE THEY'RE NOT GETTING ANY PREVENTIVE MEDICINE AND THE STUDY IS DOUBLE-BLINDED. THOUGH THEY DON'T KNOW WHAT THEY'RE GETTING INTO. WE JUST DISCUSSED WHETHER IT WOULD HAVE BEEN -- THERE SHOULD BE AN OPPORTUNITY TO HAVE A PROPER CONSENT WITH THEM THAT THIS IS DOUBLE-BLINDED OR IF THIS COULD BE NOT-DOUBLE BLINDED AND SECOND WHAT WE THOUGHT IS LIKE THE PLACEBO GROUP IF IT'S POSSIBLE GIVE A STANDARD OF CARE SO THEY'RE GETTING SOME BENEFIT. THE CONTROL GROUP IS TAKING RISK AS WELL IN A CASE WHETHER IT'S PREVENTIVE MEDICINE IS WORKING OR NOT OR MAYBE THEY COULD BE BENEFITTED IF IT WORKS. BUT THE PLACEBO GROUP IN THIS CASE IS GETTING THE RISK AS WE DISCUSSED. >> WHAT SORTS OF BENEFITS WOULD YOU THINK WOULD BE APPROPRIATE IN THE CASE? >> STANDARD OF CARE SHOULD BE GIVEN AT LEAST MAYBE TO BOTH THE GROUPS OR AT LEAST THERE SHOULD BE A BASELINE THAT THIS WILL BE PROVIDED FOR EXAMPLE AS YOU SAID THE NETS OR IF THERE SAY STANDARD OF CARE OR BECAUSE THEY'RE NAIVE, THIS STUDY COULD BE YEARS OF STUDY FOR PREVENTION BUT IF THEY GET INTO MALARIA, THERE SHOULD BE VALUABLE TREATMENTS FOR THEM. >> SO ONE QUICK THING, THERE IS TREATMENT AVAILABLE FOR THEM IF THEY GET MALARIA. SO BOTH EXPERIMENTAL AND CONTROL ARM, IF THEY'RE DIAGNOSED WITH MALARIA THEY'LL GET TREATMENT SO THAT'S ALL THERE. AND I'LL COME BACK TO THE STANDARD OF CARE TREATMENT BECAUSE I THINK THAT'S IMPORTANT. >> SOME INFORMATION I'D NEED IS POST ONCE THE TRIAL IS COMPLETED AND THE STUDY'S BLINDED, WHOEVER RECEIVED THE PLACEBO GETS THE REAL DRUG IF IT SHOWED EFFICACY POST. THAT WOULD BE INFORMATION I'D NEED TO SEE IN THE PROTOCOL THAT THOSE IN THE PLACEBO GET THE DRUG IF IT SHOWED EFFICACY AT THE END OF THE TRIAL. >> CAN YOU SAY WHY? >> IF IT SHOWS EFFICACY I WOULD ALSO WANT THOSE WHO ARE ON THE PLACEBO ARM TO GET THE DRUG SO THAT WOULD BE LIKE A POST-TRIAL BENEFIT FOR THOSE WHO DID NOT GET THE ACTUAL DRUG. >> THE IDEA THAT PEOPLE IN BOTH GROUPS SHOULD GET BENEFIT. >> ONCE THE ANALYSIS HAS BEEN DONE AND IT'S SHOWN FOR POTENCY OR EFFICACY. >> BECAUSE THEN THEY'LL GET BENEFIT AS WELL. >> I THINK SO. THIS BORDERS BETWEEN COMMENTS AND QUESTIONS. ONE QUESTION WOULD BE WHETHER OR NOT SOME LIKE THE LUMBAR PUNCTURE WOULD BE REQUIRED OR OPTIONAL PARTS OF THE STUDY BECAUSE AGAIN THEY'RE NOT PROVIDING BENEFITS NOR PARTICIPANT IT'S ONLY FOR RESEARCH LATER AND WHAT IS FOR THE 18 TO 65 CRITERIA SINCE CHILDREN ARE AT HIGHER RISK FOR MORE SEVERE SYMPTOMS OF MALL AREA -- MALARIA IN THAT GROUP. >> >> SO AN INTERESTING THOUGHT ON THE RISK RATIO. IF POTENTIAL PARTICIPANTS ARE MORE AT A HIGHER BASELINE RISK THAN IT'S A REASON IN FAVOR OF ENROLLING THEM BECAUSE THE POTENTIAL BENEFITS ARE GREATER. THIS IS WHY I WAS CURIOUS ABOUT THE PREGNANT WOMEN QUESTION. IT'S LIKE WELL, MAYBE IT'S BETTER TO PROACTIVELY SEEK OUT THOSE AT GREATER RISK. I WANT TO COME BACK TO STANDARD OF CARE AND BENEFITS TO BE PROVIDED. ONE PROPOSAL WAS THAT WE PROVIDE PARTICIPANTS WITH A HIGHER STANDARD OF PREVENTATIVE CARE. FOR EXAMPLE, WE PROVIDE THEM WITH INSECTICIDE-TREATED BED NETS, FOR EXAMPLE. SPEAKING NOW ON BEHALF OF THE RESEARCH CONDUCTING THE STUDY, I DON'T FANCY THAT AS AN ADDITION TO THE STUDY. THAT'S BECAUSE IT'S GOING TO MAKE IT MUCH HARDER FOR THE STUDY TO SHOW EFFICACY IN PREVENTING MALARIA INFECTION. IT'S GOING TO CAPTURE THE CASES OF MALARIA PEOPLE GOT WHEN THEY WERE NOT PROTECTED BY THE NETS. IF WE HAVE A STUDY WITH AN INCREASED STANDARD OF CARE WE HAVE TO INCREASE THE NUMBER OF PEOPLE WE ENROLL IN THE STUDY. WE NEED TO POWER THE STUDY TO SHOW THE PREVENTIVE EFFECT. HERE'S THE ALTERNATIVE AND THIS IS GOING TO SPEAK TO THE OTHER POINTS ABOUT BENEFITS AND THE RISK NOT THAT HIGH BECAUSE UNLIKE EVERY DAY THEY'RE CLOSELY WATCHED AND THOSE CONCERNED ABOUT THE LEVEL OF BENEFIT IS THAT WE MAKE THE CLINICS OPEN TO OTHER PEOPLE WHO ARE IN THE COMMUNITY WHO ARE NOT ENROLLED IN THE STUDY. THEY CAN THEN GO THERE AND GET SCREENED FOR MALARIA INFECTION. KEEP THE SCIENTIFIC VALIDITY OF THE STUDY BUT EXPAND THE BENEFITS TO THE COMMUNITY. DOES THAT SOUND LIKE A REASONABLE PROPOSAL? I'M GETTING SOME NODS WHICH IS A GOOD SIGN. DID YOU WANT TO SPEAK TO THIS ISSUE? >> YEAH. IF SOMEONE WANTS TO SPEAK ON THIS, LET'S DO THAT AND WE'LL COME TO THE OTHER QUESTIONS. >> ONE POTENTIAL WRINKLE. >> I CAN TOTALLY UNDERSTAND AS A RESEARCHER NOT WANTING TO OBSCURE THE RESULTS OF THE STUDY BY PROVIDING BED NETS BUT IS THERE A PLAN IN PLACE TO ACCOUNT FOR DIFFERENTIAL BEHAVIOR AT BASELINE FOR PEOPLE THAT MAYBE SOME PLAN TO ALREADY USE BED NETS WHEN THEY MOVE TO THE NEW REGION OR WHAT HAVE YOU. >> WE WOULD EXPECT THE RANDOMIZATION TO CANCEL THE BEHAVIORAL DIFFERENCES BETWEEN THE TWO GROUPS. THAT'S PREMISE ON THE IDEA THAT WE WON'T GET TWO-THIRDS OF PEOPLE USING BED NETS AND THE PREMI PREMISE IS THAT PEOPLE IN THE POPULATION WOULD NOT BE THAT DIFFERENT FROM WHAT HAPPENS IN OTHER VILLAGES WHEN PEOPLE IMMIGRATE FROM THE NON-ENDEMIC REGIONS BUT IF THAT NOT TURNED OUT TO BE THE CASE THEY'D BE IN TROUBLE. >> WOULD THEY BE ASKING AT THE DAILY VISITS WHAT OTHER BEHAVIORS PEOPLE ARE PARTICIPATING IN THAT MIGHT PREVENT MALARIA? >> THEY'D BE ASKING WHEN THEY DO THE FULLER EVALUATION. THE DAILY VISIT SAY CHECK-IN TO CHECK ON SYSTEMS THAT MAY BE INDICATIVE OF MALARIA AND THE WEEKLY VISITS ARE THE MORE THOROUGH SCREENING. GREAT POINTS, THANKS. >> I HAVE A POINT ABOUT THE AND IN RELATION FOR VULNERABLE POPULATIONS. WHY WOULD WE EXCLUDE THEM AND IT MAY POSE RISK TO CHILDREN AND THE FETUS SINCE WE KNOW PREGNANT WOMEN AND CHILDREN ARE AT A HIGHER RISK IT WOULD BE IMPORTANT TO KNOW ABOUT THE HISTORY OF THE DRUG GIVEN. >> LET'S SUPPOSE WITH A NON-PREGNANT ADULT POPULATION IT GOES TO THE EXPANDING THE SAMPLE SIZE. NOW, WE'D HAVE TO GET IN THE DETAILS AND THERE WAS GROUPS AND RESEARCH THAT MIGHT BE PEOPLE LIKE BE USING THE RESULTS OF RESEARCH. AND IT MAY INCLUDE THOSE USING PROPHYLACTIC DRUG VERSUS THE CONCERNS SCIENTISTS MAY HAVE THAT THEY MAY HAVE A CLEAN TRIAL. FIRST THING SHOW IT IN WHAT'S THOUGHT OF AS A TYPICAL ADULT POPULATION AND THEN GO TO SPECIAL POPULATIONS BUT OFTEN THE SECOND STEP DOESN'T HAPPEN. WE SHOULD THINK OF IT AS A TENSION THAT ARISES AS TO WHO GETS ENROLLED. >> TO FOLLOW-UP ON THAT THERE'S BEEN A REAL CHANGE THAT HASN'T BEEN RAISED BUT THERE'S BEEN A CHANGE IN THE ATTITUDE IN TERMS OF ENROLLING VULNERABLE POPULATIONS WHERE IT USED TO BE THE CASE THEY WERE EXCLUDED UNLESS THERE WERE GOOD REASONS AND THAT DEFAULT NOW HAS BEEN REVERSED BUT THE DEFAULT IS WHY NOT INCLUDE THEM. GIVE US AN EXPLICIT JUSTIFICATION AND THAT WAY THESE KINDS OF QUESTIONS ARE MORE ON THE RADAR OF THE RESEARCHERS. >> I WANT TO ASK ABOUT THE SOCIAL VALUE OF THE STUDY ARE THERE CONCERNS WITH THAT? >> AND I BELIEVE AT THE SAME TIME THE BENEFIT FOR THE INDIVIDUALS IS VERY LOW BECAUSE THEY'RE IMMIGRATING TO A COUNTRY THAT IS ENDEMIC AND THEY'LL BE INFECTED WITH THE DISEASE ANYWAY AT SOME POINT IN THE FUTURE SO IT'S NOT A DIRECT BENEFIT AND SINCE THERE'S NOT ENOUGH BENEFIT FOR THE PARTICIPANTS YOU'D NEED HIGH SOCIAL VALUES TO JUSTIFY THE STUDY. EVEN IF YOU PROVIDE BENEFITS THEY WOULD NOT MAKE A DIFFERENCE BECAUSE THE SOCIAL VALUE IS VERY LOW. >> YEAH. ARE THERE -- THIS IS GOING TO BE MY FINAL QUESTION, IT'S DEFINITELY THIS DRUG GIVEN WILL NOT BE BENEFITTED FOR THOSE GIVEN AND THE RESEARCHERS ENDED UP PROPOSING THAT THEY WOULD BUILD THE CLINICS AND THEY'D BE AVAILABLE FOR NOT JUST TRIAL PARTICIPANTS BUT ANYONE WHO WANTED TO USE THEM AND PROVIDE TREATMENT FOR CONTINUES THE CLINICIANS WORKING THERE COULD TREAT WHETHER THEY WERE MALARIA OR ANOTHER CONDITION. PLUS, THEY PROPOSED DIGGING FOR THE WELL TO PROVIDE POTABLE WATER. DO PEOPLE THINK THAT IS SUFFICIENT TO CARRYING OUT THE TRIAL IN THE COMMUNITY KNOWING THE RESULTS OF THE TRIAL WILL NOT BENEFIT THE COMMUNITY? >> LET ME SPEAK TO THIS SPECIFICALLY. ONE THING TO CONSIDER IS THE DIRECT BENEFIT THIS IS AN ENDEMIC REGION AND THOSE IN THE U.S. WHO HAVE ACCESS TO THE DRUG MAY POTENTIALLY TAKE THE DRUG AND IF THEY'RE PROTECTED AGAINST MALARIA THAT'S ONE LESS VECTOR THE COMMUNITY CAN THEN BECOME INFECTED FROM. THAT'S SOMETHING TO CONSIDER. THE COMMUNITY COULD INDIRECTLY BENEFIT IN THE FUTURE FOR PEOPLE VISITING. A NUMBER OF THINGS I WAS THINKING AS PEOPLE MAKE COMMENTS. IT'S NOT A TREATMENT STUDY. THIS IS A PREVENTION STUDY. THAT'S WHY I'M NOT OKAY WITH A STANDARD OF CARE TO INDIVIDUALS THAT THIS IS A PLACEBO TRIAL AND I MADE A LOT OF ASSUMPTIONS IN APPROVING IT BUT IF IT'S A DOUBLE-RANDOMIZED TRIAL WE'VE GONE THROUGH SOME OTHER PHASES SO SAFETY HAS PROBABLY BEEN ESTABLISHED. THE AGE RANGE FOR CHILDREN YOU HAVE TO GET THROUGH THIS POPULATION IN ORDER TO BRING IT TO CHILDREN. I'M TRYING TO THINK WHAT ELSE. >> I'M WATCHING THE TIME AND YOU'RE BRINGING US PERFECTLY TO A CLOSE. LET ME DRAW ON THAT AND MAYBE SUM UP WHAT'S BEEN SAID HERE. SO I THINK YOU BROUGHT UP SOME IMPORTANT ETHICAL ISSUES RELATE TOD THE TRIAL. AND THEY FIT INTO THE FRAMEWORK THAT HAS BEEN USED ELSEWHERE FOR HOW TO THINK OF THE ETHICS OF THE STUDY. AND THERE MAYBE A SOCIAL VALUE IN THINKING ABOUT A COMMUNITY OR GROUP. ETHICAL QUESTIONS RELATED TO SCIENTIFIC VALIDITY AND WHAT IS THE STANDARD OF CARE GOING TO BE AND DO WE INCLUDE CHILDREN OR EXCLUDE THEM OR THINK OF RISKS AN BENEFITS. SHOULD WE ALLOW A LUMBAR PUNCTURE AND IS IT TOO RISKY AND SO ON AND SO FORTH. AND I WANT TO FLAG RESEARCH IT'S NOT RESEARCH FOR LOW AND MIDDLE-INCOME COUNTRIES. THOSE ARE PRINCIPLES USED ELSEWHERE IN THE COURSE. AND THERE'S BENEFITS TO BE PROVIDE HAD BECOME TRICKY. THANK YOU