Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
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effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
TODAY WE'RE GOING TO TALK
ABOUT THE QUESTION OF WHETHER OR
NOT THERE SHOULD BE LIMITS ON
THE RISKS OF RESEARCH WITH
COMPETENT ADULTS.
SO, OUTSIDE OF THE RESEARCH
SETTING WE LET COMPETENT ADULTS
DO LOTS OF RISKY EVEN CRAZY
THINGS.
THEY GET TO CLIMB MOUNTAINS.
THEY GET TO CLIMB MOUNTAINS TO
RESCUE STRANDED MOUNTAIN
CLIMBERS.
AS MY COLLEAGUES POINT OUT SOME
CRAZY PEOPLE RIDE MOTORCYCLES,
THEY RIDE THEM IN CHARITY
RALLIES, SO WE ALLOW PEOPLE
OUTSIDE RESEARCH TO DO RISKY
THINGS.
NOW TURN TO THE RESEARCH
SETTINGS.
RESEARCH THAT POSES HIDE RISK IS
CONSIDERED WIDELY ACCEPTABLE
WHEN IT OFFERS PARTICIPANTS
COMPENSATING POTENTIAL FOR
CLINICAL BENEFITS.
ONE OF THE EXEMPLARS OF THIS
RESEARCH ON METHODS TO TREAT
CANCER THAT INVOLVES BONE MARROW
TRANSPLANTATION, CAN INVOLVE A
SIGNIFICANT RISK OF MORBIDITY,
EVEN MORTALITY, AND TYPICALLY
THAT RESEARCH IS REGARDED AS
ACCEPTABLE AS LONG AS THE
PARTICIPANTS HAVE A COMPENSATING
POTENTIAL FOR CLINICAL BENEFIT.
THAT RAISES THE ETHICAL QUESTION
FOR TODAY OF WHAT ABOUT RESEARCH
THAT DOES NOT OFFER THE
PARTICIPANTS THEMSELVES A
COMPENSATING POTENTIAL FOR
CLINICAL BENEFIT.
SO, GUIDELINES IN THE U.S. AND
AROUND THE WORLD HAVE VERY
STRICT LIMITS ON THE RISKS TO
WHICH RESEARCHERS CAN EXPOSE
INDIVIDUALS WHO CAN'T GIVE
INFORMED CONSENT, THE PARADIGM
EXAMPLE HERE IS CHILDREN.
THAT RAISES THE QUESTION FOR
TODAY ABOUT COMPETENT ADULTS.
TO WHAT EXTENT SHOULD WE ALLOW
COMPETENT ADULTS TO AGREE TO DO
SO TO FACE HIGH RISKS OF
RESEARCH IN THE CONTEXT OF
STUDIES THAT WON'T BENEFIT THEM
BUT OFFER THE POTENTIAL TO LEARN
THINGS THAT MIGHT HELP PEOPLE IN
THE FUTURE.
REGULATIONS INCLUDING U.S.
REGULATIONS HAVE NO UPPER LIMITS
ON RESEARCH WITH COMPETENT
ADULTS.
AT LEAST IN PRINCIPLE, ACCORDING
TO THE REGULATIONS, YOU COULD
HAVE ANY LEVEL OF RISKS, AS LONG
AS THEY ARE MINIMIZED, AS LONG
AS IT'S SOCIALLY VALUABLE, IT
GETS APPROVED AND INDIVIDUALS
CONSENT.
AT THE SAME TIME IRBs, THE
COMMITTEES THAT REVIEW AND
APPROVE RESEARCH STUDIES, TEND
TO BE VERY SKEPTICAL OF HIGH
RISK RESEARCH AND OFTEN REGARD
HIGHER RISK RESEARCH EVEN IN
COMPETENT ADULTS AS ETHICALLY
PROBLEMATIC.
SO THAT RAISES OUR QUESTION FOR
TODAY, A STRAIGHTFORWARD ONE,
NOT NECESSARILY A SIMPLE ONE,
WHICH IS WHO IS RIGHT IN THIS
CASE?
ARE THE REGULATIONS TOO
PERMISSIVE?
SHOULD WE HAVE UPPER LIMITS ON
RESEARCH WITH COMPETENT ADULTS?
OR ARE REVIEW COMMITTEES BEING
TOO CAUTIOUS?
ARE THEY BLOCKING APPROPRIATE
AND ETHICALLY ACCEPTABLE
RESEARCH?
SO TO DISCUSS THESE QUESTIONS WE
HAVE TWO PRESENTERS.
FIRST PAUL KIMMEL, SENIOR
ADVISER TO DIRECTOR OF THE
NATIONAL INSTITUTES OF DIABETES
AND DIGESTIVE AND KIDNEY
DISORDERS, NIDDK, AT THE NIH.
PAUL WILL PRESENT A CASE FOR US.
TO HELP US THINK THROUGH THE
ETHICS OF THIS CASE WE'RE
FORTUNATE TODAY TO HAVE ALEX
CAPRON, WHO IS AT THE UNIVERSITY
OF SOUTHERN CALIFORNIA, A
UNIVERSITY PROFESSOR, ALSO THE
HEALTH CARE LAW POLICY AND
ETHICS.
AND MORE IMPORTANTLY FOR TODAY'S
SESSION ALEX IS WIDELY REGARDED
AS ONE OF THE MOST IMPORTANT
COMMENTATORS ON RESEARCH ETHICS
OVER 30 YEARS IN THE U.S. AND
AROUND THE WORLD.
SO WE'RE LUCKY TO HAVE HIM HELP
US THINK THROUGH THE QUESTIONS
TODAY.
TO START US OFF, PAUL.
>> THANK YOU, DAVE.
I'M THRILLED TO BE HERE WITH YOU
AND THE AUDIENCE.
AND I'M GOING TO SLIGHTLY
REFRAIN DAVE'S QUESTION TO THINK
ABOUT ALTRUISTIC PARTICIPANTS IN
CLINICAL RESEARCH WHERE THERE
MIGHT BE SOME RISKS AND TO GIVE
YOU A FRAMEWORK I'M GOING TO
TELL YOU ABOUT THE KPMP PROGRAM,
WITHIN I NIDDK, KIDNEY PRECISION
MEDICINE PROJECT.
NO CONFLICTS OF INTEREST.
WE'RE GOING TO TALK ABOUT THIS
KIDNEY PROJECT, DESCRIBE THE
SCIENTIFIC POTENTIAL VALUE OF
LOOKING AT KIDNEY TISSUE FROM
HEALTHY INDIVIDUALS WHEN WE'RE
TRYING TO DISCERN MECHANISMS OF
DISEASE IN PATIENTS WITH KIDNEY
DISEASE, AND WE'LL DISCUSS IN
GREAT DETAIL THE POSSIBILITY OF
OBTAINING TISSUE FROM ALTRUISTIC
VOLUME VOLUNTEERS WITHOUT
KIDNEY DISEASE THREE RESEARCH
BIOPSIES.
ACUTE KIDNEY --
>> WE CAN'T SEE YOUR SLIDES.
I DON'T KNOW IF YOU BROUGHT THEM
UP YET.
>> I HAVE.
THIS IS THE THIRD SLIDE.
WE NEED SOME HELP.
>> THEY ARE OPEN ON YOUR DESK
TYPE, DID YOU SHARE SCREEN?
>> I TRY THAT AGAIN.
>> THERE YOU GO.
CLICK SLIDE SHOW, WE'LL BE GOOD.
>> CAN YOU SEE IT NOW?
>> LOOKS GREAT.
>> YOU KNOW, THERE'S NOTHING
LIKE A PRESENTATION WITHOUT A
TECHNICAL GLITCH.
SO, TO GIVE A CONTEXT FOR THE
KINDS OF PATIENTS WE'RE TRYING
TO ULTIMATELY HELP WITH THE
RESEARCH, KIDNEY DISEASE CAN BE
SOMEWHAT CATEGORIZED INTO ACUTE
KIDNEY INJURY AND CHRONIC KIDNEY
DISEASE, AND THEY IMPOSE A
SIGNIFICANT HEALTH BURDEN
GLOBALLY.
JUST IN THE UNITED STATES, THE
ESTIMATE IS BETWEEN 1 IN 7 OR 8
AMERICANS HAVE CHRONIC KIDNEY
DISEASE, AND AKI IS A COMMON
COMPLICATION OF PATIENTS IN THE
HOSPITAL, AFFECTED
DISPROPORTIONATELY ELDERLY
PEOPLE, MEN AND AFRICAN
AMERICANS IN THE UNITED STATES.
AND ACUTE KIDNEY INJURY AND
CHRONIC KIDNEY DISEASE ARE OFTEN
DIAGNOSED BY RENAL BIOPSY WITHIN
THE CLINICAL SITUATION.
THERE ARE SELECT BUT WELL
ESTABLISHED KIDNEY DISEASES,
SUCH AS NEPHROTIC SYNDROME OR
ACUTE GLOMERAL NEPHRITIS, THE
DIAGNOSIS IS UNRAVELED BY USING
A KIDNEY BIOPSY, HAVING A
PATHOLOGIST DETERMINE THE
DISEASE BY LOOKING AT TISSUE
UNDER THE MICROSCOPE.
TECHNIQUE WAS DEVELOPED IN THE
19 50s IN EXPERIMENTS ON
VOLUNTEERS WITH KIDNEY DISEASE,
REFINED OVER DECADES WITH A WELL
UNDERSTOOD RISK/BENEFIT RATIO.
BUT ALTHOUGH ACUTE KIDNEY INJURY
AND CHRONIC KIDNEY DISEASE ARE
OFTEN DIAGNOSED BY RENAL BIOPSY,
IN MANY CASES PATIENTS WITH
KIDNEY DISEASE WHO ARE CARED FOR
BY NEPHROLOGISTS NEVER HAVE
BIOPSIES.
PRECISELY BECAUSE THE CLINICAL
CONSEQUENCES ARE SUPPOSEDLY WELL
APPRECIATED.
AND TWO EXAMPLES ARE PATIENTS
WHO HAVE KIDNEY DISEASE BECAUSE
OF HYPERTENSION OR HIGH BLOOD
PRESSURE, A VERY COMMON FORM OF
CHRONIC KIDNEY DISEASE, AND A
VERY COMMON CLINICAL SYNDROME,
HOSPITALIZED PATIENTS WITH AKI,
ACUTE TUBULAR NECROSIS, ATN,
WHICH IS A DEVASTATING
COMPLICATION IN ILL PATIENTS IN
THE HOSPITAL. IT IS PREDICATED
ON UNDERSTANDING NEW DISEASES IN
THE KIDNEY DISEASE POPULATION,
AND THAT'S BECAUSE THERE ARE
REALLY VERY FEW EFFECTIVE
THERAPIES FOR PATIENTS WITH
CHRONIC KIDNEY DISEASE, WE USE A
SPECIFIC KIND OF
ANTI-HYPERTENSIVE ANGIO TENSIVE
CONVERTING ENZYME INHIBITORS OR
RECEPTOR BLOCKERS, IN A WELL
CONTROLLED RANGE FOR PATIENTS
WITH CHRONIC KIDNEY DISEASE, AND
THERE'S A NEW SET OF DRUGS THAT
HAVE BEEN PRIMARILY USED IN
DIABETIC PATIENTS, SGLT2
INHIBITORS THAT HAVE SHOWN GREAT
PROMISE FOR PATIENTS WITH AND
WITHOUT DIABETES WHO HAVE KIDNEY
DISEASE.
THERE ARE REALLY NO CURRENT
CLINICALLY EFFECTIVE TREATMENTS
FOR PATIENTS WITH AKI.
AND AS A RESULT, AKI CAN OFTEN
LEAD TO CKD AND HAVE DIVERSITY
STATING CONSEQUENCES IN LOW AND
HIGH-INCOME COUNTRIES.
TO ADDRESS THESE ISSUES OF
UNDERSTANDING PATHOGENESIS AND
TREATMENT OF PATIENTS WITH
KIDNEY DISEASE, THE NIDDK
STARTED THE KIDNEY PRECISION
MEDICINE PROJECT IN 2017.
AND IT'S FUNCTIONING UNDER A
COOPERATIVE AGREEMENT WHICH
MEANS THE NIH IS WORKING
TOGETHER WITH THE INVESTIGATORS.
THE GOAL OF THE KPMP IS TO
IDENTIFY THOSE PATHWAYS THAT MAY
WORK TO CAUSE WORSE DISEASE IN
PATIENTS WHO HAVE CHRONIC KIDNEY
DISEASE OR HAVE ACUTE KIDNEY
INJURY.
ALSO TO IDENTIFY POTENTIAL
PROTECTIVE PATHWAYS THAT MIGHT
BE USED AS TARGETS FOR DRUG
THERAPIES.
WHEN WE STARTED THE KPMP IN 2016
BEFORE WE FUNDED THE SITES WE
INVOLVED PATIENT REPRESENTATIVES
AND THE FDA BECAUSE WE WERE
CONCERNED ABOUT THE ETHICS AND
SAFETY OF DOING KIDNEY BIOPSIES
IN PATIENTS WHO WE DIDN'T
USUALLY DO KIDNEY BIOPSIES IN,
AND WE WERE CONCERNED GETTING
COMMUNITY INPUT, SO THAT WE WERE
ASSURED THAT THE RESEARCH WAS
DONE IN AN ETHICAL MANNER.
AND PATIENTS WERE INVOLVED IN
THE CALL FOR RESEARCH AND THEY
WERE INVOLVED IN THE STUDY AS IT
WAS DESIGNED BY THE STEERING
COMMITTEE, AND PATIENTS ARE
INVOLVED IN ALL ASPECTS OF THE
STUDY ON AN ONGOING BASIS, SO
WE'RE VERY PROUD OF OUR PATIENT
ENGAGEMENT WORK IN KPMP.
WHY DO WE NEED TO DO KIDNEY
BIOPSIES IN PATIENTS WHERE WE
WOULD NEVER DO KIDNEY BIOPSIES
IN THE CLINICAL SITUATION?
IN ORDER TO DEVELOP NEW
THERAPIES, WE HAVE TO UNDERSTAND
THE PATHWAYS AT A MOLECULAR
LEVEL OF KIDNEY DISEASE WE
CURRENTLY DON'T UNDERSTAND, AND
THE BEST WAY TO DO THAT IS TO
OBTAIN KIDNEY TISSUE AND TO
EVALUATE BIOCHEMISTRY AND OTHER
ASPECTS OF THE TISSUE.
AND SO TO ADDRESS OUR GAPS IN
UNDERSTANDING PATHWAYS AND
POTENTIAL TARGETS AVAILABLE KPMP
IS DOING BIOPSIES AND STUDYING
TISSUES FROM PATIENTS WITH
COMMON KIDNEY DISEASES.
SO, THE KPMP IS SET UP WITH SIX
RECRUITMENT SITES, WHERE
PHYSICIANS OBTAIN TISSUE FROM
PATIENTS IN WHOM BIOPSIES ARE
NOT CLINICALLY INDICATED, AND
SPECIFICALLY THIS IS DONE IN THE
COMMON KIDNEY DISEASES
HYPERTENSIVE KIDNEY DISEASE AND
KIDNEY DISEASE IN THOSE WITH
DIABETES AS WELL AS AKI PATIENTS
WITH THIS DISEASE ATN.
THE BIOPSIES UNDERGO OMICS
ANALYSIS, TRANSCRIPTOMICS,
PROTEOMICS, METABOLOMICS ACROSS
THE COUNTRY AND ONE OF THE
IMPORTANT ASPECTS TO MAKE THESE
PROCEDURES AS ETHICAL AND SAFE
AS POSSIBLE AND IN ORDER TO
PREVENT PATIENTS FROM UNDERGOING
ANY COSTS, WE'VE WORKED OUT A
WAY SO WE CAN COVER TREATMENTS
IF NECESSARY BY INSURANCE, WHICH
IS AN INNOVATION AT NIH.
THE KPMP WAS FUNDED IN 2017.
WE STARTED TO DO BIOPSIES IN
2019 BECAUSE IT TOOK A LONG TIME
TO OPERATIONALIZE THIS
CONSORTIUM.
WE WERE UNFORTUNATELY RIGHT
AFTER STARTING THE KPMP SLOWED
BY THE COVID PANDEMIC, BUT WE
HAVE A LITTLE MORE THAN 32
BIOPSIES FROM AKI PATIENTS,
ALMOST 100 BIOPSIES FROM CKD
PATIENTS NOW OVER THE LAST 2 1/2
YEARS.
WE'VE HAD NO DEATHS WITHIN KPMP.
I WILL TELL YOU ABOUT THE RISKS
OF RENAL BIOPSY.
IT'S STILL EARLY DAYS BUT WE'RE
VERY PLEASED THAT WE HAVE HAD
MINIMAL HARMS, TO ANYBODY.
THE COMPLICATIONS WITHIN THE
KPMP ARE CONSISTENT WITH THE
GENERAL CLINICAL EXPERIENCE.
THEY INCLUDE BLEEDING AT THE
BIOPSY SITE, FROM THE KIDNEY,
LOSS OF BLOOD RESULTING IN
CHANGES IN LABORATORY TESTS OF
HEMOGLOBIN, AND HEMATOMAS AROUND
THE KIDNEY.
AND WE HAVE A VERY EXTENSIVE
DATA SAFETY AND MONITORING BOARD
WITH PATIENT REPRESENTATIVE
WHICH HAS HELPED US EVALUATE OUR
WORK.
THE BIOPSIES HAVE BEEN VERY
INTERESTING IN THESE PATIENTS
WHO WOULD NOT USUALLY CLINICALLY
GET A BIOPSY.
AND MANY HAVE SHOWN US UNUSUAL
FEATURES THAT WERE UNSUSPECTED
IN THIS GROUP.
SO, SOME OF THE BIOPSIES HAVE
ASPECTS OF ACUTE KIDNEY INJURY
AND CHRONIC KIDNEY DISEASE,
SIMULTANEOUSLY, WHEN THAT WAS
RELATIVELY UNEXPECTED.
AND IN SUBSTANTIAL AMOUNT OF
CASES UP TO 1/5 THE BIOPSIES
YELLEDDED INFORMATION THAT HAS
BEEN UNSUSPECTED AND THAT HAVE
ACTUALLY CHANGED MEDICAL
MANAGEMENT OF PATIENTS.
COLLECTING KIDNEY TISSUE FROM
PATIENTS WITHOUT KIDNEY DISEASE
COULD HELP US IDENTIFY SPECIFIC
CHANGES IN MOLECULAR PATHWAYS
THAT ARE ASSOCIATED WITH
DISEASES LIKE HYPERTENSIVE
KIDNEY DISEASE OR DIABETIC
KIDNEY DISEASE.
BUT IN ORDER TO EVALUATE WHETHER
THERE ARE CHANGES PRESENT, WE
NEED TO HAVE REFERENCE TISSUE TO
PUT IT INTO PERSPECTIVE, TO SEE
WHAT'S NORMAL, AND WHAT'S NOT,
IN THESE NEW STUDIES.
IT'S REALLY NOT POSSIBLE TO
ESTIMATE THE CHANCES THAT
STUDYING HEALTHY KIDNEY TISSUE
WILL LEAD TO VALUABLE INSIGHTS
THAT WILL HELP TO IMPROVE THE
TREATMENT FOR PATIENTS BECAUSE
WE DON'T HAVE NEW TREATMENTS
THAT WE'RE GOING TO USE IN THE
PATIENTS WHO ARE VOLUNTEERING TO
GIVE A KIDNEY BIOPSY AND GIVE UP
TISSUE WITHIN THE KPMP.
AND WE ALSO EXPECT THAT THE
CLINICAL BENEFITS, IF WE MOVE TO
PATIENTS WITH NORMAL KIDNEY
FUNCTION, WHO ARE TOTALLY
PARTICIPATING ON AN ALTRUISTIC
BASIS WOULD NOT BE AVAILABLE.
THERE WOULD BE NO CLINICAL
BENEFIT TO HAVING A KIDNEY
BIOPSY IN A PATIENT WITHOUT
KIDNEY DISEASE.
WE HAVE BEEN ABLE TO USE SOME
REFERENCE TISSUE FROM KIDNEY
DONORS, SO THESE INDIVIDUALS DO
NOT HAVE KIDNEY DISEASE, AND
THEY ALSO DO NOT REQUIRE A
BIOPSY, THEY ARE DONATING A
HEALTHY KIDNEY TO A PATIENT WHO
NEEDS IT, KIDNEY TO TREAT END
STAGE RENAL DISEASE BUT THESE
KIDNEYS ARE NOT COMPARABLE TO
BIOPSIES IN KPMP BECAUSE
BASICALLY PATIENTS ARE
UNDERGOING GENERAL ANESTHESIA TO
REMOVE THE KIDNEY.
SO, WE WOULDN'T BE COMPARING
REFERENCE HEALTHY TISSUE TO THE
KPMP STUDIES.
SO, WHAT WE HAVE BEEN INTERESTED
IN KPMP IS TO OBTAIN KIDNEY
TISSUE FROM HEALTHY PEOPLE WHO
ARE NOT UNDERGOING GENERAL
ANESTHESIA, WE WOULD LIKE TO
ENGAGE ALTRUISTIC VOLUNTEERS WHO
WOULD SAY THEY WOULD UNDERGO
KIDNEY BIOPSY WHEN THEIR
COMPLETELY HEALTHY AND HAVE NO
CHANCE OF CHANGING ANY CLINICAL
SITUATION FOR THEM, AND THE
PROPOSAL WAS TO START BY
ENROLLING A VERY SMALL GROUP OF
HEALTHY VOLUNTEERS AND HAVING
THEM GO AFTER GIVING INFORMED
CONSENT, A KIDNEY BIOPSY FOR
RESEARCH PURPOSES USING THE SAME
KIND OF TECHNIQUES THAT WE'RE
USING IN CLINICAL PRACTICE AND
IN KPMP.
THE PROBLEM IS THAT IT'S UNCLEAR
WHAT THE RISKS OF KIDNEY BIOPSY
IN PATIENTS WHO UNDERGO A BIOPSY
FOR RESEARCH PURPOSES WOULD BE.
WE HAVE SOME GOOD DATA FOR
PATIENTS WHO UNDERGO CLINICAL
BIOPSY FOR CLINICAL REASONS, AND
IN FACT KIDNEY BIOPSY IN HEALTHY
PATIENTS, PEOPLE, MAY BE
ACTUALLY LESS RISKY BUT WE DON'T
KNOW ABOUT THAT BECAUSE WE
HAVEN'T DONE THOSE STUDIES.
THE RISKS FOR A CLINICAL KIDNEY
BIOPSY IN PATIENTS WHO HAVE
CHRONIC KIDNEY DISEASE OR ACUTE
KIDNEY INJURY IS NOT COMPLETELY
CLEAR BECAUSE THE RISK IS SO LOW
YOU NEED TO HAVE LARGE SERIES OF
UP TO 1,000 TO PERHAPS 10,000
PATIENTS, BUT IT LOOKS LIKE THE
GENERAL RISKS IN MOST STUDIES
HAVE BEEN ONE TO THREE DEATHS IN
1,000 PATIENTS, AND IN SOME
OTHER STUDIES WHICH ARE, YOU
KNOW, PRESUMABLY IN DIFFERENT
POPULATIONS MUCH SMALLER, UP TO
ONE IN SEVEN TO EIGHT THOUSAND
PEOPLE, A VERY LOW RISK IN TERMS
OF PERCENTAGES.
THE MOST COMMON INTERVENTIONS
ARE TO STOP BLEEDING, THAT
HAPPENS ABOUT 3 TIMES IN 1,000
PATIENTS, IN 1,000 PROCEDURES.
MANY PATIENTS DEVELOP
PERINEPHRIC HEMATOMA, NOT A
CLINICALLY INCONSEQUENTIAL
COMPLICATION.
MORE PEOPLE TALK ABOUT PAIN AND
SO UP TO 5% PATIENTS HAVE PAIN
IN THE RENAL OF THE KIDNEY
BIOPSY IN THE FLANK AND BACK, 5%
HAVE BLOOD IN URINE FOR A
LIMITED PERIOD OF TIME, 1 TO 2%
WILL NEED A BLOOD TRANSUSING.
THE KIDNEY BIOPSY DONE FOR
CLINICAL INDICATIONS IS NOT RISK
FREE.
WE DEBATED, AS RESEARCHERS,
WHETHER IT WOULD BE ETHICAL TO
ASK HEALTHY ADULTS TO FACE THESE
RISKS FOR RESEARCH PURPOSES.
WE HAVE HAD THE PLEASURE OF
VIGOROUS INVOLVEMENT OF
COMMUNITY ENGAGEMENT WORKING
GROUP PATIENTS, PATIENTS WHO HAD
KIDNEY BIOPSIES, IN OUR WORK,
AND WE'RE TRYING TO ENGAGE THE
PARTICIPANTS WHO HAD KIDNEY
BIOPSIES UNDER THE AEGIS OF THE
KPMP GETTING FEEDBACK AND IN
MOST CASES OUR PATIENT ADVISORS
ARE ENTHUSIASTIC ABOUT ASKING
FOR AN ALTRUISTIC VOLUNTEER TO
PARTICIPATE BUT WE WERE
CONCERNED ABOUT THE ETHICS OF
THIS APPROACH AND WE INITIATED A
BIOETHICS CONSULTATION WITH THE
BIOETHICS TEAM AT NIH.
AND AS DAVE HAS PUT IT, THE
QUESTIONS THAT COME UP FROM THIS
APPROACH TO RESEARCH IS, WHAT
ARE THE ETHICAL LIMITS ON
RESEARCH RISKS IN COMPETENT
ADULTS AND HOW SHOULD THEY BE
APPROACHED?
HOW ARE THESE LIMITS DETERMINED?
IS WHAT WE'RE PROPOSING IN KPMP
CONSISTENT WITH REASONABLE RISKS
TO TAKE TO ADVANCE A RESEARCH
AGENDA WHICH COULD END UP
HELPING MANY, MANY PATIENTS WITH
KIDNEY DISEASE, NOT ONLY IN THE
UNITED STATES BUT WORLDWIDE?
IS IT MORE PROBLEMATIC TO EXPOSE
HEALTHY INDIVIDUALS TO RESEARCH
RISKS THAN PATIENTS WHO HAVE
KIDNEY DISEASE?
AND WOULD OUR STUDY BE ETHICALLY
IMPROVED IF THE PATIENTS WERE
PAID AN HONORARIUM FOR A BIOPSY?
RIGHT NOW WE COVER COSTS OF
BIOPSIES AND COMPLICATIONS WITH
THE KPMP.
SO, I'M VERY EAGER TO HEAR THE
DISCUSSION FROM PROFESSOR CAPRON
AND VERY INTERESTED TO HEAR WHAT
OUR DISCUSSION IN THE LARGER
AUDIENCE WILL TELL US ABOUT THIS
APPROACH.
THANK YOU VERY MUCH.
>> THANK YOU, PAUL.
IT'S A PLEASURE TO BE WITH YOU
ALL TODAY.
AND I HOPE WE CAN PROVOKE SOME
QUESTIONS AND DISCUSSION ABOUT
THE ALTRUISTIC PARTICIPATION IN
GREATER THAN MINIMAL RISK
RESEARCH USING THIS EXAMPLE.
THE QUESTION I WAS ASSIGNED,
SHOULD THERE BE LIMITS ON THE
RISKS OF RESEARCH WITH COMPETENT
ADULTS?
I HAVE NO CONFLICTS TO REPORT.
THE LEARNING OBJECTIVES I THINK
HAVE BEEN DISTRIBUTED ALREADY.
SO, IN MY REMARKS I REALIZE I
MIGHT EXACERBATE PRESIDENT
TRUMAN AFTER A FRUSTRATING
MEETING WITH THE CHAIR OF HIS
COUNCIL OF ECONOMIC ADVISORS HE
EXCLAIMED, GIVE ME A ONE-ARMED
ECONOMISTS, ALL MY ECONOMISTS
SAY ONE HAND, BUT THEN, ON THE
OTHER.
I WILL TRY TO SITUATION WAIT THE
ONE HAND AND THE OTHER WHICH I
WILL DESCRIBE HISTORICALLY, AND
SO THE FIRST THOUGHT HERE IS
THAT WE HAVE TO REALIZE THE
RULES WE LIVE WITH ARISE OUT OF
A HISTORY OF ABUSES, AND THE
FIRST SET OF ABUSES WHICH
COVERED A LENGTHY PERIOD OF TIME
LIE IN NOT HAVING CONSENT.
AND THEY MIGHT LEAD TO THE
CONCLUSION ON THE ONE HAND THAT
WITH CONSENT THE RESEARCH THAT
PAUL HAS DESCRIBED WOULD BE
PERMISSIBLE.
BUT AS WE LOOK THROUGH WHAT HAS
HAPPENED, HISTORICALLY, WE CAN
SEE I THINK THAT CONSENT IS NOT
ENOUGH.
AND THIS WOULD LEAD TO THE
CONCLUSION THAT THE RESEARCH IS
NOT PERMISSIBLE.
I WILL ELABORATE ON THIS BY
TALKING ABOUT RESEARCH BEGINNING
WITH THOSE MOST INVOLVED.
THE WORRY ABOUT SUBJECTS NOT
HAVING FULL UNDERSTANDING AND
THE ROLE THAT THE INTERESTS OF
SOCIETY PLAY IN REACHING A
JUDGMENT.
I'LL THEN ADDRESS PROBLEMS
FACING ETHICS CONSULTANTS AT
NIH, OR AN IRB, LOOKING AT THE
PROBLEM OF BENEFIT, NOT BEING
ESTIMATABLE, AND LOOKING AT THE
WAYS THAT RESEARCH RISKS COULD
BE MINIMIZED BY USING OTHER
SOURCES OF TISSUE.
FINALLY, I WILL RESPOND TO THE
QUESTIONS THAT WERE POSED BY DR.
KIMMEL AND HIS COLLEAGUES.
SO, I'M GOING TO ASSUME THAT AT
LEAST AT A HIGH LEVEL THE PEOPLE
JOINING THIS WEBINAR ARE
FAMILIAR ARE THE FIRST STAGE OF
HISTORY OF RESEARCH ETHICS.
AND THE WHOLE THOUGHT HERE IS
THAT SOME PHYSICIANS HAVE ALWAYS
SOUGHT ANSWERS TO QUESTIONS
ABOUT DISEASE, AND THAT STARTING
ABOUT 150 YEARS AGO LEADING
ACADEMIC PHYSICIANS STARTED
USING THE SCIENTIFIC METHOD TO
GET ANSWERS TO THAT PUZZLEMENT
RATHER THAN SIMPLY LOOKING AT
THEIR PATIENTS, MAKING GUESSES
FOR CONSULTING ORACLES.
AND IN PARTICULAR, THE LEADING
ACADEMIC PHYSICIANS WERE THEN IN
GERMANY AND THEY INVESTIGATED
THE NATURE, CAUSE, AND
TRANSMISSION OF SERIOUS DISEASES
SUCH AS SYPHILIS AND GONORRHEA,
AND THEY DID THIS BY
INTENTIONALLY INFECTING
INSTITUTIONALIZED PERSONS, AND
POOR PATIENTS AT THE TIME MOST
PATIENTS WHO WERE TREATED IN
HOSPITALS WERE THOSE OF LOWER
SOCIOECONOMIC STATUS, AND PEOPLE
OF HIGHER STATUS USUALLY
RECEIVED THEIR MEDICAL CARE AT
HOME.
WHEN THE EXPERIMENTS BECAME
PUBLIC AROUND THE TURN OF THE
20th CENTURY, THE PUBLIC AND
PROFESSIONAL OUTCRY IN PRUSSIA
LET THE GOVERNMENT TO PUT IN
PLACE A LAW UNDER WHICH RESEARCH
WAS PERMISSIBLE ONLY WITH
CONSENT OF THOSE INVOLVED, AND
THAT WOULD ALWAYS EXCLUDE
CHILDREN OR INCOMPETENT
PATIENTS, OR THOSE WHO WERE
INSTITUTIONALIZED.
SO, ONE COULD SAY, WELL, THAT
WOULD BE THE END OF THE STORY,
AS LONG AS CONSENT IS OBTAINED
FROM A COMPETENT PERSON, THEN
THE RESEARCH IS OKAY.
BUT THAT'S DECIDEDLY NOT THE END
OF THE STORY, AS YOU KNOW.
AND INDEED, IN GERMANY ITSELF
WHERE PRUSSIAN LAW BECAME PART
OF THE GERMAN LAW PRIOR TO THE
1930s IN CONCENTRATION CAMPS
NAZI PHYSICIANS CARRIED OUT
DEADLY RESEARCH AND
INTERESTINGLY PROBABLY FAILED TO
LEARN AS MUCH FROM THE RESEARCH
AS THEY COULD BECAUSE OF THE WAY
THEY TREATED THE SUBJECTS, NONE
OF WHOM WERE OF COURSE GIVING
CONSENT.
BUT THE PROBLEMS WEREN'T LIMITED
TO THAT TOTALITARIAN REGIME.
IN THE UNITED STATES BEGINNING
EARLIER IN 1932 RESEARCHERS FROM
THE PUBLIC HEALTH SERVICE
CARRIED OUT AN OBSERVATIONAL
STUDY OF THE NATURAL COURSE OF
SYPHILIS IN SEVERAL HUNDRED
AFRICAN AMERICAN FARMERS IN
TUSKEGEE, ALABAMA.
AND THAT STUDY WENT ON, ALWAYS
DISGUISING FROM THE
PARTICIPANTS, WHAT WAS THE
NATURE OF THE STUDY AND
WITHHOLDING FROM THEM THE
BENEFITS OF PENICILLIN ONCE THAT
HAD BEEN DISCOVERED, AND USED
EFFECTIVELY AS TREATMENT FOR
SYPHILIS.
AFTER THE WAR, THE UNITED STATES
GOVERNMENT CARRIED OUT FOR MANY
YEARS, AGAIN WITHOUT CONSENT OR
INFORMATION, OR IN POPULATIONS
SUCH AS CHILDREN IN ORPHANAGES
AND PRISONERS, IN FACILITIES OF
THE STATE AND FEDERAL
GOVERNMENT, THAT INVOLVED
IRRADIATING OR GIVING FOOD OR
OTHER SUBSTANCE THAT CONTAINED
ISOTOPES.
AND THE EXPERIMENTS CARRIED OUT
BY CHESTER SOUTHAM FROM MEMORIAL
SLOAN-KETTERING IN NEW YORK AT
THE JEWISH CHRONIC DISEASE
HOSPITAL, AMONG ELDERLY
DEBILITATED PATIENTS, ANY NUMBER
OF WHOM HAD ACTUALLY SURVIVED
THE HOLOCAUST, AND THEN WERE
EXPOSED TO INJECTIONS OF LIVE
CULTURED CANCER CELLS TO SEE
WHETHER THEY REJECTED THEM, THAT
TOOK PLACE IN 1963.
AND THERE WERE MANY OTHER CASES
OF THIS SORT, THE LIST GOES ON
AND ON.
AND SO, ALL OF THIS OCCURRED
DESPITE THE FACT THAT IN 1947
THE U.S. MILITARY TRIBUNAL THAT
WAS PASSING JUDGMENT ON THE NAZI
PHYSICIANS AND IN THEIR JUDGMENT
EXPLAINED WHAT WOULD AMOUNT TO
ETHICAL RESEARCH AND THAT BECAME
KNOWN AS THE TEN POINTS, BECAME
KNOWN AS THE NIRENBERG CODE, THE
FIRST POINT BEGINS THE VOLUNTARY
CONSENT OF THE HUMAN SUBJECT IS
ABSOLUTELY ESSENTIAL.
AND THAT WAS REPEATEDLY IGNORED
BY PROMINENT RESEARCHERS
INCLUDING THOSE WORKING FOR THE
GOVERNMENT.
WHY DID THIS HAPPEN?
THE CONVENTIONAL EXPLANATION FOR
SUCH ABUSES IS THAT THE SINGLE
MINDED PURSUIT OF SCIENTIFIC
OBJECTIVES DISTORTS THE VISION,
UNDERSTANDING, PERCEPTION,
ATTITUDE OF PHYSICIAN
INVESTIGATORS DURING THIS
PERIOD.
SO THEY WERE LOOKING AT THIS
SCENE BUT THEY WERE ACTUALLY
SEEING SOMETHING DIFFERENT, THAT
THEY WERE NOT TREATING THE HUMAN
INDIVIDUALS WHO WERE THEIR
SUBJECTS IN RESEARCH, AS HUMAN
BEINGS, BUT TREATING THEM AS
THOUGH THEY WERE GUINEA PIGS, OF
COURSE THE WORST ABUSES WERE
WITH THE NAZI CONCENTRATION CAMP
DOCTORS FOR WHOM DISPENSING WITH
LIVES OF THESE PATIENTS, THESE
PERSONS RATHER, WAS THOUGHT OF
AS NOTHING, JUST LIKE TREATING A
LAB ANIMAL WHO IS EUTHANIZED
AFTER THE RESEARCH.
NOW, THAT'S OBVIOUSLY -- THIS IS
A CARICATURE, MORE OR LESS THE
EXPLANATION, HOW DID THIS
HAPPEN, HOW DID CONSCIENTIOUS
PHYSICIAN FALL INTO THIS.
IT'S REALLY THAT THEY DISTANCED
THEMSELVES FROM PEOPLE
PARTICIPATING IN THE RESEARCH IN
ORDER TO REACH THE SCIENTIFIC
GOALS THAT THEY WERE DRIVEN TO
REACH.
SO, ONE CAN SAY THAT IF THE
PROBLEM IS SIMPLY THAT
PHYSICIANS WERE DISREGARDING THE
RIGHTS OF THE INDIVIDUALS,
WHETHER THEY WERE PATIENTS OR
HEALTHY INDIVIDUALS, TO EXERCISE
THE CHOICE ABOUT WHETHER TO
PARTICIPATE IN RESEARCH, THEN
WHAT WOULD BE NEEDED WOULD BE
MAKING INFORMED CONSENT, A
GUARANTEE, MAKING SURE IT'S
ALWAYS OBTAINED, WHETHER THE
STANDARD IS A REFERENCE TO THE
NUREMBERG CODE OR THE
DECLARATION OF HELSINKI WHICH
THE WORLD MEDICAL ASSOCIATION
FIRST ADOPTED IN 1964.
THERE WERE STILL OBJECTIONS THAT
THAT WASN'T GOING TO WORK.
FOR EXAMPLE, HENRY BEECHER,
HARVARD ANESTHESIOLOGIST WHO
SHOCKED THE MEDICAL WORLD IN
1966, WITH HIS NEW ENGLAND
JOURNAL ARTICLE ABOUT ETHICS AND
CLINICAL RESEARCH, IN WHICH HE
DISCLOSED A BROAD PROBLEM, HE
SAW IT AS GOOD PEOPLE, GOOD
PHYSICIANS, WHO SIMPLY HAD
WANDERED AWAY FROM THE PATH OF
ETHICS, AND WERE PERFORMING
RESEARCH THAT WAS OFTEN RISKY
BUT WAS DONE WITHOUT THE
KNOWLEDGE OR CONSENT OF THE
PEOPLE INVOLVED.
AND HE OFTEN SAID THAT INDEED,
HE THOUGHT THE PROBLEM WAS THAT
PHYSICIANS CAN ALWAYS OBTAIN
CONSENT FROM THE PEOPLE THEY ARE
DEALING WITH, PARTICULARLY
PATIENTS BUT NOT ONLY THEM, BY
THE WAY THEY PRESENT THINGS AND
BY THE AUTHORITY THEY BRING TO
THAT PHYSICIAN-PATIENT OR
PHYSICIAN-SUBJECT ENCOUNTER.
BUT IT WAS DEEPER THAN HENRY
BEECHERREST CONCERNS ABOUT
CONSENT.
A WELL-KNOWN MORAL PHILOSOPHER,
REFUGEE FROM GERMANY HAD HANS
JONAS POSED THREE CHALLENGES IN
A 1968 CONTRIBUTION, THE
AMERICAN ACADEMY OF ARTS AND
LETTERS.
HE POSED THREE CHALLENGES.
FIRST, THE INTEREST OF SOCIETY
IN PROGRESS, WHICH IS VERY MUCH
APPARENT IN THE SUPPORT FOR
PHYSICIAN-SCIENTISTS TRYING TO
CONQUER DISEASE, THAT INTEREST
IS OPTIONAL.
IT IS NOT A MORAL IMPERATIVE.
IN HIS VIEW, WE DO NOT WRONG --
DO NOT DO A WRONG TO OUR
PROGENY, IF WE HAVEN'T WE
HAVEN'T YET CURED A DISEASE.
OBVIOUSLY IF WE'RE ATTEMPTING
AND ARE NEGLIGENT AND DON'T DO A
GOOD JOB THAT CAN BE CRITICIZED,
BUT THE CHOICE TO FAVOR
PROGRESS, BENEFIT FOR FUTURE
PEOPLE, OVER THE WELFARE OF
EXISTING PEOPLE, AND
PARTICULARLY IF THAT WELFARE
WERE ACHIEVED WITHOUT THE FULL
CONSENT AND PARTICIPATION OF
THOSE CURRENT PEOPLE, IS NOT A
WRONG.
SECONDLY, HE SAID THAT IN
CALLING FOR VOLUNTEERS FOR
RESEARCH, EVEN UNDER THE MOST
METICULOUS RULES, AMOUNTS TO A
SORT OF CONSCRIPTION OF PEOPLE
TO BE IN RESEARCH BECAUSE,
AGAIN, OF THE ROLE OF SCIENCE
AND RESEARCH IN SOCIETY THAT CAN
CREATE A SENSE THAT THIS IS
SOMETHING LIKE WARTIME SERVICE,
THIS WOULD BE SOMETHING THAT
WOULD BE IN SOME SENSE FELT TO
BE OBLIGATORY BY SOME PEOPLE.
HE SAID, SINCE SOME FORM OF
SOLICITATION IS ALWAYS NECESSARY
TO GET PEOPLE TO ENROLL, CONSENT
CANNOT BE THE FULL ANSWER TO THE
PROBLEM.
AND FINALLY, HE SUGGESTED THAT
THE PERSON'S CARRYING OUT
MEDICAL RESEARCH SHOULD BE THE
FIRST SUBJECTS, ALWAYS, BECAUSE
OF THEIR FULL AUTONOMOUS
IDENTIFICATION WITH THE PURPOSE
OF THAT RESEARCH, AND HE WENT ON
TO SAY THAT THEY HAVE THE
STRONGEST MOTIVATION, THE
FULLEST UNDERSTANDING, THE
FREEST DECISION, AND THE
GREATEST INTEGRATION WITH THEIR
OWN PERSONAL TOTAL CHOSEN
PURSUIT.
AND SO THAT IDENTIFICATION WAS
THE REASON THAT HE SAID THAT
THIS WOULD BE A WAY TO ENSURE
THE DIGNITY OF THE SUBJECT AS A
RESEARCH PARTICIPANT.
NOW, HE RECOGNIZED THAT THIS WAS
NOT A PRACTICAL SOLUTION, THAT
THERE WOULD NOT BE ENOUGH
SCIENTISTS TO SERVE AS THE LARGE
NUMBER OF SUBJECTS THAT ARE
NEEDED FOR ALL FORMS OF
BIOMEDICAL RESEARCH.
BUT THAT WENT BACK TO HIS FIRST
POINT, THAT IF THAT SLOWED THE
PROCESS OF ADVANCING RESEARCH,
IT WOULD BE FELT TO BE A GREAT
TRAGEDY BY INDIVIDUALS WHO ARE
WAITING FOR AND WANTING TO HAVE
A TREATMENT FOR THEIR DISEASE,
BUT IT WOULD NOT BE, IN HIS
VIEW, A MORAL FAILING FOR
SOCIETY TO MOVE IN THAT
DIRECTION.
SO, AROUND THIS TIME, STAGE 1
BECOMES STAGE 2.
AFTER THE PRESS REVEALED THE
TUSKEGEE STUDY, THE 40-YEAR-LONG
STUDY IN 1972, IN THE NATIONAL
RESEARCH ACT CONGRESS INCLUDED A
PROVISION THAT ESTABLISHED THE
NATIONAL PERMISSION FOR
PROTECTION OF HUMAN SUBJECTS OF
BIOMEDICAL AND BEHAVIORAL
RESEARCH, FOR YEARS, BETWEEN
1974 AND 1978, EXAMINED A WIDE
RANGE OF SPECIFIC TYPES OF
RESEARCH, FETAL, WITH PRISONERS,
WITH THE MENTALLY DISABLED,
CHILDREN, SO FORTH.
AND THE ISSUED WHAT IS KNOWN AS
THE BELMONT REPORT, NAMED AFTER
THE CONFERENCE CENTER, THE
BELMONT CENTER, WHERE THE REPORT
WAS FINALIZED IN 1978.
AND THAT REPORT IDENTIFIES IN
OUR MORAL TRADITIONS THREE
ETHICAL PRINCIPLES THAT ARE SAID
TO BE APPROPRIATE TO GUIDE THE
ETHICS OF RESEARCH AND
SUBSEQUENTLY HAVE BEEN
ELABORATED FURTHER AS THE
ETHICAL PRINCIPLES UNDERLYING
MEDICAL PRACTICE, AND THEY ARE
BENEFICENCE, RESPECT FOR
PERSONS, AND PROTECTION OF THE
SUBJECTS OF RESEARCH WHO CANNOT
GIVE CONSENT CHILDREN AND THE
LIKE, AND THE PRINCIPLE OF
JUSTICE, REQUIRING ALL
INSTITUTIONS RECEIVING FEDERAL
FUNDING FOR RESEARCH WITH HUMAN
SUBJECTS ESTABLISH AN
INSTITUTIONAL REVIEW BOARD TO
ENSURE THAT RISKS ARE MINIMIZED,
THAT THE RATIO OF EXPECTED
BENEFIT TO POSSIBLE HARM IS
APPROPRIATE, THAT THERE'S FAIR
SELECTION OF SUBJECTS, AND THAT
INFORMED CONSENT, VOLUNTARY
INFORMED CONSENT BE OBTAINED.
SO, THE PROCESS OF THE
COMMISSION'S WORK WAS TO PROVIDE
THE BACKGROUND FOR THE
REGULATIONS WHICH WERE THEN
ADOPTED FOR THE FIRST TIME IN
1981, TO GUIDE RESEARCH THAT IS
FEDERALLY SUPPORTED.
SO, WITH THE CREATION OF IRBs,
THE CONCERNS ABOUT CONSENT MIGHT
APPEAR TO HAVE BEEN QUIETED.
IRBs CAN, AFTER ALL, REVISE
CONSENT FORMS TO AVOID HENRY
BEECHER'S WORRY PATIENTS WITH
PRESENT IN A WAYS TO PERSUADE
PATIENTS AND VOLUNTEERS,
MATERIALS USED MUST BE APPROVED
BY THE IRB TO AVOID SOLICITATION
BECOMING CONSCRIPTION, AS JONAS
HAD OBJECTED.
FURTHER CONCERNING ABOUT CAPTIVE
MEMBERS OF SOCIETY, NOT JUST
INSTITUTIONS BUT LESSER
SELF-DETERMINATION BECAUSE OF
SOCIOECONOMIC STATUS OR THEIR
POSITION IN SOCIETY, CAN BE
ACHIEVED, OVERCOMING CONCERNS
ABOUT THAT, BY THE IRB
IMPLEMENTING PRINCIPLES OF
JUSTICE.
SO WE GO INTO STAGE 2, THINKING,
WELL, PERHAPS PROBLEMS WITH
CONSENT HAVE BEEN SOLVED, BUT
IRBs DON'T EXIST JUST TO
REVIEW AND REVISE CONSENT FORMS
AS MUCH TIME AS MANY OF THEM
SPEND IN THAT PROCESS.
BEFORE GETTING TO THAT QUESTION,
THE QUESTION OF AUTONOMY, THEY
MUST ADDRESS BENEFICE, RISK
MINIMIZATION, APPROPRIATE
RELATIONSHIP OF BENEFIT TO RISK.
IRBs ALSO HAVE INSTITUTIONAL
OR COLLECTIVE CONCERNS ABOUT
PUBLIC PERCEPTIONS OF RESEARCH,
WHICH CAN DETERMINE THE
ACCEPTABILITY OF HIGH RISK OF
HARM IN A PARTICULAR RESEARCH
STUDY.
NOW, TO ILLUSTRATE THAT CONSIDER
THE U.S. SPACE PROGRAM IN THE
POST-SPUTNIK ERA, 1950s TO
EARLY 196 0s WHEN THERE WAS A
RACE TO THE MOON BETWEEN THE U.
S. AND THE USSR.
IT WOULD HAVE BEEN MUCH EASIER
AND CHEAPER IF THE INITIAL
MISSION TO THE MOON HAD BEEN ONE
WAY ONLY.
AND THAT MISSION COULD STILL
HAVE PRODUCED A GREAT DEAL OF
USEFUL RESEARCH RESULTS WHICH
THE ASTRONAUTS WOULD HAVE BEEN
ABLE TO TRANSMIT BACK TO EARTH
BEFORE THEIR WATER AND OXYGEN
EXPIRED AND THEY DIED ON THE
MOON.
MOREOVER, THERE WOULD HAVE BEEN
NO DEARTH OF WILLING ASTRONAUTS,
THE FAME AND GLORY FOR THE
BRAVERY INVOLVED ON BEING THE
FIRST PERSON ON THE MOON, EVEN
IF THAT PERSON WASN'T GOING TO
COME HOME FOR THE TICKER TAPE
PARADE WOULD HAVE MEANT LIKE
VOLUNTEERS IN WARTIME FOR
SUICIDE MISSIONS WHO GAIN
IMMORTALITY, THEY GO DOWN IN
HISTORY BOOKS, THEY ARE
REMEMBERED IN CELEBRATIONS AND
CHILDREN LOOK UP TO THEM, ALL
THAT WOULD HAVE PROVIDED PLENTY
OF WILLING VOLUNTEERS WHO WOULD
HAVE UNDERSTOOD VERY WELL THE
RISK INVOLVED.
BUT THE IDEA WAS REJECTED OUT OF
HAND.
IT WAS RECOGNIZED THAT THERE WAS
AN INSTITUTIONAL INTEREST IN
HAVING THE EFFORT TO RETURN
PEOPLE, BE SUCCESSFUL, AND WHAT
HAD BEEN THE REACTION EVEN TO
SENDING DOGS INTO SPACE WHO DIED
IN THE PROCESS INDICATED THAT
THE LOSS, THE INTENTIONAL LOSS
OF HUMAN LIFE IN THIS WAY WOULD
HAVE BEEN UNACCEPTABLE.
SO THEN WITH THE IRB AND WITH
THE RECOGNITION THAT CONSENT
ISN'T EVERYTHING, WE MOVE TO
WHAT ONE MIGHT CALL STAGE 3.
REMEMBERING THAT STAGE 2 HAD
ACTUALLY RESULTED IN RESEARCH
SUBJECTS BEING MORE PROTECTED,
THE NATIONAL COMMISSION WAS FOR
THE PROTECTION OF HUMAN SUBJECTS
AND THE OFFICE THAT WAS SET UP,
THE PREDECESSOR OF CURRENT
OFFICE WAS FOR PROTECT OF
RESEARCH SUBJECTS, BUT THE AIDS
CRISIS CHANGED THAT.
AND THE OBJECTIVES OF THE
EDUCATORS, ACT UP AND OTHER AIDS
ACTIVISTS WAS TO GIVE PATIENTS
CONTROL OVER RESEARCH.
PARTIALLY, THIS MEANT LESS
PATERNALISM AND MORE WILLINGNESS
TO ALLOW RISK, AND THE FEDERAL
OFFICIALS AT NIH AND AT THE FDA
WERE EVENTUALLY BROUGHT AROUND
TO EXACTLY THAT VIEW FROM
MEETING WITH AND DISCUSSING AND
COMING TO UNDERSTAND THESE
PATIENTS, AND THEIR DESIRE TO
PARTICIPATE MORE IN RESEARCH
EVEN IF IT WAS HIGH RISK.
THE MAIN TAKEAWAY, HOWEVER, FOR
REGULATORS I THINK WAS TO ENSURE
GREATER INCLUSION IN RESEARCH,
AND SO PEOPLE WITH -- LESS
LIKELY TO EXCLUDE PEOPLE FOR
COMORBIDITIES AND SO FORTH,
ALLOW MORE CHOICE ON THE PART OF
THE RESEARCH SUBJECTS, AS TO
THEIR WILLINGNESS TO TAKE RISKS.
WHERE DO WE STAND NOW?
WE'RE IN STAGE 3, AND AS TO
PATIENT SUBJECTS, I THINK THE
CONSENSUS NOT FROM A CHANGE IN
REGULATIONS BUT FROM THE WAY
THEY ARE APPLIED IS THEY SHOULD
BE DECISION MAKERS WHETHER TO
TRADE RISKS OF ILLNESS WITH THE
LIMITATIONS OF CURRENT
TREATMENTS FOR RISK OF STILL
EXPERIMENTAL INTERVENTIONS.
AND THE USUAL VIEW ABOUT THIS IS
THAT THAT CHOICE, THEIR ROLE IS
AS DECISION MAKERS COMES AT THE
POINT WHERE THOSE INTERVENTIONS
THAT ARE BEING TESTED ARE ONES
THAT A RESEARCHER AND THE IRBs
HAVE ALREADY DECIDED MEET THE
REQUIREMENTS, WELL DESIGNED,
RISKS HAVE BEEN MINIMIZED, AND
THAT OVERALL THE BENEFITS, NOT
NECESSARILY TO THE PARTICIPANTS
IN THE RESEARCH, BUT TO THE
ENTERPRISE, THE EVENTUAL
DEVELOPMENT OF THE KNOWLEDGE,
DISCOVERY OF A TREATMENT,
UNDERSTANDING OF DISEASE, THESE
BENEFITS OUTWEIGH THOSE RISKS.
BUT TODAY THAT VIEW GOES EVEN
FURTHER, THE ARGUMENT ABOUT
PATIENTS AS DECISION MAKERS IS
EMBODIED IN THE RIGHT TO TRY
LAWS AROUND THE COUNTRY UNDER
WHICH WITH THE COOPERATION OF
PRODUCER OF THE EXPERIMENTAL
INTERVENTION, USUALLY A
PHARMACEUTICAL COMPANY, PATIENTS
ARE ABLE TO SEEK EXPERIMENTAL
INTERVENTION OUTSIDE OF
PROTOCOL.
IN OTHER WORDS, NOT SIMPLY WITH
THOSE LIMITATIONS THAT APPLY TO
AN APPROVED PHASE 3 TRIAL.
ON THE ONE HAND, THEREFORE, WE
COULD SAY THAT COMPETENT ADULTS
SHOULD HAVE FREEDOM TO CONSENT,
EVEN TO SOMETHING THAT'S HIGH
RISK.
BUT, WE'RE STILL IN STAGE 2 AS
TO NORMAL VOLUNTEERS.
A CENTRAL PURPOSE OF THE ENTIRE
APPARATUS OF PRIOR REVIEW OF
RESEARCH IS TO LIMIT THE FREEDOM
OF RESEARCHERS TO SEEK OUT
PEOPLE WHO WILL TAKE BIG RISKS
AND/OR RISKS THAT ARE NOT
JUSTIFIED BY ADEQUATE BENEFIT.
ON THE OTHER HAND, IRBs CAN
AND SHOULD PROTECT EVEN
COMPETENT ADULTS FROM ACCEPTING
UNDUE RISKS, SO WE HAVE ON THE
ONE HAND FREEDOM TO CONSENT,
EVEN WHEN THERE'S RISKS, ON THE
OTHER I THINK THE SYSTEM SAYS WE
DON'T HAVE CONSENT AS THE FULLY
SUFFICIENT CASE IS FOR GOING
AHEAD.
LET ME TAKE A QUICK RUN AND
CONCLUSION AT THE QUESTIONS DR.
KIMMEL'S PRESENTATION ENDED
WITH.
FIRST, ARE THERE ETHICAL LIMITS
ON RESEARCH RISKS IN COMPETENT
ADULTS?
I SAY YES.
ESPECIALLY FOR NORMAL
VOLUNTEERS.
I MYSELF MIGHT ARGUE THAT HAS
THINGS BACKWARDS.
WE SHOULD BE MORE CONCERNED
ABOUT RISKS FOR PATIENTS BECAUSE
OF DIFFICULTIES OF THEIR
CONSENT, BUT THE CONVENTIONAL
VIEW IS WE SHOULD BE MORE
CONCERNED ABOUT NORMAL
VOLUNTEERS.
IF SO, DR. KIMMEL ASKED HOW ARE
THESE LIMITS DETERMINED?
THEY ARE DETERMINED BY IRBs,
RELYING ON MEMBERS' KNOWLEDGE,
WHAT IS KNOWN ABOUT RISKS, AND
OTHER RESEARCH, AT THEIR OWN AND
OTHER INSTITUTIONS.
THERE'S NO UNIFORM STANDARD.
EMPIRICAL STUDIES THAT HAVE BEEN
DONE SHOW DIFFERENT STANDARDS
BEING APPLIED.
IS THE PRESENT STUDY CONSISTENT
WITH WHATEVER LIMITS THERE ARE?
I THINK THERE'S NO WAY FOR ME TO
ANSWER AS TO WHAT THE CLINICAL
CENTER IRB HAS DONE IN THE ABOUT
NORMAL VOLUNTEERS IN RESEARCH
WITH COMPARABLE RISKS.
IS IT MORE PROBLEMATIC TO EXPOSE
HEALTHY INDIVIDUALS TO RESEARCH
RISKS YES, ESPECIALLY IN THIS
INSTANCE, IS THE OBVIOUS ANSWER.
FIRST BY THE RESEARCHEST
DESCRIPTION, NOT HAVING A KNOWN
BENEFIT DEFEATS THE RISK/BENEFIT
COMPARISON.
IF YOU THINK OF DIVISION YOU
HAVE ZERO AS THE BOTTOM PART OF
THE FRACTION.
WILL IT BE BENEFICIAL TO COMPARE
WITH NORMAL TISSUE?
WE DON'T KNOW.
DOES GENERAL ANESTHESIA AFFECT
WHEN MAKING COMPARISONS WITH
DISEASED TISSUE?
DEPARTMENT SEEM TO ME THERE'S AN
ANSWER.
DR. KIMMEL MAY SAY THERE IS BUT
THE FIRST POINT IS AN UNKNOWN.
AND IT SEEMS TO ME THAT THE
OTHER REASON WHY IT'S
PROBLEMATIC IS THAT RISK WOULD
BE MINIMIZED BY USING OTHER
SOURCES.
THE PRINCE NON-MALEFICENCE
INVOLVES AVOIDING RISK, HEALTHY
PERSONS SHOULD NOT BE SUBJECT TO
KIDNEY BIOPSY SOLELY FOR
RESEARCH BEFORE DETERMINING
STUDIES CANNOT BE DONE WITH
TISSUE OBTAINED FROM LIVING OR
DECEASED KIDNEY DONORS.
DECEASED KIDNEY DONORS WHOSE
KIDNEYS ARE PERFECT USABLE FOR
TRANSPLANTATION HAVE NOT
UNDERGONE GENERAL ANESTHESIA IN
REMOVAL OF THOSE KIDNEYS.
CARE WILL BE NEEDED TO AVOID
THERAPEUTIC MISCONCEPTION BY
KIDNEY DONORS, LIVING KIDNEY
DONORS AND YOU NEED TO INFORM
RECIPIENT SHOULD BE THERE
CONCERNED TAKING A BIOPSY WOULD
CHANGE THE UTILITY BUT BIOPSIES
ARE ALREADY DONE IN TRANSPLANT
SETTINGS.
AND FINALLY, WOULD THE STUDY BE
ETHICALLY BETTER OR WORSE IF THE
PARTICIPANTS WERE PAID, E G1 --
E G, $1,000, THE ARGUMENTS IN
FAVOR OF PAYMENT INCLUDE PAYMENT
IS PERMITTED, NOT INHERENTLY
UNETHICAL, IF ALL OTHER ETHICAL
PRINCIPLES ARE SATISFIED, PARTS
PARTICIPATION IS PERMISSIBLE,
THAT IS THE IRB AND
INVESTIGATORS HAVE GONE THROUGH
THE PROCESS THEY NEED TO, AND SO
IF THERE IS AN INCENTIVE TO
PARTICIPATE BY GIVING MONEY,
THERE'S NOTHING WRONG WITH
PARTICIPATION.
BUT THE ARGUMENTS AGAINST
PAYMENT INCLUDE RISKY
EXPERIMENT, IT IS DISINGENUOUS
TO THINK PARTICIPANTS SHOULD BE
PAID SIMPLY FOR TIME AND
INCONVENIENCE, LIKE $1,000.
YOU'RE HAVING TO GO INTO THE
HOSPITAL, THE CLINICAL SETTING,
AND THERE'S A LIKELIHOOD
APPARENTLY SOME SUBSTANTIAL
LIKELIHOOD OF BLEEDING, INTERNAL
BLEEDING, ALSO INTO THE KIDNEY,
CAUSING INTO THE URINE, PAIN AND
DISCOMFORT AND SO FORTH.
SO $1,000 WOULD BE FINE FOR THAT
BUT WHAT MAKES THIS UNUSUAL IS
THE THREE-TENTHS OF A PERCENT
LIKELIHOOD OF DEATH BASED ON THE
EXISTING KNOWLEDGE.
OBVIOUSLY, EXISTING KNOWLEDGE
FROM A DIFFERENT SUBJECT BASE,
THAT IS TO SAY THE PEOPLE WHO
ARE UNDERGOING RESEARCH
BIOPSIES, AS PART OF THE STUDY
WHO HAVE KIDNEY DISEASE, ARE NOT
THE SAME AS THE NORMAL
VOLUNTEERS, BUT WE DON'T HAVE
DATA ON THAT AND IN THESE
CIRCUMSTANCES YOU PROBABLY TURN
TO THE DATA THAT YOU DO HAVE,
AND THAT'S WHAT DR. KIMMEL HAS
INCLUDED IN HIS PRESENTATION.
AND THE QUESTION THAT HE ASKS.
BUT, IT IS ALSO TRUE THAT
SETTING THOSE FINANCIAL REWARDS
WILL OFFSET A RISK AND THE
FINANCIAL REWARDS ARE VERY
LIKELY GIVEN THOSE RISKS TO BE
THOUGHT TO BE JUSTIFIED ABOVE
$1,000, WOULD CREATE AN UNDUE
INDUCEMENT THAT WOULD UNDERMINE
VOLUNTARINESS AND WOULD INDUCE
MORE POOR AND VULNERABLE
INDIVIDUALS TO ENROLL, THE EXACT
OPPOSITE OF THE CAUTION THAT
JONAS SUGGESTED ABOUT BEGINNING
WITH THE RESEARCHERS THEMSELVES.
SO, I THANK YOU AND I LOOK
FORWARD TO THE DISCUSSION.
>> THANK YOU, ALEX.
SOME PEOPLE HAVE SUGGESTED THAT
THE WAY IRBs SHOULD EVALUATE
PROPOSALS LIKE PAUL'S IS TO LOOK
AT ACTIVITIES AND CONTEXT
OUTSIDE OF RESEARCH, WHERE WE
LET PEOPLE FACE RISKS IN THE
CONTEXT OF ACTIVITIES THAT ARE
DESIGNED TO BENEFIT OTHERS.
SO, KIDNEY DONATION, LIVING
KIDNEY DONATION IS AN OBVIOUS
EXAMPLE.
OTHER PEOPLE HAVE TALKED ABOUT
THE RISKS OF RESCUING STRANDED
HIKERS, OTHER PEOPLE TALKED
ABOUT THE RISKS OF BEING AN EMT
OR BEING A FIREMAN, I WAS
WONDERING IF YOU HAD THOUGHTS ON
THAT APPROACH, WHEN IRBs,
THESE KINDS OF PROPOSALS, WOULD
THAT BE A GOOD STANDARD TO KEEP
IN MIND?
>> WELL, IF IT WERE, THE FACT
THAT WE KNOW KIDNEY DONATION HAS
A RISK THAT IS A TENTH OF THE
RISK THAT PAUL IS HYPOTHESIZING
HERE, THE ONLY ONE THAT THEY
HAVE TO GO ON, WOULD INDICATE
THAT IT DOESN'T SUPPORT THIS ON
THE RISK LEVEL ALONE.
MOREOVER, THAT VOLUNTARY CHOICE
THERE IS WITHIN THE CONTEXT OF
PROVIDING A WELL-KNOWN,
WELL-ESTABLISHED BENEFIT.
SO I THINK -- I WANT TO BE
UNDERSTOOD.
I ACTUALLY HAVE MUCH MORE
RESPECT FOR INDIVIDUALLY
INFORMED CONSENT, WHAT I'VE
TRIED TO EXPLAIN HERE IS WHAT I
THINK THE REGULATIONS, THE
SYSTEM OF REGULATIONS WE HAVE
NOW, WHICH IN EFFECT
SUBSTITUTED -- SUBSTITUTES A
COMMITTEE'S PATERNALISM FOR THE
OLD PATERNALISM OF PHYSICIANS
WHO USED TO MAKE THESE CHOICES,
AND THE DOCTORS THAT HENNY
BEECHER WERE COMPLAINING ABOUT
WERE DOING THAT THINKING I KNOW
WHAT IS BEST.
WE NOW HAVE SOMETHING ELSE, THE
WHOLE RATIONALE OF HAVING THAT
SYSTEM OF PRIOR REVIEW IS TO
LIMIT SOMETHING WHICH IS JUST AN
AGREEMENT BETWEEN THE INDIVIDUAL
SUBJECT AND THE RESEARCHER.
AS FOR EMPLOYMENT SITUATIONS AND
WAR, WHERE WE, YOU KNOW, WE
COLLECTIVELY DO CONSTRICT,
CONSCRIPT, EXCUSE ME, PEOPLE TO
GO INTO WAR RISKS ARE HIGH, FAR
ABOVE THREE IN A THOUSAND, SO
THAT ANALOGY GOES TOO FAR, IN MY
VIEW.
>> I WANT TO THANK PAUL AND ALEX
FOR A VERY INTERESTING AND
LIVELY SESSION.
AND THANK EVERYBODY FOR ETHICS
GRAND ROUNDS FOR THIS ACADEMIC
YEAR.
AND HOPEFULLY WE'LL SEE PEOPLE
BACK HERE AGAIN THE FIRST
WEDNESDAY IN OCTOBER, AT NOON,
FOR ANOTHER SESSION.
SO THANKS, YOU GUYS.
REALLY APPRECIATE IT.
LOOK FORWARD TO SEEING EVERYBODY
AGAIN.
BYE-BYE.