SO, WELCOME TO THE THIRD
SESSION OF ETHICAL AND
REGULATORY ASPECTS OF CLINICAL
RESEARCH.
I'M HOLLY, YOU MAY RECOGNIZE ME
FROM THE FIRST TWO SESSIONS.
TODAY, I'M GOING TO START WITH
THE RELATIVELY BRIEF LECTURE ON
STUDY DESIGN AND THEN DAVE
WENDLER FROM OUR DEPARTMENT IS
GOING TO JOIN US IN-PERSON AND
THEN SEEMA SHAH IS GOING TO
JOIN US BY SOON.
IF YOU HAVE SELF ENROLLED BUT
NOT SELF REGISTERED, PLEASE GO
AHEAD AND DO THAT ABOUT A
THOUSAND OF YOU HAVE
SELF-ENROLLED AND ABOUT 700
SELF REGISTERED.
IF YOU WANT A CERTIFICATE YOU
NEED TO TAKE THED EXTRA STEP
AND SELF-REGISTER.
AND FOR QUESTIONS TODAY I
CREATED A PLACE IN THE
DISCUSSION BOARD, PLEASE PUT
YOUR QUESTIONS THERE DURING THE
LECTURE AS THAT'S THE EASIEST
WAY FOR MIRROR TO FIND THE
QUESTIONS.
DISCLAIMER, GOOD STUDY DESIGN
IS KEY TO CONDUCTING ETHICAL
RESEARCH.
THIS IS FROM, DOCUMENT FROM NOW
ALMOST QUITE A LONG TIME AGO,
BUT REMAINS TRUE.
RESEARCHERS, US, HAVE A
FUNDAMENTAL OBLIGATION TO PLAN,
DESIGN AND CONDUCT STUDIES WITH
HONESTY, TRUTHFULNESS AND
INTEGRITY.
VALUES HOW RESEARCHERS
INTERPRET THEIR WORK.
SO I'M GOING TO SPEND A LITTLE
TIME ON THE FIRST TWO OF THESE
CIRCLED ETHICAL REQUIREMENTS
TODAY.
WE ALREADY COVERED INDEPENDENT
REVIEW BUT THAT'S SORT OF A KEY
COME POENT OF THE REVIEW OF THE
STUDY DESIGN.
SO I'M JUST GOING TO GIVE US,
SOME BASICS, SO WE'RE REALLY
ALL ON THE SAME PAGE.
SO THERE ARE BASICALLY, TWO
TYPES OF RESEARCH AND THIS IS A
LITTLE OVER SIMPLIFYING SO
YOU'LL SEE WHY I'M MAKING THE
DISTINCTIONS, THERE IS BASIC,
OBSERVIAL, YOU'RE OBSERVING AND
COLLECTING DATA.
YOU CAN DO THAT RETROSPECTIVELY
LOOKING BACK FORWARDS OR
LOOKING FORWARD.
RETROSPECTIVELY, MEANS THAT YOU
MAY LOOK AT MEDICAL CHARTS
MAYBE FIVE YEARS OF MEDICAL
CHARTS.
EXPERIMENTAL INCLUDES SOME SORT
OF INTERVENTION AND ALMOST
ALWAYS PERSPECTIVE T WOULD BE
HARD TO DO A RETROSPECTIVE
TRIAL.
NOW IN IF THAT VAOERMENT AL
DESIGN THERE ARE A COUPLE OF
THINGS THAT OFTEN HAPPEN, FIRST
THERE IS SOME SORT OF
MANIPULATION, CHANGING,
ARTIFICIALLY, WE'RE NOT
OBSERVING, WE'RE MANIPULATING
AT LEAST ONE VARIABLE.
SOMETIMES THERE IS CONTROL, AND
YOU DO THAT IN ORDER TO REDUCE
THE LIKELIHOOD THAT EXTERNAL
FACTORS WILL INFLUENCE THE
STUDY OUTCOME AND THEN
RANDOMIZATION TO HOPEFULLY
ENSURE THAT YOU HAVE AN
UNBIASED SELECTION AMONG THOSE
WHO GET THE INTERVENTION AND
THOSE WHO DON'T.
NOW, THERE IS A SOMETIMES IT'S
IMPOSSIBLE TO RANDOMIZE, RIGHT?
YOU MAY WANT TO COMPARE TO
INTERVENTIONS.
BUT ONE INTERVENTION REQUIRES A
INJECTION, THE OTHER REQUIRES A
PILL.
YOU CAN'T REALLY--I'M SORRY,
YOU CAN'T REALLY RANDOMIZE IN A
WAY THAT IS MEANINGFUL TO THE
PERSON BECAUSE THEY'RE GOING TO
KNOW WHICH ONE THEY GET.
YOU CAN RANDOMIZE THE
ASSIGNMENT, BUT YOU CAN'T BLIND
THE INDIVIDUAL TO WHAT THEY'RE
GETTING.
AND SO A QUASI DESIGN IS WHEN
THERE IS NO RANDOMIZATION.
SO THE FIRST QUESTION WE'RE
GOING TO ASK ABOUT ANY STUDY IS
WHETHER OR NOT IT HAS SOCIAL
VALUE, AND DAVE WENDLER WHO IS
GOING TO FOLLOW ME IS GOING TO
TALK A BIT ABOUT SOCIAL VALUE.
SO I'M NOT GOING TO SAY MUCH
ABOUT IT NOW.
BUT FOR THE SAKE OF ARGUMENT,
WE'RE GOING TO SAY THAT A
PROJECT SHOULD NOT GO FORWARD
UNLESS THERE IS SOCIAL BENEFIT.
THAT THERE IS DIRECT BENEFIT TO
PATIENTS OR VALUE TO FUTURE
PATIENTS OR GAINING KNOWLEDGE
THAT WILL LEAD YOU TO BENEFIT
FOR FUTURE PATIENTS AND/OR FOR
INDIVIDUAL PATIENTS.
AND SCIENTIFIC VALIDITY IS A
COMPONENT AND A IMPORTANT
RESPECT IS THE STUDY DESIGN
VALID?
AND EASY WAY TO THINK ABOUT
THIS CONCEPT IS TO THINK ABOUT
SAMPLE RISE, RIGHT?
WHEN YOU'RE DESIGNING YOUR
STUDY, YOU NEED TO HAVE ENOUGH
PARTICIPANTS IN ORDER TO ANSWER
YOUR SCIENTIFIC QUESTION.
IF YOU DON'T HAVE ENOUGH, YOU
CAN'T ANSWER YOUR QUESTION.
AND YOU HAVE LET'S SAY, YOU,
YOU EN ROLL 100, YOU REALLY
NEED 200.
YOU HAVE WASTED THE RESOURCES
THAT IT TOOK YOU TO DO THAT
HALF OF THE TRIAL AND YOU'RE
NOT GOING TO GET AN ANSWER.
SO THAT WOULD BE A BAD STUDY
DESIGN BECAUSE YOU HAVE THE
SAMPLE SIZE TOO SMALL OR IT'S
TOO LARGE, RIGHT.
WILL THES IMAGINE THAT YOU ONLY
NEED 100 PEOPLE TO EXPOSE TO
THE INTERVENTION AND CONTROL
BUT YOU AND, YOU'VE ENROLLED
200, THAT MEANS YOU'VE EXPOSED
100 PEOPLE TO MORE RISK THAN
THEY NEEDED TO BE AND ALSO
WASTED SOME RESOURCES.
NOW AN IMPORTANT QUESTION ABOUT
SCIENTIFIC VALIDITY, IS THERE
UNCERTAINTY ABOUT THE POTENTIAL
BENEFIT OF THE PROPOSED
INTERVENTION?
IF THERE IS NO UNCERTAINTY,
THEN WE CANNOT GO FORWARD.
IF WE ALREADY KNOW THE ANSWER,
WE CANNOT ETHICALLY OR
SCIENTIFICALLY MOVE FORWARD.
IF YES, IF THERE IS UNCERTAINTY
THEN A RANDOMIZE CONTROL TRIAL
MAY BE ACCEPTABLE AND A
FOLLOW-UP QUESTION WOULD BE IS
RANDOMIZATION TO A PLACEBO
ACCEPTABLE.
SO WHEN WE TALK ABOUT A
RANDOMIZE CONTROL TRIAL, THERE
IS UNCERTAINITY, RIGHT?
THERE IS AN INDIFFERENCE ABOUT
COMMUNITY PHYSICIANS ABOUT
WHICH TREATMENT IS SUPERIOR
THIS IS REFERRED TO AS ECO
POISE, BUT IT MEANS INDIFFERENT
TO A COMMUNITY OF EXPERTS.
IF YOU'RE DOING A STUDY ABOUT
DIABETES, IT WOULD BE REALLY
IMPORTANT FOR THOSE PHYSICIANS
WHO ARE EXPERTS IN DIABETES OR
PROVIDING CARE IN DIABETES,
THERE IS INDIFFERENCE AMONG
THEM, NOT AMONG ALL CLINICIANS,
FOR EXAMPLE.
AS I MENTIONED BEFORE, THERE IS
THIS CONCEPT OF BLINDING, WHERE
THERE IS YOU MAY WANT BLIND THE
INDIVIDUALS FROM THEIR
ASSIGNMENT.
YOU MAY ALSO WANT TO BLIND THE
INVESTIGATORS SO YOU CAN DO A
SINGLE BLIND OR A DOUBLE BLIND
WHERE THE INVESTIGATORS AND THE
SUBJECTS ARE BLINDED.
SO WHAT ABOUT WHETHER WE CAN
USE A PLACEBO OR AN ACTIVE
CONTROL?
SO JUST AS A REMINDER, A
PLACEBO, RIGHT IS GENERALLY,
LET'S TAKE THE CLASSIC EXAMPLE
OF A PILL, IT LOOKS, IT'S A
PILL THAT LOOKS JUST LIKE THE
DRUG BUT DOESN'T CONTAIN ANY
MEDICINE.
AND WE DO THIS, AND IT'S
IMPORTANT THAT WE SHARE THIS
WITH POTENTIAL PARTICIPANTS, WE
DO THIS TO FIND OUT WHETHER THE
REAL MEDICINE WORKS LIKE WE
HOPE IT TO.
AND WE NEED TO COMPARE THE
PEOPLE WHO GET THE MEDICINE TO
WHOAS WHO DON'T TO SEE IF THE
MEDICINE WORKS.
SO THE NEXT QUESTION IS WHEN IT
IS ETHICALLY APPROPRIATE TO
INCLUDE A PLA TAOEB O?
AND--PLACEBO, AND THE COMMON
LINE IS WHEN THERE IS NO GOOD
STANDARD TREATMENT.
SO IMAGINE IT'S 1988, WE KNOW
THAT H.I.V. CAUSES AIDS BUT WE
HAVE NO TREATMENT.
SO THE FIRST TRIALS OF AZT, THE
FIRST ANTI VIRAL WAS TESTED,
WAS TESTED IN A TRIAL WHERE
HALF THE PARTICIPANTS GOT A
PLACEBO, THE OTHER HALF GOT
ACT, AND THAT WAS ETHICALLY
ACCEPTABLE BECAUSE THERE WAS NO
GOOD STANDARD TREATMENT WH. A
STANDARD TREATMENT EXISTS,
THERE IS EXPECTATION THAT IT
THE STUDY WILL BE HAVE AN
ACTIVE CONTROL, MEANING THAT
THE OLD MEDICINE IS GOING TO BE
TESTED AGAINST THE NEW MEDICINE.
THERE ARE A COUPLE OF OTHER
EXAMPLES THAT WHEN A STANDARD
TREATMENT EXIST, IT IS
ETHICALLY ACCEPTABLE TO USE A
PLACEBO.
SO ONE, IS MAYBE OBVIOUS.
WHEN THE PLACEBOS ARE ADDITIVE,
SO THERE IS A STANDARD OF CARE,
IT'S ACCEPTABLE TO THE STANDARD
OF CARE PLUS THE NEW THING.
AND STANDARD OF CARE, RIGHT?
IT'S MERELY ADDITIVE.
ANOTHER EXAMPLE WHEN THE
MEDICAL CONDITION AND QUESTION
IS NOT SERIOUS.
SO LET'S SAY A DRUG COMPANY
WANTS TO DEVELOP A NEW PAIN
RELIEVER AND THEY WANT TO EN
ROLL PEOPLE WHO HAVE HAD A
HEADACHE FOR A MONTH, WE'RE
TALKING REGULAR HEADACHE, IT'S
ACCEPTABLE TO ASK PEOPLE TO NOT
TAKE A PAIN RELIEVER SO IT
WOULD BE OKAY TO RANDOMIZE.
AND WHEN BEING AWAY FROM
MEDICATION WILL NOT CAUSE
SERIOUS IRREVERSABLE DAMAGE.
YOU HAVE TO BE CAREFUL BECAUSE
SOME COULD EXPERIENCE HARM.
BUT IF YOU'RE TALKING ABOUT A
MEDICATION THAT WILL NOT RESULT
IN THAT, IT MAY BE OKAY TO ASK
PARTICIPANTS TO STOP TAKING THE
DRUG THAT THEY'RE TAKING AND BE
RANDOMIZE WITH A DRUG VERSUS A
PLACEBO, THIS WILL DEPEND ON
THE CONTEXT, JUSTIFICATIONS, ET
CETERA.
OOPS, WRONG DIRECTION.
OH, SO THIS IS ANOTHER
INTERESTING THING FOR PIECE OF
PLACEBO.
WHY NOT JUST HAVE A
NO-INTERVENTION ARM?
SO LET'S SAY YOU'RE TRYING A
NEW TREATMENT, WHY NOT JUST
HAVE PEOPLE GET NO INTERVENTION
AND THE INTERVENTION?
AND MEANING, THAT HALF THE
PEOPLE WITH GET THE PAIN PATCH,
THE OTHER HALF WOULDN'T GET THE
PAIN PATCH.
SO THE CONCERN HERE, IS IF YOU
JUST GIVE HALF THE PEOPLE THE
PAIN PATCH AND THE OTHER GROUP,
NOTHING, WHEN THE OUTCOME CAN
BE SUBJECTIVE LIKE PAIN OR
EMOTIONAL OR ENDURANCE OR
SOMETHING LIKE THAT.
THE INDIVIDUALS WHO GET THE
PAIN PATCH, MIGHT REPORT
INFORMATION IN A WAY THAT IS
BIASED BY THE WAY THAT THEY
HAVE THE PAIN PATCH OR VICE
VERSA SO YOU WANT TO HAVE A
INDIVIDUAL THAT HAS ACTIVE
INGREDIENT OR A PATCH THAT DOES
NOT HAVE THE ACTIVE INGREDIENT.
ANOTHER REASON WHY YOU WANT TO
HAVE SOMETHING IN TERMS OF A
COMPARISON IS WHEN RISK
BEHAVIORS MIGHT BE AFFECTED BY
THINKING ONE RECEIVED THE
EXPERIMENTAL TREATMENT.
SO WE CAN THINK BACK TO COVID
FOR EXAMPLE, IF YOU WERE IN A
TRIAL AND YOU KNEW THAT BECAUSE
YOU GOT A SHOT, YOU GOT THE
VACCINE, IF YOU DIDN'T GET THE
SHOT, YOU DIDN'T GET THE
VACCINE, ONE POSSIBILITY IS IF
YOU DIDN'T GET THE SHOT, YOU
WOULD BE HYPER VIGILANT ABOUT
AVOIDING COVID.
AND IN COMPARING YOU WITH THOSE
WHO GOT THE VACCINE, WE WON BE
ABLE TO TELL THE DIFFERENCE SO
IT COULD BE IMPORTANT FOR
EVERYBODY TO GET THE SHOT.
I WANT TO TRANSITION A LITTLE
AND BRING YOUR ATTENTION TO A
DOCUMENT THAT YUZ JUST
PUBLISHED LAST MONTH.
THE WORLD HEALTH ORGANIZATION,
PUBLISHED GUIDANCE FOR BEST
PRACTICES FOR CLINICAL TRIALS.
FOR THOSE ACTIVELY ENGAGED IN
AND INTERESTED IN CLINICAL
TRIALS, THIS IS A REALLY NICE
DOCUMENT IN HITTING SOME OF THE
SORT OF MOST IMPORTANT KEY
ASPECTS OF THINKING ABOUT
CLINICAL RESEARCH AND CLINICAL
TRIALS.
AND INCLUDED THIS LITTLE
DIAGRAM BECAUSE THEY'RE ALSO
TALKING ABOUT THE RESEARCH HE
ECOSYSTEM AND THE IMPORTANT
PARTS OF THAT SYSTEM THAT
SUPPORT ALL THE RESEARCH THAT
IS BEING DONE.
SOY RECOMMEND THAT THOSE OF YOU
INTERESTED, TAKE A LOOK AT THAT
AND I JUST PULLED THIS ONE
PIECE OF THE PUZZLE OUT OF THE
DOCUMENT, WHERE THEY TALK ABOUT
THE KEY SCIENTIFIC AND ETHICAL
CONSIDERATIONS FOR CLINICAL
TRIALS.
AND YOU WON'T BE SURPRISED BY
ANY OF THESE PRONOUNCEMENTS
THAT IT CAN BE DESIGNED, AND
RESPECTS THE RIGHTS OF
WELL-BEING PARTICIPANTS AND I
THINK THESE THREE ARE SORT OF
NOT NEW BUT I LIKE THAT THEY
PUT THESE IN THE LIST THAT THE
RESEARCH NEEDS TO BE
COLLABORATIVE AND TRANSPARENT,
BE DESIGNED TO BE FEASIBLE FOR
THEIR CONTEXT, AND MANAGE TRIAL
QUALITY EFFECTIVELY AND
EFFICIENTLY.
SO THE LAST THREE ARE ETHICAL
BUT ALSO IMPORTANT PRACTICALLY
IN THINKING ABOUT DESIGN.
AND THEN, ANOTHER ARTICLE THAT
I JUST WANTED TO BRING YOUR
ATTENTION TO OR ANOTHER SET OF
PRINCIPLES, AGAIN THINGS THAT
YOU WOULD NOT BE SURPRISED TO
HEAR.
BUT THEY ADD, STUDY FINDINGS
MUST BE REPORTED PROMPTLY
DURING AND AFTER THE TRIAL.
AND I WOULD SAY IN THE LAST TEN
YEARS OR SO, MAYBE EVEN 20,
THERE IS BEEN MORE EMPHASIS ON
MAKING SURE THAT STUDY FINDINGS
GO BACK TO THE STUDY POPULATION
THAT PARTICIPATED.
SO BACK IN THE DAY, THE
EXPECTATION WAS YOU DID YOUR
RESEARCH, DID YOU YOUR CLINICAL
TRIALS AND THEN YOU PUBLISHED
IT AND THAT'S IT, YOU CAN VONN
VAID YOUR FINDINGS TO THE
SCIENTIFIC COMMUNITY, BUT
MAYBE, YOU ALSO HAVE AN
OBLIGATION TO SHARE THOSE
FINDINGS WITH THOSE WHO
PARTICIPATED IN THE TRIAL.
AND IT DOESN'T MEAN YOU GIVE
THEM LIKE HERE ARE YOUR
FINDINGS, BUT PROVIDE THEM WITH
THE AGGREGATE FINDINGS, THE
PRIMARILY FINDINGS IN AND LAY
LANGUAGE, IN A WAY THAT THEY
CAN UNDERSTAND.
THAT IT'S IMPORTANT FOR
INDIVIDUALS TO APPRECIATE THAT
THEY'RE CONTRIBUTION LEAD TO
AND OUTCOME AND I WOULD SAY
THAT'S TRUE, WHETHER IT'S
POSITIVE OR NEGATIVE.
THAT THEY'RE CONTRIBUTION LEAD
TO SOMETHING THAT WILL ADVANCE
SCIENCE AGAIN REGARDLESS OF
WHETHER IT'S POSITIVE OR
NEGATIVE IN TERMS OF WHETHER
THEY ANSWERED, WERE ABLE TO
ANSWER THE QUESTION THEY SET
OUT TO.
SO A COME OF MORE COMMENTS
ABOUT TERMINOLOGY WHEN WE THINK
ABOUT TRIALS.
AND I'M SURE THAT WE'VE ALL
MENTIONED THESE IN THE FIRST
COUPLE OF SESSIONS BUT JUST
WANT TO CLARIFY.
SO THERE ARE, AGAIN, PROBABLY I
THINK IT WAS IN THE 1970, THE
FDA FORMALLY DEFINED TRIALS AS
PHASE 1, PHASE 2, PHASE 3 AND
PHASE 4.
AND THIS WAS SORT OF, I KNOW
DR. LETTER PRESENTED THE EARLY
HISTORY OF FDA AND HOW THEY
CAME TO DEVELOP EVEN GUIDELINES
HOW YOU CAN PREPARE A
PARTICULAR SOLUTION, HOW IT CAN
BE LABELED, WHETHER YOU FOUND
IT TO BE SAFE, WHETHER YOU
FOUND IT TO BE AFFECTIVE.
IN ALL OF THAT MOMENTUM, THERE
WAS INTEREST AN INTEREST IN
PHARMA COMPANIES MOVED FORWARD
IN THEIR TRIAL DEVELOPMENT, IT
WAS IMPORTANT FOR THERE TO BE A
SORT OF EXPECTATION OF HOW
THINGS MOVE FORWARD.
SO WHEN WE TALK ABOUT PHASE 1
STUDIES, THOSE ARE THE ONES
THAT ARE FIRST IN HUMAN, RIGHT.
THERE IS IN MOST CASES, THERE
IS SOME SORT OF ANIMAL RESEARCH
AND YOU NOW HAVE R GOING TO SEE
WHAT HAPPENS WHEN YOU PUT IT
INTO A HUMAN.
AND GENERALLY, WE'RE GOING TO
TALK A LITTLE MORE IN DETAIL
BUT GENERALLY THOSE ARE FOR
SAFETY.
IS IT OKAY FOR A HUMAN TO
RECEIVE IT IN A RELATIVELY
SMALL NUMBER OF PEOPLE.
FROM THOSE 1100 TRIALS ABOUT 70
GO TO PHASE 2.
ABOUT A THIRD OF THOSE PHASE 3,
AND 6 OR 7 MAKE IT TO PHASE 4
OR TO MARKET.
SO AGAIN JUST TO GIVE YOU A
SENSE OF HOW MUCH RESEARCH
HAPPENS AT ONE END TO GET
RELATIVELY FEW AFFECTIVE
OUTCOMES IN THE END.
AND JUST AGAIN TO GIVE YOU A
LITTLE CONTEXT, THE NIH
CLINICAL CENTER IS UNIQUE IN A
SENSE THAT 95 PERCENT OF THE
TRIALS CONDUCTED HERE ARE EARLY
PHASE TRIALS, PHRASE 1 AND
PHASE 2.
THAT'S NOT THE CASE IN MOST
ACADEMIC MEDICAL CENTERS.
JUST TO SAY THAT WE ARE AT THE
SORT OF EXPLORATORY END OF THE
PIPELINE.
IN 2023, WHICH IS THE MOST
RESENT DATA THAT I COULD FIND,
YOU KNOW, ALMOST HALF WERE
PHASE 2 A LITTLE LESS PHASE 1,
VERY FEW PHASE 3, PHASE 3 WOULD
BE A LARGE COMPARATIVE TRIAL.
SO LET'S TALK A LITTLE ABOUT
EACH ONE AS I SAID, THE PHASE 1
IS USUALLY A RELATIVELY SMALL
POPULATION, FIRST IN HUMAN,
SAFETY, SOMETIMES DOSAGE OR THE
MAXIMUM TOLERATED DOSE.
MEANING THAT YOU GIVE THE
INDIVIDUALS IN THE TRIAL
PERHAPS, LARGER AND LARGER
DOSES IN ORDER TO FIND THE WAY
THAT IS TOO MUCH AND BACK OFF
ONE.
AND YOU USE THAT DOSE TO GO
INTO PHASE 2.
SO IT'S ONE LOWER THAN THAT
MAXIMUM ROLL TATED DOSE.
IN PHASE 2, YOU START TO LOOK
AT THE BIOLOGIC AFFECT.
IN PHASE 1, THEY CAN BE
RELATIVELY SHORT.
IN PHASE 2, THEY MAY START TO
GET A LITTLE LONGER IN ORDER TO
DOCUMENT SOME BIOLOGIC AFFECTS.
SXL PHASE 3, WE'RE NOW GETTING
LARGER MORE THAN 3000 AS YOU
CAN RECALL FROM THE COVID
TRIALS, TENS OF THOUSANDS OF
PEOPLE IN SOME CASES.
THE INTERVENTION THAT IS GOING
TO MOVE FORWARD IS BASED ON THE
RESULTS FROM PHASE 2 AND THIS
IS WHERE YOU START TO LOOK
AFFECTIVE AND CONTINUE TO LOOK
AT SAFETY AND RISK BENEFIT IN
TERMS OF ADOPTING INTO CLINICAL
PRACTICE.
PHASE 4 ARE OFTEN REFERRED TO
AS POST MARKETING TRIALS AND IN
THOSE, WE'RE LOOKING AT LONG
TERM SAFETY.
NOT EVERY INTERVENTION GOES
INTO A POST MARKETING TRIAL.
IN THOSE CASES WHERE THERE IS A
HIGHER EXPECTATION OF RISK OR
SERIOUS EVENTS THERE IS AN
INTEREST IN FOLLOWING THE LONG
TERM SAFETY.
SO IN TERMS OF OVERSIGHT, WE
SPEND A LONG LECTURE ON REVIEW
BOARDS.
THOSE ARE THE LOCAL GROUPS
AFFILIATED WITH THE INSTITUTION
THAT THE INVESTIGATOR IS AT AND
THEY'RE DOING THE INITIAL
REVIEW OF THE RESEARCH TO SEE
WHETHER OR NOT IT IS
APPROPRIATE TO MOVE FORWARD.
ANOTHER THING THAT IS OFTEN IN
PLACE IS A DATA MONITORING
COMMITTEE.
SO IN GENERAL, A DATA
MONITORING COMMITTEE, THEY'RE,
THERE ARE AT LEAST TWO
PRIMARILY TYPE.
ONE TYPE OF DATA MONITORING
COMMITTEE IS ASSIGNED TO A
PARTICULAR STUDY.
SO AGAIN, LET'S USE COVID AS AN
EXAMPLE THE COVID TRIALS EACH
ONE HAD A DATA MONITORING
COMMITTEE.
THE OTHER TYPE IS DATA
MONITORING COMMITTEE THAT IS A
HUB FOR A RANGE OF TRIALS, OR A
GROUP OF TRIALS OR YOU KNOW,
THE TRIALS DON'T NECESSARILY
HAVE TO BE RELATED BUT THEY'RE
ALL LOOKING AT A PARTICULAR
CONDITION AND INTERVENTIONS.
FOR EXAMPLE, I SAT ON THE NHIBI
NATIONAL HEART AND BLOOD
INSTITUTION PEDIATRIC HEART
NETWORK, DMC AND WE REVIEWED
ALL OF THE TRIALS THAT WERE
CONDUCTED UNDER THAT UMBRELLA.
SO THE GOAL OR THE ROLE OF THE
DATA MONITORING COMMITTEE, IS
TO MONITOR THE TRIAL ONCE IT'S
IN THE FIELD.
IF YOU REMEMBER, THE IRB DOES
THEIR REVIEWS AND APPROVES OR
NOT THE PROTOCOL.
THEY GENERALLY DON'T HAVE MUCH
TO DO WITH THE TRIAL ONCE IT'S
LAUNCHED.
THE INVESTIGATORS ARE ASKED TO
PROVIDE ANNUAL REVIEW.
BUT THE IRB IS NOT LOOKING AT
THE DATA COMING OUT OF THE
TRIAL EXCEPT FOR ADVERSE EVENTS
WHICH THEY MAY BE REPORTED TO.
BUT THE DATA MONITORING
COMMITTEE PICKS UP ONCE THE
TRIAL STARTS.
AND ONE REALLY IMPORTANT
COMPONENT OF THAT MOVIN' TO
GOER IS TO PROTECT SUBJECTS
FROM PREVIOUSLY ADVERSE EVENTS.
SO, IMAGINE, THERE IS BEEN SOME
ANIMAL STUDIES, THERE IS BEEN
SOME PHASE 1, THERE IS BEEN
SOME PHASE 2 STUDIES, NOT A LOT
OF TIME THAT'S PASSED SO MAYBE
THERE IS GOING TO BE AN ADVERSE
EVENT THAT COMES INTO A YEAR
INTO THE TRIAL THAT IT WOULD BE
REALLY IMPORTANT TO MEASURE.
TO FOR EXAMPLE, WITH THE COVID
VACCINE TRIALS, THERE WAS SOME
UNLIKELY BUT POTENTIAL ADVERSE
EVENT THAT THOSE, SO THIS IS
KNOWN FROM OTHER VACCINE
PRODUCTS, THAT IF YOU GET THE
VACCINE, AND ARE THEN EXPOSED
TO DISEASE, YOU MAY HAVE AN
EVEN WORSE RESPONSE TO THE
VIRUS.
AGAIN HIGHLY UNLIKELY, IT WAS
NOT EXPECTED NOR DID IT HAPPEN
IN THE COVID VACCINE TRIALS.
BUT ONE OF THE JOBS OF THE
COMMITTEES WAS TO MONITOR THE
DATA TO MAKE SURE THAT DID NOT
HAPPEN.
NOW IF THAT HAPPENS, IT'S THEIR
JOB TO DECIDE WHETHER OR NOT
THAT SIGNAL MEANS THAT THE
STUDY HAS TO STOP.
SO ONE REASON IT MIGHT HAVE TO
STOP IS BECAUSE THE ADVERSE
EVENT IS TO SEVERE AND SO
UNANTICIPATED THAT YOU NEED TO
STOP THE TRIAL FOR A WHILE AND
LOOK INTO WHAT HAPPENED, MAYBE
IT NOTHING TO DO WITH THE
INTERVENTION THAT THE PERSON
RECEIVED BUT YOU DON'T WANT TO
MOVE FORWARD WITH THE TRIAL IF
THERE IS A POSSIBILITY THAT
OTHERS WHO ARE RECEIVING THE
TREATMENT ARE GOING TO HAVE
THAT SAME ADVERSE EVENT.
SO THEY'RE MONITORING FOR
ADVERSE EVENTS.
THEY'RE ALSO LOOKING AT HOW IS
THE TRIAL DOING?
SO AGAIN, LET'S IMAGINE YOU'RE
DOING YOUR TRIAL AND YOU NEED
IN ORDER TO ANSWER I COULDN'T
QUESTION, A SAMPLE OF 200 IN
ORDER TO FIND OUT WHETHER THE
NEW TREATMENT IS BETTER THAN
THE OLD TREATMENT.
AND YOU'RE PLAN TO GO DO THAT
OVER A YEAR.
THE DATA MONITORING COMMITTEE
IS ALSO LOOKING AT YOUR
PROGRESS.
SO IF HALFWAY THROUGH, YOU ONLY
HAVE 50 PARTICIPANTS AND YOU'RE
ANTICIPATED ENROLLMENT WAS 100,
THE DATA COMMITTEE MAY SAY,
OKAY WHAT'S GOING ON?
WHY AREN'T YOU AT WHERE YOU
WANT TO BE AND WHAT ARE YOU
DOING TO ADDRESS THAT?
BECAUSE IT'S IMPORTANT FOR A
TRIAL TO MOVE FORWARD AND IT'S
FUNDED FOR A CERTAIN PERIOD, NA
IS IMPORTANT FOR THE DATA
MONITORING COMMITTEE TO BE
AWARE, WHAT HAPPENS IF WE CAN'T
FULLY EN ROLL THE TRIAL?
SO THEY MIGHT SAY, TELL US WHAT
YOU'RE DOING TO INCREASE
ENROLLMENT, SO MAY ADD A NEW
SITE OR THEY MAY DEVELOP
RELATIONSHIP WZ LOCAL PROVIDERS
OR SOMETHING, BUT AGAIN, IT'S
JUST A WAY TO REMIND THE
INVESTIGATORS FROM AN
INDEPENDENT EXTERNAL BODY HOW
THINGS ARE GOING.
AND I SHOULD HAVE MADE THAT
MORE CLEAR AT THE BEGINNING.
THE DATA MONITORING COMMITTEE
IS MADE UP OF INDIVIDUALS WHO
ARE INDEPENDENT FROM THE STUDY
GENERALLY INDEPENDENT FROM THE
PIs LOCAL INSTITUTION.
IF FOR EXAMPLE, LET'S SAY YOU
HAVE A DATA MONITORING
COMMITTEE AND YOU ADD A NEW
SITE AND THAT SITE P.I., WORKS
WITH THE HEAD OF DMC, THE CHAIR
MAY HAVE TO RECUSE HER OR
HIMSELF BUT IT'S INDEPENDENT IN
THE SENSE THAT THEY DON'T HAVE
ANY EXPECTATION THAT THEY'RE
DECISIONS ARE SOMEHOW
INFLUENCED BY OUTSIDE CONCERNS
OR BIAS.
SO THE DATA MONITORING
COMMITTEE ALSO HAS WHAT ARE
REFERRED TO AS IN THE END,
STOPPING RULES OR INTERIM
ANALYSIS, THE LAST.
SO ONE THING THAT YOU WANT TO
MAKE SURE IS TRUE IS THAT YOU
ARE NOT EXPOSING SUBJECTS TO
SOMETHING THAT IS OVERLY RISKY
OR WITHHOLDING SOMETHING OF
BENEFIT FROM A GROUP WHO COULD
BENEFIT.
SOLT, INTERIM ANALYSIS IS THE
DATA MONITORING COMMITTEE
RECEIVES DATA THAT IS SOMETIMES
BLINDED IN THE SENSE THAT IT
DOESN'T SAY THE NAME OF THE
DRUG A AND THE NAME OF THE DRUG
B, IT LITERALLY SAYS DRUG A
VERSUS B.
IT LOOKS LIKE THE NEW DRUG,
DRUG B OR SORRY, ONE OF THE
DRUGS, IS DOING MUCH BERT THAN
THE OTHER.
AND IN TERMS OF AN INTERIM
ANALYSIS, IT LOOKS LIKE IT'S
STATISTICALLY DOING BETTER THAN
THE A IN THIS CASE.
AND SO, THEY COULD DECIDE
ACCORDING TO THE INTERIM
ANALYSIS AND THE STOPPING RULES
THAT, WE HAVE A STATISTICALLY
SIGNIFICANT DIFFERENCE AT THIS
POINT EARLIER THAN WE THOUGHT
AND WE THINK THE TRIAL SHOULD
BE STOPPED AND THE INTERVENTION
UNBLINDED.
NOW WHEN YOU UNBLIND THEM, IT
COULD BE EITHER THAT PEOPLE
GETTING THE NEW DRUG ARE BETTER
OR THE PEOPLE GETTING THE OLD
DRUG ARE BETTER, YOU DON'T KNOW.
BUT YOU KNOW THAT SOMETHING IS
GOING ON AND IS THERES
STATISTICALLY SIGNIFICANT
DIFFERENCE.
AND SO THAT WOULD BE AN EXAMPLE
OF SHORTENING A TRIAL BECAUSE
IT'S DOING EVEN BETTER THAN YOU
IMAGINED.
AND IN THIS CASE, IT COULD BE
THAT IT'S THE NEW OR THE OLD
BUT IT'S A REASON TO STOP
BECAUSE WITHHOLDING THE
TREATMENT B PUTS THE
PARTICIPANTS IN A WORSE OFF
POSITION AND NOT GIVING THE B
TO THOSE WHO ARE GETTING A, YOU
KNOW, THEY SHOULD ALL NOW GET
THE INTERVENTION.
AND THE OTHER THING TO THINK
ABOUT IS THAT, BAD THINGS CAN
HAPPEN AS WELL.
SO STOPPING RULES ARE IN PLACE,
SOMETIMES STOPPING RULES REFER
TO LIKE, WE, NO MORE THAN ONE
DEATH ON THE, SO STOPPING RULES
ARE LAID OUT IN ADVANCE, THAT
SAY, IF THIS HAPPENS, WE ARE
GOING TO STOP THE TRIAL.
AND YOU MAY REOPEN THE TRIAL OR
STOP AND CLOSE THE TRIAL.
SO THAT'S ALL TO SAY THAT
ESPECIALLY FOR PHASE 3 TRIALS
AND SOMETIMES TRIALS THAT ARE
SORT OF HIGH PROFILE OR THERE
IS A CONCERN ABOUT SEVERE
ADVERSE AFFECTS, PHASE 22
STUDIES HAVE DATA COMMITTEES IN
ORDER TO MAKE SURE THAT THE
DATA IS COMING OUT IN A
REASONABLE TIMELY FASHION AND
THAT NOTHING ESPECIALLY, BAD OR
ESPECIALLY GOOD IS HAPPENING IN
ORDER TO STOP IT AS NEEDED.
SO, WITH THAT, I AM GOING TO
JUST REMIND YOU THAT GOOD STUDY
DESIGN IS KEY TO CONDUCT OF AN
ETHICAL STUDY.
AND WOULD BE HAPPY TO ANSWER
QUESTIONS.
LET ME SEE IF THERE ARE ANY OUT
IN THE VIDEO LAND.
LOOKS LIKE JONATHAN HAS A
QUESTION.
>> HI, THANKS HOLLY.
I HAD A QUESTION ABOUT
THRESHOLD OF CERTAINTY OR
UNCERTAINTY.
>> YES.
>> LET'S SAY THAT SCIENTIST
JUST WANT TO SEE IF A STUDY IS
REMRIKABLE.
SEEMS THEY HAVE A
CERTAIN--REPLICATABLE.
>> IT'S ABOUT THE FIRST TIME
YOU'RE DOING A STUDY.
>> IN TERMS OF REPLICATION,
REPLICATING IS GOOD, IT'S GOOD
TO REPLICATE THE FINDING AT
LEAST IN ONE MORE TRIAL, IT'S
REALLY THE EXCEPTION TO THE
RULE THAT ONE TRIAL CHANGES
CLINICAL PRACTICE.
WE CAN TALK ABOUT MORE EXAMPLES
OF THAT.
BUT OFTEN, IT'S THE CASE THAT
THIS GROUP IS DOING A TRIAL AND
THEY FIND THIS AND ANOTHER
GROUP IS DOING A TRIAL AND THEY
FIND THIS.
A GROUP OF PEOPLE LOOK AT THE
DATA AND SAY WE HAVE ENOUGH NOW
TO CHANGE CLINICAL PRACTICE.
THERE IS VALUE BUT A DIFFERENT
EXPECTATION OF UNCERTAINTY ONCE
YOU'VE DONE THE INITIAL TRIAL.
THE OTHER IMPORTANT THING IS,
I'M SURE YOU ALL KNOW, NOT
EVERY STUDY ESPECIALLY THOSE
WITH NEGATIVE RESULTS APPEAR IN
THE LITERATURE.
SO IT'S ANOTHER REASON WHY IT'S
REALLY IMPORTANT TO HAVE
NEGATIVE RESULTS IN THE
LITERACY, AND I DON'T MEAN BY
NEGATIVE BY BAD RESULTS.
WHAT I MEAN, LET'S SAY YOU TEST
A VERSUS B AND YOU FIND OUT
THEY'RE NO DIFFERENT.
WELL MABLE THE COMPANY THAT
SPONSORED YOU IS NOT INTERESTED
IN MOVING FORWARD.
MAYBE THE JOURNAL DOES NOT
CARE, YOU DIDN'T FIND ANYTHING,
YOU JUST FOUND THAT THEY'RE THE
SAME.
IF THAT DOES NOT GO INTO THE
LIT RA SEWER, AND SOMEBODY SAYS
HEY I WANT TO KNOW THIS
QUESTION THEY LOOK IT UP.
SOMETIME THAT COMMUNITY LEVEL
OF AGREEMENT HAS TO BE MORE
THAN JUST LOOKING AT THE
LITERATURE.
SOMETIMES THERE IS A STATE OF
-OF-THE-ART, NIH WILL SPONSOR
THINGS LIKE STATE-OF-THE-ART
TREATMENT FOR HELP SITES C SO
THEY GET THE EXPERTS IN THE
ROOM AND THEY DEVELOP SOMETHING
LIKE IS A RESEARCH AGENDA THAT
HAS TO INFLUENCE HOW THE FIELD
GOES FORWARD.
THAT'S A MORE COMMUNITY
ENGAGEMENT OF FINDING WHAT TO
DO NEXT.
BUT OFTEN IT'S REALIZED ON THE
LITERATURE.
DANIEL?
>> THIS IS SUPER INTERESTING.
MY QUESTION IS REGARDING THE
DATA MONITORING COMMITTEES.
>> YES.
>> SO FOR AN IRB THERE IS
CLINICIAN SCIENTIST, I'M
WONDERING FOR LIKE THE
MONITORING COMMUNITIES ARE
THOSE JUST COMPRISED OF PEOPLE
THAT ARE GOING TO BE INTERPRET
RAW DATA OR DO THEY HAVE
SCIENTIST LIKE IF IT'S A TRIAL
RELATED TO CANCER, IS IT GOING
TO BE MOSTLY ONCOLOGIST?
>> GREAT QUESTION.
AND I'M SORRY I DIDN'T MENTION
THIS EARLY, SO THANK YOU SO
MUCH FOR THE QUESTION.
SOL IN GENERAL, THEY ARE AS I
SAID EITHER ASSIGNED TO A TRIAL
OR ASSIGNED TO A SET OF RELATED
TRIALS.
AND SO THERE WILL ALWAYS BE
EXPERTS IN THAT FIELD ON THE
DATA MONITORING COMMITTEE OR
WHOEVER IS CREATING THE DATA
MONITORING COMMITTEE, WHETHER
IT'S THE STIRRING COMMITTEE FOR
A STUDY OR A UPON A SPONSOR IS
SAYING YOU MUST HAVE A DMC.
IN ADDITION TO THAT IN MY
EXPERIENCE, THERE IS ALWAYS A
BIO STATUS.
RIGHT, I KNOW ENOUGH BIOSTATS
TO GET ME TO HERE BUT YOU
REALLY NEED SOMEBODY WHO KNOWS
A LOT ABOUT BIOSTATISTICS WITH
SOME OF THESE STUDIES THAT ARE
COMPLICATED.
AND IN MY EXPERIENCE THERE IS
AN EMPHASIS--ON THE TABLE, THAT
IS NOT EVERY GROUP IS GOING TO
HAVE CONTENT EXPERTS OF
BIOSTATUS SND TICIAN BUT A LOT
OF THEM DO.
THE OTHER THING THAT IS TRUE
THERE IS USUALLY SOMEBODY WHO
IS IN THE BODY WHO IS A
BIOSTATUSSTICIAN AND HER OR HIS
JOB IS TO PREPARE A REPORT FOR
THE DATA MONITORING COMMITTEE.
AND PART OF THE COMMITTEE IS
GOING TO BE CLOSED WHICH MEANS
ONLY COMMITTEE MEMBERS ARE ON,
BECAUSE THEY'RE GOING TO BE
GIVEN DATA THAT IF THE P.I.
SAW, IT MAY BIAS THEIR CHOICE
OR PARTICIPANT.
SO THERE IS AN INSIDE MAN OR
WOMEN WHO IS PREPARING THAT
DATA AND THEY'RE AN EXPERT IN
THAT FIELD AND THEY WILL GIVE
BACK.
IN MY EXPERIENCE, AND I KNOW
DAVE HAS EXPERIENCE TOO,
THEY'RE RELATIVELY SMALL, THERE
ARE THREE OR FOUR CONTENT
NETWORKS.
IF THERE IS A NETWORK TRIAL,
THERE MAY BE A COUPLE MORE
BECAUSE YOU NEED MORE EXPERTISE
TO COVER THE WATER FRONT, AS IT
WHERE.
NOT ALL IRB HAS THE SPECIFIC
EXPERT SEES LIKE DATA
MONITORING COMMITTEE WOULD.
ANYMORE QUESTIONS?
I'M GOING TO CHECK AGAIN TO SEE
IF THERE IS ANY OTHER OUT IN
VIDEOLAND.
OKAY.
WELL AS A REMINDER FOLKS, IF
YOU DO HAVE QUESTIONS, YOU CAN
PLACE THEM IN THE DISCUSSION
BOARD UNDER SESSIONING 3
QUESTIONS.
OH, THERE ARE QUESTIONS, OH MY
GOSH.
LET'S SEE IF I CAN ANSWER ONE
MORE BEFORE WE TRANSITION TO
DAVE.
OKAY, GREAT.
SO COULD YOU GIVE, I'M GOING TO
SO MAXINE ASKED CAN YOU GIVE
EXAMPLE OF MOST RESENT STUDIES
FAIL IN PHASE 3 OR PHASE 4.
I'M TRYING TO UNDERSTAND WHY SO
MANY INTERVENTIONS DO WELL
THROUGH PHASE 2 AND THEN CRASH
AND BURN.
SO BASICALLY, ONE OF THE
REASONS WHY IT GOES DOWN FROM,
YOU KNOW, 100 TO IN PHASE 1
DOWN TO 70 IN PHASE 2 TO DOWN
TO 30ISH IN PHASE 3, IT'S TIME.
THEY'RE ABOUT SAFETY AND
BIOLOGICAL METABOLISM OR
LOOKING IN A PHASE 2 WHETHER OR
NOT THE PARTICULAR INTERVENTION
HAS AN AFFECT IN A PARTICULAR
TYPE OF TUMOR IN ONCOLOGY FOR
EXAMPLE, IT'S NOT UNTIL PHASE 2
TRIAL THAT YOU'RE NOW GIVING ME
INTERVENTION TO A LARGE GROUP
OF REGULAR OLD PEOPLE IN THE
SENSE THAT YOU KNOW, YOU'VE
ONLY EXPOSED RELATIVELY SMALL
BUZZ IN THE PHASE 1 AND PHASE 2
TRIALS.
SO IT'S IN THE PHASE 3 WHERE
YOU'RE DOING THE HEAD TO HEAD
TESTING OF COMPOUND A VERSUS
COMPOUND B OR PLACEBO VERSUS
COMPOUND A.
AND YOU'RE NOT GOING TO FIND
THAT THE NEW COMPOUND IS
AFFECTIVE.
YOU'RE DOING THE TRIAL IN ORDER
TO ANSWER THE QUESTION.
YOU ANSWER THE QUESTION, THE
QUESTION IS NO, IT DOESN'T MOVE
FORWARD TO MARKET.
NOW THERE COULD BE SOME OTHER
COMMERCIAL MARKET FORCE THAT'S
INFLUENCE WHETHER A PARTICULAR
INTERVENTION GOES TO PHASE OUT
TO MARKET.
IT COULD BE THAT THE DIFFERENCE
IS REALLY SMALL OR NOT LARGE
ENOUGH TO SAY, WE SHOULD
THEREFORE CHANGE PRACTICE.
BUT GENERALLY, IT'S BECAUSE THE
TRIAL, THE QUESTION IS ANSWERED
IS IT MORE AFFECTIVE AND THE
ANSWER IS NO.
BUT, WITH THAT, THANK YOU FOR
YOUR QUESTIONS AND I'LL ANSWER
THE OTHER TWO HERE ON LINE
LATER.
WITH THAT, I'M GOING TO
INTRODUCE DAVE WENDLER.
DAVE IS ALSO A MEMBER OF OUR
DEPARTMENT FACULTY.
HE CAME TO THE NIH BACK IN 1993
AS A POST DOCTORAL FELLOW.
DAVE HAS BEEN WITH THE
DEPARTMENT SINCE 1993 AND HAS A
WIDE RANGE OF INTEREST.
I'M GOING TO MENTION A COME AS
THEIR RELEVANT TO THE CLASS.
DECISION-MAKING SURROGATE AND
AS RELEVANT TO TODAY,
SYSTEMATIC EVALUATION OF RISK
AND POTENTIAL BENEFITS SO.
DAVE, I'M GOING TO HAND IT ON
TO YOU.
HERE IS YOUR CLICKER.
UNLESS YOU'RE GOING TO MOVE
AROUND.
>> I WOULD LIKE TO.
>> I'LL GIVE YOU THIS.
>> I CANNOT CONTROL MYSELF.
>> Reporter:.
WILL THEDER.
THANKS.
DOES THAT SOUND OKAY.
ARE WE OKAY TO GO?
GOOD MORNING.
I'M GOING TO TRY TO DO TWO
THINGS DURING THIS TALK, WHICH
I HOPE DON'T COME OUT AS
CONTRADICTORY.
SO THE TWO THINGS FIRST ARE TO
ARGUE THAT DOING RISK BENEFIT
ASSESSMENT IS CENTRAL TO THE
ETHICS OF CLINICAL RESEARCH.
BUT, IT'S NOT DONE VERY OFTEN,
IT'S NOT DONE SYSTEMATIC I
DON'T THINK IT'S DONE VERY WELL.
AND SO THE FIRST THING I WANT
TO DO IS JUST PRESENT A
FRAMEWORK FOR DOING SYSTEMATIC
ASSESSMENT OF RESEARCH RISK AND
THEN MAKE THE ARGUMENT THAT
IT'S IMPORTANT TO DO IT
SYSTEMATIC.
AND THIS IS ANTIDOTAL, BUT I'M
CONVINCED NOW, I'VE BEEN DOING
THIS FOR 30 YEARS, PEOPLE
AREN'T JUST DOING THIS AND
THEY'RE NOT DOING IT IN A
SYSTEMATIC WAY.
THAT'S THE FIRST PART.
SO FOR PEOPLE JUST CARE ABOUT
THE BASICS OF THIS, THAT
FRAMEWORK IS ENOUGH YOU CANNOT
PAY ATTENTION TO THE REST OF
THE TALK.
BUT THE SECOND PART OF THE
TALK, IS TO THINK SOME OF THE
DIFFERENT CHALLENGES,
COMPLEXITIES THAT ARISE WHEN
YOU START TO THINK ON HOW TO DO
RISK A BENEFITS.
I THINK THE BASICS ARE PRETTY
STRAIGHTFORWARD BUT ALSO A LOT
OF REALLY INTERESTING QUESTIONS
THAT ARISE ONCE YOU START
THINKING ABOUT THESE CAREFULLY.
AND THESE ARE QUESTIONS A LOT
OF HAVE NOT BEEN ADDRESSED.
SORRY, I'M GOING TO TRY TO NOT
BE UNPLEASANT DURING THIS TALK.
OKAY.
SO, PEOPLE NOW KNOW THE BELMONT
REPORT, BELMONT REPORT IS ONE
OF IF NOT THE FOUNDING DOCUMENT
OF RESEARCH ETHICS IN THE
UNITED STATES.
AND HERE'S SOME THINGS THAT
THEY HAVE TO SAY WITH RESPECT
TO RISK BENEFIT ASSESSMENT.
THEY SAY THINGS LIKE WE SHOULD
DO IT AS SYSTEMATIC AS WE CAN,
AS CLEARLY AS WE CAN.
I LIKE THIS LAST ONE, WHICH IS
NEVER DONE, IS THAT YOU
SHOULDN'T JUST DO IT BASED ON
INTUITION, BUT RISK BENEFIT
ASSESSMENT THEY'RE EMPIRICAL
QUESTIONS, IF I TAKE A A DRUG
WHAT ARE THE CHANCES IT'S GOING
TO HELP ME?
WHAT ARE THE CHANCES IT GTS
GOING TO HURT ME?
IN ORDER TO ADDRESS THEM, IT'S
VALUABLE TO HAVE AS MUCH AS THE
RELEVANT DATA AS YOU CAN.
BELMONT, EMPHASIZED THAT 50
YEARS AGO AND BASICALLY NOBODY
DOES IT.
SO ONE OF THE THINGS THAT WE'VE
BEEN TRYING TO ARGUE IS TRYING
TO CONVINCE PEOPLE OF THE VALUE
AND THE IMPORTANCE OF DOING
THAT.
SO I'M JUST GOING TO GIVE.
SO WHEN I GIVE TALKS, I USUALLY
GIVE TWO TANGENTS BUT WHAT I
REALIZE IF I PUT THEM ON THE
SLIDES, I'M SNEAKING INTO MORE
TANGENT.
THIS IS A PAPER, YOU CAN SEE WE
DID 20 YEARS AGO WHEN SEEMA WAS
A POST FELLOW.
AND THIS WAS A SURVEY OF
PERSONS WHO HAD WORKED IN
PEDIATRIC RESEARCH, REVIEWED
PEDIATRIC STUDIES AND WE GAVE
HEM A LIST LIKE A BLOOD DRAW, A
ALLERGY SKIN TESTING, BONE
MARROW, BY OP BIOPSY OR AND WE
ASKED.
WHEN YOU HEAR SEEMA'S WALK,
YOU'LL HEAR MORE.
THE FOC PUS ARE TWO THINGS, ONE
THAT RB CHAIRS SEEM TO BE VERY
CAUTIOUS.
THAT WAS THE FIRST THING.
THE SECOND THING WAS THAT THIS
WAS DISBURSAL, AND ALMOST A
THIRD THOUGHT IT WAS MORE THAN
A MINOR INCREASE OVER MINIMUM
RISK.
SO WHY ARE WE GETTING SO MUCH
DISBURSEION.
I THOUGHT IT WAS ESPECIALLY
INTERESTING, THESE WERE
INTERVIEWED.
WE CALLED UP 188IRB CHAIR
PERSONS AND GAVE THEM A LIST
AND TOLD ME, ARE THESE MINOR
INCREASE?
SO YOU MULTIPLY 188 TIMES 8 OR
9 WHATEVER THE HECK THAT TURNS
OUT TO BE, IT'S ALMOST 15,200
AND IN ONE CASE ZERO CASES DID
ANY OF THE CHAIRPERSON SAY, I
DON'T KNOW.
AND THAT WAS REALLY STRIKE,
BECAUSE A LOT OF THESE THINGS
THEY DIDN'T HAVE DATA ON AND
THEY SHOULD HAVE SAID, I DON'T
KNOW BECAUSE I CANNOT DO WHAT
BEAUMONT TELLS ME TO DO.
I CANNOT DO THIS SYSTEMATIC
BECAUSE I DON'T HAVE IT AND I
DON'T KNOW IT.
NOBODY DID THAT, SO WHAT'S
GOING ON?
I THINK WHAT PEOPLE ARE DOING
IS AND PART OF THE PROMISE AND
THIS IS MY PREVIOUS CAREER WITH
SPENCE STUDY BIOLOGY, AND I
THINK ONE OF THE THINGS WE DID
FROM EVOLUTION IS THAT THE
REASON WHY WE'RE HERE RIGHT
NOW, IS BECAUSE OUR PREDECESSOR
WERE PRETTY GOOD ASSESSORS OF
RISK AND THEY MADE THOSE
ASSESSMENTS, REALLY REALLY FAST.
SO YOU IMAGINE, TWO
POPULATIONS, THEIR SOUNDS IT
COULD BE A SABER TOOTH TIGER,
THEY STARTED DISCUSSING, COULD
THIS BE A SABER TOOTH TIGER.
THE OTHER GROUP RAN AWAY.
GUESS WHO SURVIVED AND
REPRODUCED?
THE SECOND ONE.
WE INHERENTED THIS RESPONSE
WHERE WE MAKE RISK ASSESSMENT
REALLY FAST.
THAT CAN BE VALUABLE IN SOME
CASES BUT IN OTHER CASES, IT
GIVES US TO STRAY ESPECIALLY IN
RESEARCH WHERE WE'RE DEALING
WITH UNFAMILIAR THINGS WHERE
THE THINGS WE RELY ON.
THAT'S IRB, JUST GIVE YOU ONE
ANOTHER EXAMPLE.
I STARTED TO DO THIS FOR A LONG
TIME SO PEOPLE SOMETIMES CALL
ME UP AND ASK CAN YOU TELL HELP
US DECIDE IF THAT'S HIGH-RISK
OR LOW RISK.
THESE ARE INVESTIGATORS WHO
STUDY METABOLISM, THEY OFTEN DO
GLUCOSE TOLERANCE TEST IS MORE
THAN MINIMUM RISK.
AND YOU HAVE TO HELP US
CONVINCE THEM WE'RE BECAUSE
CONFIDENT THAT THEY'RE MINIMUM
RISK.
AND I SAID GREAT, SO WHEN YOU
DO THESE TESTS.
YOU KNOW WHAT THE GUY SAID TO
ME?
WHAT ARE YOU TALKING ABOUT WHY
WITH WE PRESENT DATA THIS IS A
RENOWNED RESEARCHER WHO SPEND
HIS CAREER COLLECTING DATA BUT
WHEN IT COMES TO ETHICS, HE'S
LIKE WHAT DATA GOT TO DO WITH
THIS, THEY'RE JUST MINIMUM RISK.
SO NOBODY IS DOING THIS. AND
YOU NOTICE THAT PAPER, 30 YEARS
AFTER BELMONT, THIS EXAMPLE
ALMOST 45 YEARS AFTER BELMONT,
IT'S BEEN A LONG TIME AND
PEOPLE ARE STILL NOT DOING IT.
SO THAT'S THE GROUND AND WHY
FRAMEWORK AND THEN I'M GOING TO
PRESENT ONE.
DON'T GET TOO WORKED UP.
I'M GOING TO TALK ABOUT RISK
AND BENEFITS AND THEN PEOPLE
GET CONFUSED.
THESE ARE THE TERMS THAT
REGULATION USE.
AND THEN SAY THEY A RISK IS A
CHANCE OF A HARM IF I'M GOING
TO STICK A KID WITH A NEEDLE,
THAT'S GOING TO RISK.
--HURT.
THAT MUST BE A RISK THAT MUST
BE SOMETHING ELSE.
NOW THESE ARE TERMS ABOUT RISKS.
RISKS APPLY TO A THING THAT
WHERE YOU'RE NOT SURE THINGS
ARE GOING TO HAPPEN OR WHEN
YOU'RE SURE THAT BAD THINGS ARE
GOING TO HAPPEN.
AND BENEFIT IS ALSO POTENTIAL
BENEFIT, SPECULATIVE AND
CHANCES OF BENEFIT.
SO THINK ABOUT THESE TERMS VERY
BROADLY.
OKAY, SO HERE'S THE FRAMEWORK
THIS YOU'RE GOING TO GO THROUGH
AND WE'RE TALKING ABOUT OUR
WONDERFUL ALUMNS, THE FIRST
AUTHOR WAS POST DOCK FELLOW.
WHAT I'M GOING TO DO IS
BASICALLY GO THROUGH, AND
DESCRIBE HOW IT WORKS OR SHOULD
WORK AND AS I MENTIONED AT THE
TOP I'M ALSO GOING TO GO INTO
SOME OF THE MORE COMPLEXITIES.
OKAY, SO TO START, ONE THING TO
NOTICE IS THAT, BASICALLY EVERY
CLINICAL TRIAL IS A COMPOSITOR
AGGREGATE OF LOTS OF DIFFERENT
THINGS.
YOU BRING PEOPLE IN, YOU
MEASURE THEM, WEIGH THEM, YOU
TAKE BLOOD DRAWS AND GIVE THEM
A DRUG AND SCAN.
SO THERE IS A LOT OF COMPONENT
THAT MAKE UP A GIVEN STUDY.
SO THE POINT IS, WHY ARE YOU
DOING THE RISK ASSESSMENT ON IF
THERE IS A LOT OF DIFFERENT
COMPONENTS?
THE ANSWER IS, WHAT YOU SHOULD
DO IF YOU DO FIRST, ON THE
PERSPECTIVE OF IRB.
ASSESS EACH ONE OF THOSE AND
MAKE SURE THEY'RE ACCEPTABLE
AND THEN LOOK AT THE AGGREGATE
OR THE STUDY AS A WHOLE.
SO DO BOTH THE COMPONENT AND
STUDY AS A WHOLE.
NOW, NOT ONLY THE LOSS OF
INTERVENTION BUT OFTEN
DIFFERENT KINDS OF
INTERVENTIONS.
A LOT OF STUDIES WILL INCLUDE
CLINICAL AND RESEARCH
INTERVENTION SO THIS IS WHAT IS
CALLED ADD ON TRIAL WHERE YOU
GIVE EVERYBODY STANDARD OF CARE
AND FOR THE ONE ARM YOU ADD
SOMETHING ON TOP TO SEE IF THAT
IMPROVES STANDARD OF CARE.
SO FOR THE MOST PART, WHAT IRB,
THEY HAVE BE EVALUATE THE
RESEARCH NOT THE COMPONENT OF
CLINICAL CARE.
AND THIS A STATEMENT TO TRUKT
TO DO THAT FROM THE REGULATIONS.
THEY SHOULD BE LOOKING AT THE
RISKS AND BENEFIT FROM THE
RESEARCH AND DISTINGUISHED FROM
THINGS THAT THERAPY TO SAOUBT
EVEN IF THEY WEREN'T IN THE
RESEARCH.
SO THE THOUGHT HERE IS WHY DO
YOU DO THAT?
THE THOUGHT IS IF IT'S
CLINICALLY INDICATED THEN THE
PROVIAL OF THAT INTERVENTION IS
GOING TO BE ACCEPTABLE, THAT'S
WHAT IT MEANS ESSENTIALLY FOR
IT TO BE INDICATED.
SO FOR THE MOST PART, IRB DON'T
HAVE TO WORRY.
THE CAVEAT DURING CAVEATS IF WE
GO THROUGH THIS TALK.
HERE THE WORRY WHAT IRBs NEED
TO WORRY THAT THE ADD ON IN THE
RIGHT ARM OF THE STUDY THAT MAY
INFLUENCE THE STANDARD OF CARE.
IT MIGHT MAKE IT FOR RISKY.
SO YOU CAN'T COMPLETELY BRAK IT
OFF, THE CLINICAL INTERVENTION,
YOU HAVE TO THINK ABOUT IF
THERE ARE ANY INTERACTIONS
BETWEEN THE RESEARCH AND
CLINICAL INTERVENTIONS.
SO HERE'S THE FRAMEWORK, FIRST
STEP IS THAT, REMEMBER YOU'VE
GOT.
THIS IS THE STICK FOR THE
DEPARTMENT.
CLINICAL RESEARCH IS NOT
ACCEPTABLE UNLESS IT'S SOCIALLY
VALUABLE.
YOU FIRST MAKE SURE THAT FOR
EACH OF THE RESEARCH
INTERVENTIONS THAT THERE IS A
SOCIAL VALUABLE REASON WHY IS
THAT INTERVENTION IN A STUDY?
SO YOU ASK THE INVESTIGATE
--INVESTIGATOR, WHAT ARE YOU
GOING TO LEARN FROM THE THIRD
MRI THAT YOU COULDN'T LEARN
FROM THE SECOND AND YOU WANT A
GOOD EXPLANATION FOR THAT.
ONE OF THE THINGS THAT I'M
GOING TO EMPHASIZE IS I SIT ON
IRBs WHEN I TALK TO PEOPLE IN
THE IRB, I TALK ABOUT HOW
IMPORTANT THIS IS IN PRACTICE
AND I RAT ABOUT THIS.
AND WHEN THE IRB SAID, OKAY
TELL US WHETHER THE RISKS OR
BENEFIT OF THIS STUDY ARE
ACCEPTABLE?
AND MY ANSWER IS ALMOST ALWAYS,
I HAVE ABSOLUTELY NO IDEA.
BECAUSE TO MAKE THESE
ASSESSMENT WHETHER OR NOT YOU
NEED THE THIRD MRI, WHETHER
TESTING THIS NEW TREATMENT FOR
LEUKEMIA, BEING ABLE TO MAKE
THOSE JUDGMENTS, HAVE YOU TO
KNOW A LOT YOU HAVE TO KNOW A
LOT OF STUFF THAT I JUST DON'T
KNOW FOR INSTANCE LEUKEMIA.
SO WHENEVER YOU NEED THESE, YOU
REALLY NEED PEOPLE WHO HAVE
CONTENT EXPERTISE TO MAKE THESE
JUDGMENTS.
YOU CAN RELY ON PHILOSOPHER FOR
THE FRAMEWORK BUT YOU CANNOT
RELY ON PHILOSOPHER TO DO THE
WORK.
YOU PUT THEM ALTOGETHER AS THE
PACKAGE THAT THEY ARE AND YOU
EVALUATE THE OVERALL STUDY TO
SEE IF IT HAS SOCIAL VALUE.
TYPICALLY, PEOPLE WILL POINT
OUT, YOU HOPE TO GATHER
IMPORTANT DATA FROM EVERY TRIAL
BUT PRESUMABLY AT LEAST IT'S
RARE THAT ANY TRIAL IS GOING TO
GIVE YOU DEFINITIVE DATA
USUALLY YOU HAVE TO COMPARE
DATA FROM OTHER TRIALS AND
AGAIN THIS REQUIRES A LOT OF
EXPERTISE.
OKAY, SO LET'S JUST TALK ABOUT
SOME OF THE CHALLENGES AT THIS
STEP.
SO ONE OF THE THINGS THAT I
THINK IS ALWAYS INTERESTING.
AND MY EXPERIENCE IN BEING IRBs
FOR 20 YEARS, THE ANSWER DIFFER
TO THIS QUESTION.
IMAGINE THAT THE INVESTIGATOR,
SUBMITS A PROTOCOL TO YOU.
THAT'S HOW THE IRBs WOFRJT
WHAT'S THE JOB OF THE IRB?
IS THE JOB JUST TO LOOK AT THAT?
STUDY THAT GOT SUBMITTED TO
THEM AND SEE WHETHER OR NOT
THAT STUDY IS ETHICALLY
APPROPRIATE OR SHOULD SOMEBODY
DO, WELL YOU WANT TO DO X WITH
THIS POPULATION BUT HERE'S THE
OTHER THING THAT WOULD BE MORE
VALUABLE, THAT WOULD BE MORE
INTERESTING, THAT WOULD GIVE US
MORE VALUABLE DATA?
IS IT THE JOB OF THE IRB OR
SOMEBODY ELSE TO MAKE SHE'S
COMPARATIVE JUDGMENT ACROSS
STUDIES TO THIS STUDY RATHER
THAN THAT STUDY?
THAT AT LEAST THE IRBs I SAT
ON, ALMOST NEVER DO MAYBE THEY
SHOULD BE DOING IT OR SOMEBODY
SHOULD BE DOING IT.
AND THE OTHER IS COMPARATIVE
WITHIN A TRIAL, WELL YOU JUST
DESIGNED IT WITH JUST TWO MRIs
BUT IF YOU ADD THIRD MRI, IT
WOULD MAKE YOUR TRIAL MORE
VALUABLE.
I THINK THE STUDY PROPOSED IS
OKAY, BUT HERE'S A MUCH BETTER
STUDY.
SHOULD YOU SAY THEN TO THE VERG
YOU CANNOT DO THIS BECAUSE YOU
CANNOT DO THIS BETTER ONE.
OR DOES IT HAVE TO MEET
SUFFICIENT STANDARD.
AND THE QUESTION AS YOU GO
THROUGH ABOUT WHO SHOULD MAKE
THE JUDGMENTS.
WE CAN TALK ABOUT ENHANCEMENTS
SO THIS ANNETTE AND I USED TO
HAVE THIS DEBATE WHEN WE WROTE
THAT PAPER.
SO TYPICALLY, MOST FOCUS ON
DISEASES AND ILLNESSES LIKE
CANCERS AND THINGS LIKE THAT.
BUT WHAT ABOUT TRIALS TO DO
WHAT PEOPLE CALL ENHANCEMENTS
WHICH IS NOT TO TREAT AN
ILLNESS OR DISEASE BUT TO MAKE
PEOPLE WHO ARE HEALTHY EVEN
BETTER OFF, TO MAKE THEM LIVE
LONGER?
IS THAT IS EQUALLY VALUABLE AS
DOING SOMETHING LIKE TREATING
CANCER?
AND AGAIN, SHOULD PEOPLE BE
MAKING THOSE ASSESSMENTS AND IF
SO WHO SHOULD BE MAKING THEM?
SO THIS IS JUST SOME
SUGGESTIONS.
I WHAT I GIVE THAT PREVIOUS
SLIDE, I GET A LOT OF PUSH BACK
FROM IRBs FOLKS, THAT'S WHAT
YOU HAVE BEEN DOING.
SO I TRIED TO COLLECT SOME
EVIDENCE TO SUGGEST IN SOME
CASES I THINK IRBs SHOULD BE
DOING THAT AND THESE ARE CASES,
NOW INTERESTINGLY THEY'RE FROM
PANDEMICS OR EPIDEMICS SO THE
FIRST ONE WAS IN WEST AFRICA
DURING EBOLA, WHERE THE PROBLEM
WAS THERE IS ONLY SO MANY
PATIENTS.
AND ALL OF A SUDDEN, YOU'VE GOT
ALL OF THIS MONEY AND RESOURCES
GOING INTO THE AREA TO STUDY
EBOLA.
AND WHAT THESE GUYS POINT WAS,
IS THAT THERE IS A LIMITED
AMOUNT OF PATIENTS FOR ALL THE
STUDIES THAT WE WANT TO DO.
SO IF WE WANT TO GET THE MOST
SOCIAL VALUE OUT OF THIS
SITUATION WE'RE GOING TO NEED
TO PRIORITIZE WHICH OF THE
STUDIES WE ALLOW TO ACCESS
THESE PATIENTS AND WHICH ONES
WE DON'T AND THEN A SIMILAR
THING, THIS IS ARGUMENTS MORE
RECENTLY DURING COVID WHERE
THERE IS ARGUMENTS EARLY IN THE
PANDEMIC, WE WANTED LEARN AS
MUCH AS WE COULD ABOUT COULD
VID, AT LEAST INITIALLY IN THE
LONG RUN THERE WERE LOTS AND
LOTS OF PATIENT BUT INITIALLY
THERE WEREN'T THAT MANY.
THESE, THIS GROUP ARGUED THAT
WITHIN INSTITUTIONS, SO FOR
INSTANCE THE NIH CLINICAL
CENTER SHOULD BE PRIORITIZING,
JOHN HOPKINS, SO THAT'S
POTENTIAL BENEFIT SOCIAL VALUE.
SO THE NEXT THING TO LOOK AT IS
THE RISKS.
SO THE IDEA IS TO IDENTIFY THE
RISK OF EACH OF THE
INDIVIDUALS INTERVENTIONS AND
TRY TO REDUCE THEM TO THE
EXTENT THAT YOU CAN.
NOW I'LL COME BACK TO THIS IN A
SECOND.
ONE THING THAT EVERYBODY AGREES
IN THIS STEP IS YOU SHOULD LOOK
AT ALL THE RISKS THAT I VERY
VERY BROADWAY.
SO OBVIOUSLY THAT MEANS HEALTH
RISKS, LIKE IS THIS DRUG GOING
TO KNOCK OUT MY KIDNEYS AND I'M
GOING TO BE ON DIALYSIS THE
REST OF MY LIFE.
FOR INSTANCE, ECONOMIC RISKS.
WHAT IF KNOCKING OUT MY KIDNEYS
I HAVE A COPAYMENT OF 1,000 AND
I'M GOING TO PAY THOUSANDS TO
GET THAT KIDNEY PROBLEM FIXED,
HOW ABOUT PSYCHOLOGICAL HARMS
OF BEING ON DIALYSIS, NOW I'M
DIALYSIS AND THERE IS A STIGMA.
I'M GOING TO TALK ABOUT
POTENTIAL BENEFITS.
IT SEEMS RIGHT, PEOPLE CARE
MORE THAN THEIR BODIES, THEY
CARE ABOUT THEIR BANK ACCOUNTS,
SOME CARE MORE ABOUT THEIR BANK
ACCOUNTS THAN THAT ARE BODIES
SO WE SHOULD BE WORRIED ABOUT
ALL TYPES OF RISKS.
SO THERE IS A COUPLE OF
CHALLENGES WITH THIS, AND THE
BASIC IDEA IS WHAT THIS STEP
SAYS, IS IN ORDER TO DECIDE
WHETHER A STUDY IS ACCEPTABLE
BEFORE IT CAN BEGIN, THE IRB
HAS TO MAKE SURE THAT THE RISKS
ARE ACCEPTABLE.
OBVIOUSLY CONUNDRUM IS THAT IS
THE POINT OF CLINICAL TRIALS,
AT LEAST EARLY PHASES TRIALS
ARE DESIGNED TO FIGURE OUT WHAT
THE RISKS OF A GIVEN
INTERVENTION ARE.
SO THE GOAL OF THE TRIAL IS TO
FIND OUT WHAT THE RISKS ARE HOW
ARE YOU EVALUATE WHETHER THOSE
RISKS ARE ACCEPTABLE.
IT SEEMS LIKE YOU'VE GOT TO DO
THE TRIAL BEFORE YOU DECIDE
WHETHER THE TRIAL IS ETHICAL TO
DO.
SO IN THIS, THEY NEED TO BE
CREATIVE, THEY NEED TO EXPAND
BEYOND THE GIVEN INTERVENTION
IF THERE IS NO DATA.
SOMETIMES THERE IS, SOMETIMES
THIS INTERVENTION HAS BEEN USED
BEFORE IN OTHER POPULATIONS SEE
HOW YOU CAN EXTRAPOLATE TO THIS
POPULATION.
SOMETIMES THIS SPECIFIC DRUG
HAS NOT BEEN GIVEN TO THIS
POPULATION BUT DRUGS OF THE
SAME CLASS HAS BEEN GIVEN AND
YOU TRY TO EXTRAPOLATE FROM
THAT DATA AND MAYBE THERE IS A
MECHANISM.
SO BASICALLY, THEY'RE TRYING TO
MAKE ARGUMENT FOR SIMILAR AND
SEEING HOW YOU CAN APPLY THEM
TO THIS ONE.
WITH THE THOUGHT THAT THE
FURTHER YOU'RE EXTRAPOLATING,
THE GREATER THE UNCERTAINTY AND
THEN YOU SHOULD FACTOR INTO THE
RISK ASSESSMENT WITH A THOUGHT
THAT THE MORE UNCERTAIN YOU ARE
THE RISKIER THE INTERVENTION OR
STUDY IS.
SO HERE'S ANOTHER CHALLENGE.
THE FIRST ONE WAS YOU'VE FWOT
TO KNOW SOMETHING ABOUT THE
INTERVENTION.
HERE THE POINT IS, YOU HAVE TO
KNOW WHO THE INTERVENTION IS
GOING TO BE PUT INTO?
SO THE RISK OF A CERTAIN DRUG
CAN VERY DRAMATICALLY DEPENDING
ON WHO IS GOING TO RECEIVE IT
BUT YOU DON'T KNOW WHO IS GOING
TO RECEIVE IT UNTIL THE TRIAL
STARTS.
SO THE EXAMPLE I HAVE HERE, IS
DRUGS THAT ARE CLEARED BY THE
KIDNEYS, THEY MAY BE VERY SAFE
FOR PEOPLE THAT HAVE GOOD
KIDNEY FUNCTION.
BUT THEY MAY BE VERY DANGEROUS
THE DRUG MAY BE BUILDUP IN THE
PEOPLE THAT ARE KIDNEY FUNCTION.
THE OTHER IS TO EXTENT OF RISK
AND BENEFITS DEPEND ON WHO EN
ROLLS IN THE STUDY.
SO THE WAY IRBs TRY TO HANDLE
THIS IS WITH EXCLUSION AND
INCLUSION, YOU TRY TO FIGURE
OUT WHO IS GOING TO PHASE
EXCESSIVE RISKS AND THEN YOU
TRY TO EXCLUDE THEM.
THE OTHER THING THAT I
MENTIONED HERE, IS THE
IMPORTANCE, SOMETIMES YOU JUST
DON'T KNOW HOW GIVEN DRUG IS
GOING TO AFFECT PEOPLE.
SO THERE IS IMPORTANCE OF
MONITORING THE TRIAL AS YOU GO
ALONG AND THIS GOES BACK TO
HOLLY'S TALK IF YOU START TO
MONITORING IN THE THIRD OR
FOURTH PARTICIPANT, YOU START
TO SEE A TREND OF SIGNIFICANT
HARM, YOU NEED TO STOP THE
STUDY AND REEVALUATE AND SEE
WHETHER OR NOT IT'S OKAY TO
KEEP GOING.
OKAY, SO LET'S GET INTO MORE OF
THE WEEDS.
I ADDED THIS ONE YESTERDAY TO
MAKE SURE I REALLY DRIVE YOU
GUYS NUTS.
SO WHEN I TALK ABOUT RISK, I'VE
BEEN TALKING ABOUT THE RISKS TO
THE INDIVIDUAL WHO ARE IN THE
STUDY.
AND THAT'S THE RISK ASSESSMENT
IN CLINICAL RESEARCH IS DONE.
MORE RECENTLY PEOPLE START
TODAY WORRY ABOUT THE RISK THAT
ARE CALLED THIRD PARTIES SO.
HERE'S AN OBVIOUS EXAMPLE.
CHALLENGE TRIALS ARE TRIALS
WHERE YOU TAKE AN INFECTIOUS
AGENT LIKE A VIRUS AND INJECT
IT INTO A COUPLE OF RESEARCH
PARTICIPANT AND SEE WHAT
HAPPENS.
MAYBE YOU'RE GOING TO TEST
DIFFERENT TREATMENT OR THE
NATURAL HISTORY OF DISORDER.
SO OBVIOUSLY INJECTING VIRUSES
POSES RISK TO THEM, THAT'S WHAT
WE'VE BEEN TALKING ABOUT.
BUT THE POINT HERE, IS THAT CAN
POSE RISK TO OTHER PEOPLE IF
YOU'RE IN RESPECTING THE
PARTICIPANT AND THE PARTICIPANT
WORK WITH THE NURSE SXZ THEY GO
ON WEEKEND PASSES, THE
PARTICIPANTS GO HOME, THEY
COULD TRANSMIT THAT INFECTION
TO LOTS OF OTHER PEOPLE.
SO WHAT DO YOU THINK?
THAT MEANS, I WILL NOT FORCE
PEOPLE TO THINK.
THAT SEEMS LIKE WE SHOULD TAKE
THAT INTO ACCOUNT?
DON'T YOU AGREE?
SO YOU SHOULD TAKE THIRD PARTY
RISKS INTO ACCOUNT?
SO THESE ARE SOME REAL EXAMPLES.
WE DID AN ETHICS GROUNDS ON
THIS, ABOUT TEN YEARS AGO.
WHERE WHERE THERE WAS A
PARTICIPANT WHO WAS A PERFECT
CANDIDATE FOR THE STUDY AND
THEY OFFERED A CHANCE OF
PARTICIPANT.
AND THE PARTICIPANT COULDN'T
LEAVE PEOPLE BEHIND.
SO WITH THE POTENTIAL
PARTICIPANT WAS GOING TO DO WAS
GOING TO DRIVE FROM THE WEST TO
BATHESTA WITH THOSE TWO PEOPLE
IN THE CAR.
AND THE HOME PHYSICIAN WAS
REALLY WORRIED THAT THAT DRIVE
COULD BE DANGEROUS TO THE OTHER
TWO PEOPLE.
NOT THE PARTICIPANT BUT TO THE
OTHER TWO PEOPLE.
ANOTHER EXAMPLE WE JUST HEARD
IN A RESENT ETHIC GROUNDS WAS,
PARTICIPANT WHO WAS UNDERGOING
PULMONARY TRANSPLANT, THAT
REQUIRED THEM TO STAY HERE FOR
ABOUT 3 MONTHS T.TURNS OUT THEY
HAD KIDS THAT WERE VERY
ATTACHED AND PEOPLE WERE
WORRIED THAT THE PARTICIPANT
BEING AWAY FROM THE THREE KIDS
FOR THREE MONTHS WOULD BE
TRAUMATIC FOR THE KIDS THAT HAD
TO BE WATCHED BY THE
GRANDPARENTS.
IT TURNS OUT IN THAT CASE, THEY
DID COME AND PARTICIPATED AND
IT WAS REALLY TRAUMATIC FOR THE
TWO LITTLE KIDS.
AND THIS IS A COUPLE OF YEARS
LATER EXAMINE THE KIDS ARE
STILL EXPERIENCING THE AFFECTS
OF IT.
SO IN THE SECOND POOL, WE SAY
OF COURSE YOU SHOULD TAKE
ACCOUNT OF THIRD PARTY'S.
IF YOU HAVE TO DRIVE MORE THAN
50 MILES TO GET HERE, YOU CAN'T
BE IN OUR TRIAL?
THEN WE HAVE TO GET ALL OF THIS
INFORMATION ABOUT HOW MANY KIDS
THEY HAVE AND WHETHER THEY FLY
OR DRIVE.
NOT ONLY IS THAT INTRUSIVE BUT
IT BECOMES TO BE TOO MUCH.
SO I THINK THIS IS A REALLY
CHALLENGE BOTH IT SEEMS LIKE
SOMETHING WE SHOULD BE DOING ON
THE ONE HAND BUT THEN WHEN YOU
GENERALIZE THE PRINCIPAL IT
SEEMS IMPOSSIBLE TO DO.
AND I HAVE NO IDEA WHAT THE
ANSWER TO THIS PUZZLE IS AND IF
ANYBODY KNOWS THIS, I WOULD BE
INTERESTED TO HEAR DURING THE
QUESTION AND ANSWER.
OKAY, NOW THE A LITTLE BIT OF
IF PHILOSOPHY OF SCIENCE, THAT
GETS YOU TO THINK A LITTLE BIT.
SO WE'VE BEEN TALKING ABOUT
RISK AND INTERVENTIONS LIKE
GIVING SOMEBODY A DRUG.
RIGHT YOU INJECT SOMEBODY WITH
A DRUG.
WHAT ARE THE RISK?
WELL IT'S THE POTENTIAL THAT
HARMS ARE GOING TO BE
EXPERIENCED AS A RESULT OF THAT.
THAT SEEMS PRETTY EASY TO
IMAGINE.
WHAT IS IMPORTANT TO NOTICE
THOUGH, IN SOME CASES IT
DOESN'T MATTER, IT'S IMMATERIAL
POLICITY BUT IN SOME CASES IT'S
REALLY IMPORTANT THAT WHENEVER
WE DO RISK MANAGEMENT
ASSESSMENT, WE'RE APPEALING TO
SOME BASE LINE OR COMPARISON
WHERE WE'RE MAKE THE JUDGMENT.
SO HERE'S AN EXAMPLE.
DOES A PHASE 2 OF A TREATMENT
THAT HAS BEEN SHOWN SAFE, IT
OFFERS A SMALL CHANCE TO THEY
HAVE A SERIOUS ILLNESS AND
THERE IS A SMALL CHANCE THAT
THIS WILL HELP THEM.
SO IT'S SUPPOSE TO BE A TRICK
QUESTION, ANYBODY WANT TO TAKE
A SHOT AND ADDRESS THE CLICK OR
SHOULD I CLICK TO THE NEXT
SLIDE.
IT DEPENDS, SO IT DEPENDS ON
WHAT?
IT DEPENDS ON WHAT IS GOING TO
HAPPEN TO THESE PEOPLE IF THEY
DON'T EN ROLL IN MY TRIAL.
OUTSIDE OF MY TRIAL, THEY WOULD
NOT GET ANYTHING THEY WOULD
JUST SIT AT HOME AND WATCH TV
THEN BEING IN THE TRIAL IS
BENEFICIAL FOR THEM BECAUSE
THERE IS A SMALL CHANCE OF
BENEFIT.
A SMALL CHANCE OF BENEFIT IS
BETTER THAN NO CHANCE.
SO OVERALL, THE COMPARISON IS
POTENTIAL BENEFIT.
BUT IN CONTRAST, IMAGINE THERE
IS A DRUG THAT CURES THIS
DISEASE, YOU TAKE IT ONCE AND
IT CURES YOU.
IF THE CHOICE IS BETWEEN TAKE
ITING THE DRUG AND BEING ON MY
TRIAL, IT LOOKS REALLY RISKY.
BEING IN MY TRIAL BEN BEING
CURED.
IS THIS, WHAT THE COMPARISON
IS, OR WHAT IS AVAILABLE TO
PEOPLE OTHERWISE, THERE IS
DRAMATICALLY, VARIES DRAUM YOU
CANLY IN THE U.S. AND ACROSS
THE WORLD.
SO WHAT THAT MEANS IN THE END
IS WHETHER A STUDY IS
BENEFICIAL OR RISKY, IS GOING
TO DEPEND ON WHERE YOU DO IT.
IF YOU DO IT IN CERTAIN
POPULATIONS, IT MAY BE
BENEFICIAL, IT MAY BE RISKY.
THAT'S CLICK ATED --COMPLICATED
AND IT DRIVES PEOPLE NUTS.
SO IT'S IMPORTANT TO KNOW IF
THESE PEOPLE WEREN'T IN OUR
TRIAL WHAT WOULD HAPPEN TO THEM
INSTEAD AND HOW DOES WHAT WE'RE
PROPOSE TO GO DO WITH THEM IN
THE TRIAL COMPARED TO WHAT WHAT
HAPPEN TO THEM INSTEAD?
AND THE TRIAL MAY BE RISKY IN
SOME PLACES BUT BENEFICIAL IN
OTHERS.
IS THERE GOING TO BE A SESSION,
INTERNATIONAL, SO SOMEBODY IS
PROBABLY GOING TO TALK ABOUT
THIS.
THIS IS A BIG DEAL ESPECIALLY
WHEN YOU TALK ABOUT RESEARCH IN
INTERNATIONAL SETTINGS AND THIS
THIS WAS A BIG DEAL IN H.I.
V.STUDIES ABOUT 30 YEARS AGO
THAT TURNED INTO BIG FIGHTS.
WHICH STILL IS TRUE, NOT AS
MUCH AS IT USED TO BE.
20-30 YEARS AGO IF YOU LIVED IN
CERTAIN PLACES, THERE WERE VERY
VERY GOOD TREATMENTS FOR H.I.V.
IN OTHER PARTS OF THE WORLD
WHERE THERE WAS A LOT OF
H.I.V., THOSE TREATMENTS WERE
NOT AVAILABLE.
SO NOW IMAGINE YOU HAVE THIS
IDEA OF SUPER CHEAP DRUG THAT
IS NOT AS GOOD AS THE FANCY
ONES YOU CAN GET IN MARYLAND
BUT BETTER THAN NOTHING.
NOW, NOTICE IF YOU RAN THAT
TRIAL IN MARYLAND IT'S GOING TO
BE LIKE THE EXAMPLE THAT WE
GAVE BEFORE WHERE THERE IS A
CHANCE OF A CURE BEFORE, BUT
LIKE A REALLY GOOD TREATMENT.
WHERE IT LOOKS LIKE A RISKY AND
MAYBE UNETHICAL STUDY.
BUT IF YOU DO IT IN AFRICA
WHERE THEY DON'T HAVE ACCESS TO
THOSE TREATMENTS.
IT LOOKS LIKE THIS IS
BENEFICIAL.
BUT NOW WHAT YOU'RE SAYING IS
THAT A TRIAL THAT UNETHICAL TO
DO HERE BECAUSE THE RISK IS
GOOD TO DO IN AFRICA.
AND THAT MADE PEOPLE REALLY
NERVOUS TO SAY THAT AND SOME
PEOPLE THOUGHT THAT THEY MUST
BE WRONG SOMEHOW AND WE HAVE TO
FIGURE OUT AND THERE WERE SOME
HUGE FIGHTS ABOUT THIS.
THE IMPORTANT POINT IS THE
COMPARISON, CAN HAVE REALLY
PRACTICAL IMPLICATIONS FOR SOME
OF THESE TRIALS.
OKAY.
THERE IS END OF PHILOSOPHY FOR
A SECOND.
SO NOW WE'VE IDENTIFIED THE
INTERVENTION INTERVENTIONS.
I JUST DO THIS BECAUSE THIS IS
PERSONAL TRAUMA FOR ME, I STILL
GET FREAKED OUT BY BLOOD DRAWS
I HAD AN INCREDIBLY HARD TIME
WHEN I WAS A LITTLE KID, I
STILL DO ACTUALLY.
AND THEN I'VE GOTTEN DOZEN OF
BLOOD DRAWS AND THEN A NURSE
SAYS TO ME LOOK OUT THE WINDOW.
AND I LOOKED OUT THE WINDOW AND
SHE DID IT AND I SAID ARE YOU
GOING TO DO IT AND IT SHE SAYS,
WE'RE DONE.
IT'S NOT THE SENSATION, IT'S
SEEING THIS THING GOING INTO
YOUR BODY AND IT JUST WENT AWAY.
WE KNOW PEOPLE WHO KNOW WHAT
THEY'RE DOING AND PEOPLE TO BE
CREATIVE IN HOW THEY'RE DOING
THIS STUFF.
I KNOW THAT PEOPLE JIGGLING OF
THE CHEEK, MY DENTIST, SORRY
THESE ARE ANY TANGENTS, IF I'M
LATE, I'M SORRY.
NERVE PATHS SO IF YOU STICK
SOMEBODY DOWN HERE, THE REASON
WHY IT HITSER, ALL OF THESE
NERVE PATHWAY AND YOUR BRAIN
DOES SOME COMPLICATED THINGS
AND IT SAYS OUCH.
WELL, THESE PATHWAY COMES
TOGETHER AT VARIOUS POINTS.
THEY CAN'T TRANSMIT MORE THAN
ONE SIGNAL.
AND SOME OF THOSE NERVE
PATHWAYS PRIOR SIZE SORT OF
DULL POUNDING SENSATIONS OVER
SHARP STICKY ONES.
MY DENTIST USED TO DO, WHEN MY
DENTIST WAS STICKING THAT BIG
NEEDLE IN MY CHEEK, WHAT YOU DO
IS JIGGLE MY CHEEK AND THAT
DULL SENSATION WILL GET
PRIORITIZED AND I WOULD NOT
FEEL THE GETTING STUCK.
I THINK I WAS 40 BEFORE
SOMEBODY DID THAT TO ME, AND I
THOUGHT PEOPLE SHOULD BE DOING
THIS MORE OFTEN.
OKAY, SECOND POINT IS SOMETIMES
YOU MINUTE EYES RISK IS DO
LESS, DO FEWER BLOOD DRAW AND
FEWER MRIs BUT IT CAN UNDERMINE
THE SOCIAL VALUE WHERE WE HAVE
TO BALANCE.
THE FAIRNESS ISSUE IS ALSO THIS
IS ONE THAT WE'VE HAD HUGE
DEBATE IN OUR DEPARTMENTS OVER
YEARS.
HERE'S ANOTHER WAYS TO
AGGREGATE, EX CLUE ANYBODY WHO
FACES REALLY HIGH-RISK FROM IT.
IF YOU DO THAT, YOU'RE GOING TO
MINIMIZE THED AGGREGATE RISK
BUT AT THE SAME TIME, THE STUDY
HAS A CHANCE FOR BENEFIT.
AND SOME PEOPLE, ORGANIZE THAT
THAT'S UNFAIR.
OKAY.
SO HERE'S SOME EXAMPLES.
EXPERIMENTAL DRUG FOR SERIOUS
CONDITIONS WITH VERY FEW
AFFECTIVE OPTIONS.
THIS IS A CONSULT WE HAD A
COUPLE OF YEARS AGO.
SIGNIFICANT BLEEDING THAT
REQUIRES TRANSFUSION.
SO THE INVESTIGATOR COMES TO US
AND SAYS, I THINK THIS IS
REALLY IMPORTANT TRIAL, THIS IS
REALLY IMPORTANT DRUG TO TEST
BUT I'M TERRIFIED THAT I'M
GOING TO KILL SOME OF MY
PARTICIPANT BECAUSE OF BLEEDING.
AND WHAT I WANT TO DO IS
EXCLUDE ANYBODY WHO FACE A
HIGH-RISK OF BLEEDING.
WHO IS THAT?
PEOPLE WHO BLEEDING DISORDERS,
PEOPLE WHO HAVE LOW PLATELETS
FOR WHATEVER REASON.
AND SOME FOR RELIGIOUS REASONS?
SO YOU SHOULD EXCLUDE ALL OF
THESE PEOPLE.
IS THAT FAIR?
THESE ARE THE KIND OF REALLY
IMPORTANT DEBATES AND QUESTIONS
THAT ARISE WHEN WE START TO
THINK ABOUT RISK BENEFIT
ASSESSMENT WITH OTHER VALUES
LIKE FAIRNESS.
SO POTENTIAL BENEFITS SO.
SOCIAL VALUE, AND NOW RISK AND
NOW POTENTIAL BENEFITS OF THE
INTERVENTION.
AND AS WITH RISK, WE LOOK TEPPO
TENSION BENEFITS ABOVE AND
BEYOND WHAT PEOPLE WOULD GET IF
THEY WERE OUTSIDE OF THE TRIAL.
SO NOW, I WANT TO COME BACK TO
THE POINT, I WAS HARPING ON
EARLIER REMEMBER WHEN I TALKED
ABOUT FINANCIAL RISKS,
PSYCHOLOGICAL RISK, STIGMA
RISKS.
AND WE SAID, YOU COUNT ALL OF
THEM, IT'S OBVIOUS THAT YOU
SHOULD COUNT ALL OF THEM.
SO HERE'S THE QUESTION, DOES
THE POINT APPLY TO POTENTIAL
BENEFITS?
SHOULD YOU INCLUDE NOT JUST THE
POTENTIAL BENEFITS OF
CLINICALLY GETTING BETTER BUT
BENEFITS OF OTHER SORTS OF
THINGS THAT CAN HAPPEN TO YOU.
SO BEFORE WE TALK ABOUT
ECONOMIC RISK, IF THERE IS A
CHANCE THAT IT'S GOING TO KNOCK
OUT MY KIDNEYS AND I'M GOING TO
HAVE TO PAY OUT-OF-POCKET.
THAT'S ECONOMIC STUDY.
AND IF WE TAKE EVERYBODY
PARTICIPATE GETS $500, SHOULD
THAT COUNT AS A BENEFIT IF
THERE IS ECONOMIC RISKS OVER
HERE, AND ECONOMIC BENEFITS
OVER THERE.
AND I WILL JUST SAY THAT ALMOST
THE CONSENSUS IN THE
LITERATURE, EVERYBODY HAS GOT
TO TAKE THOSE INTO
CONSIDERATION.
THE ECONOMIC BENEFIT DON'T,
THEY SHOULDN'T CONSIDER THEM AT
ALL.
AND SO OBVIOUSLY, THERE IS THIS
QUESTION OF, DOES THAT MAKE
SENSE?
SHOULD WE TREAT THEM
DIFFERENTLY AND IF SO WHY
SHOULD WE TREAT THEM
DIFFERENTLY?
SO IT'S ONE OF THE OTHER
QUESTIONS I'M GOING TO LEAVE US
WITH NOW.
SO ONCE WE IDENTIFY THE RISKS,
MINIMIZE THEM, POTENTIAL
BENEFITS AND TRY TO MAKE THEM
LARGER TO THE EXTENT THAT YOU
CAN AND THIS PUTS US BACK IN
THE WORRY ABOUT FAIRNESS AGAIN.
WHEN I WAS IN THE INFECTIOUS
DISEASE IRBs THEY WERE JUST
TESTED BLOOD INHIBITORS, IT
REALLY REVOLUTIONIZED, WHERE
H.I.V. WENT FROM A DISEASE THAT
KILLED EVERYBODY TO A DISEASE
THAT EVERYBODY CAN LIVE WITH.
AND THE QUESTION WAS WHERE DO
WE DO THE TRIALS, DO WE DO IT
IN PEOPLE THAT ARE RELATIVELY
HEALTHY WITH THE ASSUMPTION
THAT THERE WILL BE LESS RISK
BECAUSE THEY'RE HEALTHIER AND
IN BETTER SHAPE OR DO WE DO IT
IN PEOPLE WHO ARE REALLY REALLY
SICK WHO PROBABLY FACE GREATER
RISK BUT IT IF HELPS THEM, IF
IT ACTUALLY WORKS, THEY'RE
GOING TO GAIN A LOT MORE.
SO WE DEBATED THAT AND IT'S
INTERESTING, I THINK ABOUT IT
NOW.
I ALWAYS SAY IF IRBs HAVE TO BE
ON THE CAUTIOUS SIDE BUT IN
THIS CASE, WE ACTUALLY MANDATE
THED THAT THE STUDY BE DONE IN
PEOPLE WHO WERE SICK.
SO WE DID PEOPLE WHO HAD LOW
COUNTS I THINK UNDER 50.
SO WE FOCUSED ON THE POTENTIAL
BENEFIT RATHER THAN MINIMIZING
THE RISK.
SO NOW WE KNOW WHAT THE RISK,
SOCIAL VALUE AND BENEFITS ARE
SO WE'RE SUPPOSE TO PUT IT
ALTOGETHER AND HERE THE STEP,
BASICALLY TO THE POTENTIAL
BENEFITS TO THE PARTICIPANT
PLUS THE SOCIAL VALUE, PUT
THOSE TOGETHER AND TO THOSE
JUSTIFY THE RISKS AND THE BURNS
AND COSTS OF DOING THE STUDY.
YOU GOT, YOU HAVE AN ACCEPTABLE
STUDY YOU CAN BASICALLY STOP
DOING THE RISK BENEFIT
ASSESSMENT.
IF NO, THEN YOU NEED A COUPLE
MORE STEPS, THEN I'LL TALK
ABOUT SOME ADDITIONAL STEPS.
THE FIRST THING, SO PEOPLE
AGONIZE OVER THIS ALL THE TIME.
SO THERE IS THIS BIG DEBATE
ABOUT THE WAY IN WAY YOU SHOULD
TREAT CLINICAL RESEARCH IN THE
WAY SAME AS CLINICAL CARE.
THIS IS A CASE WHERE I THINK
PEOPLE GET TOO CONFUSED WHETHER
IT COMES TO RESEARCH ETHICS.
SO WHEN I SAY THIS, THE IRB
SHOULD LOOK AT THE BENEFITS
WHETHER THEY JUSTIFY THE RISKS.
THEY'RE LIKE HOW DO YOU DO THAT?
OUT WEIGH RISK, THAT'S A
METAPHOR, WHAT ARE ANY OF THESE
THINGS MEAN?
AND MY RESPONSE TO THAT IS, I
KNOW THIS IS HARD, BUT NOTICE
THAT'S WHAT DOCTORS AND
CLINICIANS DO EVERYDAY.
THAT'S THE JOB OF CLINICIANS IS
TO ASK THEMSELVES FOR THIS
PATIENT, TO THE POTENTIAL
BENEFITS OF THIS DRUG, OUT
WEIGH THE RISK OF THIS IT
PATIENT.
NOW IT'S HARDER TO DO IT IN
RESEARCH BECAUSE WE DON'T HAVE
AS MUCH DATA BUT AT LEAST I
THINK THAT THE APPROACH, THE
SORT OF BASIC IDEA IS EXACTLY
THE SAME.
SO I TERMED THIS THE INFORMED
CLINICIAN TEST AND WHAT THE IRB
SHOULD DO IS PRETEND OR CALL
ONE UP.
AND ACTUALLY ASK THEM, HERE'S
THE SITUATION, HERE ARE THE
PATIENTS, HERE IS THE DRUG WE
WANT TO GIVE THEM.
HERE'S WHAT WE KNOW ABOUT IT,
DO YOU THINK THE POTENTIAL
BENEFITS JUSTIFY THE RISK?
IF THEY SAY YES, IT'S A
PROSPECT OF BENEFIT STUDY IF
THEY SAY NO, IT'S A WHAT I CALL
A NET RISK STUDY.
A LITTLE BIT MORE PHILOSOPHY
HERE IS SO, WHAT I'VE BEEN
SAYING IS YOU LOOK AT THE
INDIVIDUAL INTERVENTIONS AND
THEN THE WHOLE BADGE.
--PACKAGE.
WHAT ARE YOU SUPPOSE TO DO?
WHAT ARE YOU SUPPOSE TO LOOK AT
THE INDIVIDUAL INTERVENTIONS
AND HERE'S THE BENEFITS.
DO THE POTENTIAL BENEFITS HAVE
TO JUSTIFY THE RISKS?
SO IMAGINE A STUDY LIKE THIS,
IMAGINE A STUDY WHERE I'M GOING
TO GIVE PEOPLE A POTENTIAL
TREATMENT FOR KIDNEY DISEASE OR
LIVER DISEASE, REALLY COULD
HELP THEM LOOKS REALLY
PROMISING, LOTS OF POTENTIAL
BENEFITS.
BUT IN ORDER TO DO THE STUDY
SCIENTIFICALLY, I HAVE TO DO A
BIOPSY THAT POSES RISK AND I'M
ONLY DOING IT FOR RESEARCH
PURPOSES.
IF YOU LOOK AT THE LIVER BIOPSY
OR KIDNEY BIOPSY ON ITS OWN IT
LOOKS LIKE NOT BENEFIT
INTERVENTION AND AT LEAST IN
CHILDREN YOU WOULDN'T BE
ALLOWED TO DO IT AND PEOPLE
WOULD BE REALLY WORRIED ABOUT
DOING IT IN ADULTS.
IS THAT THE WAY YOU'RE SUPPOSE
TO DO IT?
POTENTIAL BENEFITS HAVE TO
JUSTIFY THE RISK OR DO YOU PUT
IT TOGETHER AND SAY I KNOW
THAT, BUT THE POTENTIAL
BENEFITS OF GETTING THE DRUG,
THEY JUSTIFY THE RISK OF NOT
ONLY THE DRUG BUT ALSO THE RISK
OF LIVER OR KIDNEY BIOPSY.
SO BEING IN THE STUDY IS
PROSPECT OF BENEFIT FOR THE
PEOPLE WHO ARE GOING TO GET
INTO IT.
THAT'S THE A QUESTION OF YOU
HAVE TO LOOK AT EACH ONE
INDIVIDUALLY JUSTIFYING THE
RISKS OF ANOTHER.
SO HOPEFULLY THAT'S CLEAR IF
IT'S NOT, WE CAN DEFINITELY
COME BACK TO IT, I THINK THAT'S
A REALLY INTERESTING CHALLENGE.
HERE'S A PRACTICAL EXAMPLE OF
THIS, WE WROTE A PAPER ON THIS.
IMAGINE A TRIAL IN KIDS, SOME
PEOPLE GET THIS POTENTIALLY
BENEFICIAL INTERVENTION AND
SOME PEOPLE GET A PLACEBO.
WHAT IS THE RISK BENEFIT
ASSESSMENT FOR THE PROFILE OF
THAT OVERALL STUDY.
WHAT SOME PEOPLE WILL SAY IS,
WELL, AT THE OUTSET BEFORE
AMORIZATION, THERE IS A CHANCE
YOU GET THE DRUG AND IF YOU GET
THE DRUG, THAT JUSTIFIES BEING
RANDOMIZE TO THE PLACEBO.
WHAT WE ARGUE IS THAT'S A
MISTAKE AND YOU NEED TO
INDIVIDUALLY LOOK AT THE RISK
BENEFIT OF THE TWO ARMS OF THE
TRIAL AND THAT MEANS THAT THE
RISKS OF THE PLACEBO HAVE TO BE
ACCEPTABLE AND YOU CAN'T
JUSTIFY THEM BY THE FACT THAT
THERE WAS A CHANCE THE PERSON
COULD HAVE GOTTEN BUT DIDN'T
ACTIVE TREATMENT.
SO THAT'S JUST ONE SPECIFIC
EXAMPLE OF THAT.
OKAY, SO WE'RE TALKING ABOUT
BENEFITS JUSTIFY THE RISK.
IF YOU DO, YOU HAVE A PROSPECT
OF BENEFIT STUDY.
IF YOU DON'T, HAVE YOU A WHAT I
CALL A NET RISK TRIAL.
SO THE NEXT CHALLENGE IS
THINKING ABOUT NET RISK HOW
MUCH NET RISK IS ACCEPTABLE.
SO, WHEN IT COMES TO
INDIVIDUALS WHO CAN'T CONSENT
LIKE KIDS, THERE ARE SOME
PEOPLE WHO THINK IT'S JUST EN
ETHICAL, THIS DEBATE HAS BEEN
GOING ON FOR YEARS.
SOME SAY IT'S UNETHICAL TO POSE
ANY RISK FOR THE BENEFITS TO
PEOPLE.
WE NEED TO TALK ABOUT THAT IF
PEOPLE ARE INTERESTED.
WHILE LOTS OF PEOPLE HAVE THAT
WORRY, IF YOU LOOK AT MOST
GUIDELINES, THEY ALLOW SOME
RISKS IN KIDS PARTICULARLY AND
THTS BUZZ WORD YOU'LL HEAR
ABOUT, WHETHER OR NOT THE RISK
ARE MINIMUM OR GREATER THAN
MINIMAL.
AND I THINK YOU'LL HEAR ABOUT
THIS.
SO WHAT IS MINIMAL RISK?
THE STANDARD BASED ON A LOT OF
REGULATIONS, WHAT IRBs ARE
SUPPOSE TO DO.
THEY'RE SUPPOSE TO COMPARE THE
RISK TO THE RISK ENCOUNTERED IN
DAILY LIFE.
AND IF THE RISK ARE EQUAL TO OR
LOWER THAN, COUNTS, IT COUNTS
AS A MINIMAL RISK.
THAT'S THE STANDARD THAT WHEN I
WAS STUDY I TALKED ABOUT
BEFORE, THAT WE DID WITH SEEMA,
THAT'S THE QUESTION WE WERE
ASKING THEM.
IF YOU NOTICE, IF I SAY TO YOU,
ALLERGY SKIN TESTING, ALLERGY
SKIN TESTING 11-YEAR-OLD, I
HOPE ALL OF YOU GUYS WOULD SAY
I HAVE NO IDEA.
YOU HAVE TO TELL ME WHAT THE
RISK VALUES OF SKIN TESTING
BEFORE I CAN COMPARE THEM AND
THAT'S THE THING THAT I WAS
POINTING THAT NONE OF THOSE
IRBS CHAIRS DID.
THIS IS A STUDY THAT WE DID
WITH WHO IS A PROGRAM AT UCLA
WHO WAS A POST-BACK HERE.
THERE HAVE NOT BEEN DA DA ABOUT
WHAT THE PUBLIC THINKS.
SO WE DID A SURVEY AND WE FOUND
IS, REALLY STRONG SUPPORT AMONG
THE PUBLIC INCLUDING PARENTS
FOR EXPOSING KIDS TO RESEARCH
RISKS INCLUDING BONE MARROW
BIOPSY WHICH POSES MORE RISKS.
OKAY, THAT'S KIDS, YOU'RE GOING
TO GET MORE OF THAT.
SO THAT LEAVES THE QUESTION
ABOUT WHAT ABOUT COMPETENT
ADULTS?
SHOULD THERE BE LIMITS WHERE
RESEARCHERS EXPOSE ADULTS TO
RISK FOR THE BENEFITS OF OTHERS?
AND HOW DO WE DECIDE THAT?
AND DOES IT DEPEND ON THINGS ON
WHETHER THE PARTICIPANTS ARE
HEALTHY OR WHETHER THEY'RE SICK.
PEOPLE DEBATE THAT A LOT.
HERE IS SOME COMMON ANSWERS
THAT RUNS A WHOLE RANGE.
YOU MAY SAY LOOK, COMPETENT
ADULTS GET TO DECIDE WHAT THEY
DO WITH THEIR LIVES INCLUDING
FACING RISKS.
SO IF IT'S JUST UP TO THEM.
OTHER PEOPLE HAVE REALLY STRICT
STANDARDS, THEY THINK, NO
ACTUALLY AND SOME IRBs DO THIS.
SHOULD NOT BE MUCH MORE IF ANY
GREATER THAN THE RISK THAT
WE'RE WILLING TO EXPOSE
CHILDREN.
SOME PEOPLE ARE REALLY STRICT
ABOUT THIS AND OTHER PEOPLE
HAVE ARGUED, FRANK MILLER USED
TO BE IN THIS DEPARTMENT AND HE
ARGUED LET'S LOOK AT RESEARCH
PARTICIPATION, LET'S LOOK AT
WHAT RISKS ARE ACCEPTABLE IN
OTHER ALTRUISTIC, IT'S
INTERESTING AT THE END OF THIS
PAPER, ALTHOUGH THEY SUGGEST
THAT'S STANDARD, THEY'RE LIKE
WELL MAYBE THAT'S TOO HIGH.
SOME SUGGEST SIMILAR THINGS BUT
IN PUBLIC SERVICE LIKE
FIREFIGHTERS AND THOSE ARE
GOING TO SET THE LIMITS FOR
RESEARCH RISKS WITH COMPETENT
ADULTS.
OKAY, SO JUST A BRIEF SUMMARY,
DOING SYSTEMATIC RISK BENEFIT
ASSESSMENT IS RIGHT, BELMONT
ASSESSMENT WAS RIGHT.
I DON'T THINK PEOPLE ARE DOING
IT RIGHT.
AND I THINK IF WE DID IT MORE
SYSTEMATIC, IT WOULD MAKE THE
RESEARCH BETTER AND MORE
ETHICAL AND THE SECOND PART
WHICH I HOPE DIDN'T GET TOO
CONFUSING AND DETRACT FROM
UNDERSTANDING THE FRAMEWORK, IS
THERE IS REALLY INTERESTING
QUESTIONS FOR US FOR ANYBODY
INTERESTED IN ETHICS TO FIGURE
OUT.
OKAY.
SO THANK YOU.
[APPLAUSE]
>> DAVE, WE HAVE ABOUT TEN
MINUTES FOR QUESTIONS.
IT LOOKS LIKE DANIEL HEADED TO
THE MICROPHONE.
I HAVE TWO QUESTIONS FROM
OUTSIDE.
THIS IS FROM KIM, SHE SAID
RAGGEDER THE INFORMED CLINICIAN
TESTS, IT'S SLIGHTLY DIFFERENT
FOR THE CLINICIAN BECAUSE WE
MAKE THE DECISION AT THE
INDIVIDUAL LEVEL WHERE AS THE
IRB MAKES THE DECISION AT THE
POPULATION LEVEL.
>> YEAH, I THINK THAT'S RIGHT.
AND SO THE WAY I THINK ABOUT
THE INFORMED CLINICIAN TESTS,
WHAT THE INFORMED CLINICIAN HAS
TO DO, THEY HAVE TO ASK A
QUESTION NOT ABOUT A SPECIFIC
INDIVIDUAL.
THEY HAVE TO AOFK OF THE
INDIVIDUAL WHO QUALIFY FOR THIS
STUDY GIVEN THE INCLUSION
EXCLUSION CRITERIA ARE
CURRENTLY WORDED.
IS IT IN THEIR MEDICAL INTEREST
TO BE IN THIS STUDY?
AND THE CLINICIAN MAY GIVE A
COUPLE OF DIFFERENT ANSWERS,
THEY MAY YES OR NO AND THEY MAY
SAY WELL IT DEPENDS.
FOR OTHERS IT'S REALLY RISKY.
AND IF THAT'S THE ANSWER THEY
GIVE AND I ASSUME THIS IS KIM'S
WORRY, THAT'S IMPORTANT
INFORMATION FOR THE IRB MAYBE
WHAT THE IRB WANTS TO DO IS GO
BACK AND RETHINK THE INCLUSION
AND EXCLUSION CRITERIA AND SAY,
OKAY, IS THERE A WAY THAT WHAT
WE CAN DO IS REJIGGER THEM.
SO NOW THERE IS THE FAIRNESS
FOR THE BACKGROUND, BUT
BRAKENING THAT FOR A SECOND,
THEY MAY WANT TO THINK ABOUT
REDOING THE INCLUSION EXCLUSION.
I THINK THERE IS SOME CASE
WHERE THEY CAN DO THAT IS
PRETTY CLEAR.
IF THEY CANNOT DO IT T I'VE
BEEN ON SOME IRBs WHERE WE
MANDATED LITERALLY AN
INDIVIDUAL, WHICH DOES NOT
HAPPEN.
IT CAN BUT YOU CAN BUILD A
PROTOCOL.
SO RATHER THAN FIDDLING WITH
NEM, WHAT WE'RE GOING TO DO IS
HAVE AN INDIVIDUAL COMMISSION
LOOK AT EACH INDIVIDUAL PERSON
AND ASSESS IT FOR THEM.
THAT'S SOMETHING THAT YOU CAN
DO.
IT'S NOT NECESSARILY SOMETHING
THAT YOU CAN DO 5,000 AND A BIG
PHASE TRIAL.
>> BUT EVEN THAT JENNA IS
--GENERAL ASSESSMENT, YES, NO,
MAY FEND AND MORE THAN WHAT THE
IRB MAY HAVE AT HAND.
>> ABSOLUTELY.
>> DANIEL.
>> THANKS FOR THIS, THIS IS
REALLY INTERESTING.
MY QUESTION WAS ABOUT THE
FALLACY OF THE PACKAGE DEAL.
>> YEAH.
>> I WONDER WHETHER YOU CANNOT
JUST NOT APPEAL TO WHETHER OR
NOT HIGHLY BENEFICIAL LIKE NET
BENEFICIAL INTERVENTION RIGHT
SIDE CONTINGENT UPON A HIGHLY
RISKY BENEFICIAL LIKE WITH A
BIOPSY.
THROUGH SOMETHING RISKY LIKE
THAT, THAT SEEMS RELEVANT
VERSUS JUST, YOU KNOW, NOTHING
IS CONTINGENT AND HIGHLY RISKY.
IF THAT'S THE CASE, IT SEEMS
LIKE WE CAN JUST JUSTIFY, LIKE
IF WE HAVE A REALLY REALLY
BENEFICIAL INTERVENTION, IT'S
NOT LIKE WE CAN TACK ON A
HIGHLY RISK INTERVENTIONS.
>> GREAT.
YEAH, DON'T SIT DOWN YET, LET
ME GIVE YOU AN EXAMPLE AND HOPE
WHAT YOU THINK.
SO DANIEL, I GET TO BE
PHILOSOPHICAL FOR A SECOND.
COMPARE TWO DIFFERENT CASES.
SO WHEN I, WHEN I WHEN I DO
THESE WE HAVE THESE DEVASE --WE
DON'T THINK IT'S A FALLACY.
TAKE THE CLINICAL SETTING,
THERE ARE A LOTS OF
INTERVENTION THAT'S WE GIVE
PATIENTS THAT OFFER THEM
SPECIFICALLY NO BENEFIT AT ALL
AND ARE RISKY.
AND THE REASON WE GIVE THEM THE
INTERVENTION IS THEY SET THEM
UP FOR OTHER BENEFITS.
CENTRAL LINES, RIGHT, SO
CENTRAL LINES IS IV GOES
STRAIGHT IN TO YOUR BASICALLY
SMASHING INTO PEOPLES, I SHOULD
NOT SAY SMASHING INTO YOU'RE
LOVINGLY INSERTED.
AND YOU CAN GET RISKY AND HURT
AND GET BLEEDING AND IT DOESN'T
DO YOU ANY GOOD TO HAVE THIS
THING STICK INING YOUR CHEST
PER SE.
THE REASON IS BECAUSE THERE ARE
CERTAIN DRUGS THAT'S HOW YOU
ADMINISTER THEM.
THAT PUTS YOU IN POSITION TO
GET THE EXPERIMENT, PUT YOU IN
POSITION TO GET TREATED.
SO NOBODY, I NEVER HEARD A
CLINICIAN SAY, YOU CANNOT JUST
FIGHT RISK OF THE CENTRAL LINE
BY POTENTIAL BENEFIT OF ANOTHER
INTERVENTION.
THAT'S A FALLACY OF A PACKAGE
DEAL.
NOBODY SAYS THAT, OF COURSE YOU
HAVE TO GET THE CENTRAL LINE.
OKAY, NOW TAKE A DIFFERENT CASE.
TAKE THE CASE OF GIVING A DRUG,
WHERE THIS EXACT BENEFIT OF THE
DRUG WE WERE JUST TALKING ABOUT
IN THE CLINICAL CASE, EXACT
SAME THING.
AND IN ORDER TO FIGURE OUT
WHETHER OR NOT THIS DRUG WORKS,
YOU NEED TO FIGURE OUT WHETHER
IT GOES INTO THE TUMOR.
TO FOUND OUT IF IT GOES INTO
TUMOR, YOU NEED TO TAKE A
LITTLE BIT OF KIDNEY OR LIVER
AND PUT IN THE LAB AND SOMEBODY
TELLS YOU WHETHER THE DRUG GOT
IN THERE OR NOT?
THE RISK OF BIOPSY ARE THE
EXACTLY THE SAME OF THE CENTRAL
LINE.
WHAT DO YOU THINK ABOUT THAT?
SO HERE'S WHAT I SAID, ISN'T IT
THE SAME.
THE RISKS ARE THE SAME AND IN
ORDER TO GET THE EXPERIMENTAL
DRUG, WE NEED TO DO THIS OTHER
THING.
WHAT PEOPLE WHO ARE BY THE
FALLACY, SAY NO, YOU COULD GIVE
THEM THE, THE EXPERIMENTAL.
SO THE QUESTION FOR YOU AND WHY
I WANT TO YOU STAY THERE, ARE
THOSE CASES SIMILAR OR
DIFFERENT?
DO YOU HAVE A SENSOR TOO HARD
TO THINK?
>> I DON'T KNOW.
IT'S GOOD QUESTION.
>> THAT'S FAIR.
>> IF SOMEBODY ELSE DOES.
>> WE DON'T HAVE TO PURSUE THAT
ONE, THAT IS HARD BUT THAT'S
SORT OF A DID LEMMA AND I THINK
IRBs RIGHT NOW ARE WORKING ON
THE STHAOUMTION IT'S ALWAYS A
FALLACY IN A SETTING.
>> QUOTE UNQUOTE STEP IN AND
RECOMMEND IMPROVEMENT ON A
PROTOCOL.
>> YEAH.
SO ON THE ONE HAND, YOU MAY
THINK WELL PEOPLE ARE PUTTING
ALL SORTS OF RESOURCES INTO AND
INVESTIGATION IF THERE ISN'T,
YOU KNOW, IF THERE IS WAY TO
SEE IMPROVE IT AND IF IRB
MEMBER SPOTS OR RECOGNIZE THAT,
THERE IS POTENTIAL FOR
IMPROVEMENT, WHY NOT?
ON THE OTHER HAND, THERE IS A
DIVISION ON LABOR AND THROWING
IDEAS FOR IMPROVEMENT IN SOME
CASES WITH DRASTICALLY CHANGE
FOR INSTANCE, THE RISK BENEFIT
FOR PROTOCOL AND THAT MAY DELAY
THE REVIEW IN PROCESS.
WHICH THEN, BRING IN WILL BRING
IN THE QUESTION OF, YOU KNOW,
RESOURCES, I JUST WANTED TO
HEAR MORE ABOUT WHAT YOU
THOUGHT ABOUT THIS PARTICULAR?
>> YEAH, SO CAN I GET YOUR
ANSWER TO MY QUESTION WHICH IS
I DON'T KNOW.
>> SURE.
>> SO I THINK, I THINK SO
HERE'S WHAT SOME PEOPLE WILL
SAY, SOME PEOPLE WILL SAY, IRBs
SHOULDN'T BE DOING THAT AT ALL,
BECAUSE WHAT THE JOB OF A IRB
IS IS TO EVALUATE WHATEVER
PROTOCOL GETS PRESENT TODAY
THEM?
AS LONG AS THAT'S ACCEPTABLE,
THEY SHOULD NOT BE DOING ANY
COMPARISON OR ACROSS DIFFERENT
STUDIES THEY CAN DO.
I THINK THAT'S WRONG.
I THINK THAT'S JUST A MISTAKE.
I THINK THERE IS DIFFERENT WAYS
TO ARGUE FOR IT.
ONE WAY IS TO SAY, THAT IT'S
KIND OF CONSEQUENCETIAL TO SAY,
LOOK WHAT YOU SAID THEY'RE
SUPPOSE TO BE DOING, IS WHETHER
OR NOT THE THING THAT THEY'RE
PROPOSE ISING ETHICAL.
BUT PART OF MAKING THAT
DETERMINATION IS SQUG THE
QUESTION ON WHAT THEY CAN DO
OTHERWISE.
AND IF YOU CAN NOT SAY, YOU
CANNOT SAY, THAT'S ONE WAY TO
ARGUE.
BUT SOMETHING LIKE THAT IS
RIGHT.
BUT SO THEN THE QUESTION IS, I
THINK THE IMPORTANT HARD ONE IS
WHAT YOU'RE POINTING TO WHICH I
THINK IS A PRACTICAL OF WHO
DOES IT.
I THINK FOR SOME OF THESE
THINGS, COMPARE ACROSS STUDIES,
IRBs ARE NOT IN A POSITION TO
DO THAT.
SO WE NEED SOMEBODY FURTHER UP
STREAM FUNDING AGENCIES,
INSTITUTIONS MAKING THOSE
DETERMINATION SXZ OPENFULLY
IRBs BEING ABLE TO RELY O ON.
>> THANKS.
>> ANOTHER SLIGHT VARIATION ON
THAT IS A LOT OF RESEARCH THAT
IRBs REVIEW HAVE BEEN REVIEWED
BY A GROUP OF SCIENTISTS.
SO IF IT'S AN NIH GRANT, IT'S
GONE THROUGH A PEER REVIEW OF
SCIENTIST THAT KNOW THAT FIELD.
AND HAVE SAID THIS IS A GREAT
PROTOCOL, WE THINK IT OUGHT TO
BE FUNDED AND BY THE TIME IT
GOES THROUGH IRB IT HAS GONE
THROUGH THAT PROCESS.
SO SOME WAY SAY IF THERE IS
BEEN A SCIENTIFIC REVIEW,
THAT'S A REASON MAYBE TO ONLY
STUDY ON IMPORTANT VERSUS AN
INVESTIGATOR THAT HE PLAN, SHE
PLANS TO FUND WITH
DISCRETIONARY FUNDS.
THAT MAYBE WAS REVIEWED AT THE
DEPARTMENT LEVEL, BUT MAYBE NOT
REALLY STRICTLY AND NOW IT'S ON
THE IRBs DESK.
I WOULD SAY, YOU KNOW, THAT'S A
CASE WHERE THE IRBs REALLY
OUGHT TO PAY ATTENTION TO THE
STUDY DESIGN AND WHETHER IT'S
BEEN WELL DESIGNED, WHETHER IT
CAN ACTUALLY ANSWER THE
RESEARCH QUESTION BECAUSE NO
OTHER GROUP HAS PROVIDED A
ROBUST SCIENTIFIC REVIEW.
DID YOU HAVE A QUESTION, WE
HAVE TIME FOR ONE MORE?
>> FIRST OF ALL THANK YOU SO
MUCH FOR THE TALK IT'S REALLY
FASCINATING AND I THINK I'LL
TAKE A AWAY A LOT OF QUESTIONS
AFTER THIS LECTURE.
ONE OF THE QUESTIONS I HAD WAS
THINKING ABOUT INTERNATIONAL
STUDIES AND THE CONCEPT OF
FAIRNESS.
SO LIKE, INTERNATIONAL, THERE
IS DIVERSITY OF CULTURE ETHICAL
BELIEVES AND SOME MAY VOLVE
TAKING ON MORE RISKS OR NET
RISKS.
AS FOR EXAMPLE, I CAN TAKE MORE
INDIVIDUAL RISK IF IT BENEFITS
SOCIETY.
FOR EXAMPLE, WHAT IF YOU HAD
LIKE A WESTERN CULTURE WHO
TAKES ON LESS NET RISKS BECAUSE
THEY ARE MORE INDIVIDUALISTIC.
IS IT OKAY FOR ADULTS TO TAKE
ON MORE RISKS IF IT BENEFITS
SOCIETY.
WHAT ARE YOUR THOUGHTS AND DO
YOU THINK THAT'S FAIR?
IT FEELS LIKE WE'RE ALL
PARTICIPATING AND THINKING IT'S
ETHICAL BUT AT THE SAME TIME IF
I IMPART MY WESTERN VIEW, IT
DOES NOT ETHICAL FOR ONE GROUP
TO TAKE ON MORE RISKS THAN THE
OTHER.
>> I LOVE THAT QUESTION.
AND I THINK IT'S, I THINK IT
APPLIES AS YOU SUGGESTED ACROSS
THE BOARD BUT I THINK IT'S
ESPECIALLY RELEVANT WHEN YOU
THINK ABOUT SOMEBODY LIKE KIDS.
SO A LOT OF STANDARD FOR
MINIMUM RISK ARE BASICALLY AS I
SAID, COMPARE THE RISK TO THE
RESEARCH TO THE RISK THOUGHT TO
BE ACCEPTABLE FOR ORDINARY KIDS
IN THAT SOCIETY.
SO DOES THAT MEAN IF WE'RE IN A
SOCIETY THAT WE'RE NOT WILLING
TO TAKE RISKS THEN YOU CAN ONLY
HAVE A TINY PEDIATRIC RISK BUT
IN OTHER COUNTRIES WHERE WE'RE
WILLING TO TAKE MORE RISKS,
THAT I THINK IS A REALLY GOOD
GREAT.
AND IT RAISES QUESTIONS THAT I
THOUGHT ABOUT A FOR A WHILE,
WHICH IS THAT IT HAS PRACTICAL
IMPLICATIONS, BECAUSE THE
REGULATIONS IN CERTAIN
COUNTRIES ARE VERY DIFFERENT.
SO THERE ARE CERTAIN COUNTRIES,
I THINK IT'S STILL TRUE.
BUT A COUPLE OF YEARS AGO,
THERE WERE CERTAIN COUNTRIES
THAT HAD LAWS THAT SAID, YOU
CANNOT EXPOSE A KID TO ANY
RESEARCH.
SO EVEN MINIMAL RISK WAS NOT
ALLOWED.
AND THE PERSON NEXT DOOR
ALLOWED THAT.
DO WE SAY, COUNTRIES GET TO
DECIDE.
NOW HERE'S THE WORRY IMAGINE WE
DO ALL THE RESEARCH AND WE
LEARN ALL OF THESE THINGS AND
THEN THE OTHER COUNTRIES IS
LIKE, YEAH, THIS IS GREAT, WE
DON'T HAVE TO EXPOSE OUR KIDS
TO MY RISK AND WE LEARN ALL OF
THIS STUFF OVER HERE.
THAT DOES NOT SEEM RIGHT?
WHAT DO YOU DO ABOUT THAT?
I DON'T KNOW.
BUT I THINK IT'S A GREAT
QUESTION.
AND I THINK YOU'RE RIGHT, THE
PROBLEM ARISES AND WHAT WE DO
ABOUT IS HARD AND INTERESTING.
>> THANK YOU.
>> THANKS, AGAIN DAVE FOR
JOINING US.
WE'RE GOING TO TAKE OUR
15-MINUTE BREAK AND THEN WE'RE
GOING JOINED ON THE BIG SCREEN
BY SEEMA SHAH WHO IS BEAMING IN
FROM CHICAGO.
WELCOME BACK EVERY ONE TO
SESSION 3 AND IT'S MY PLEASURE
TO INTRODUCE DOCTOR, PROFESSOR
SEEMA SHAH SHE A PROFESSOR OF
IN PAOED PEDIATRICS, SHE IS AN
EXPERT OF PEDIATRICS AND GLOBAL
HEALTH RESEARCH AS WELL AS
ETHICAL ISSUES IN DETERMINATION
OF DEATH AND THE FUN FACT THAT
I MENTIONED EARLIER, AS DAVE
WAS A FELLOW HERE, A SEEMA WAS
ALSO A FELLOW HERE AND ALSO A
MEMBER OF OUR FACULTY.
SO WITH THAT, I'M GOING TO HAND
IT OVER TO SEEMA.
>> THANKS SO MUCH, HOLLY, IT'S
REALLY A PLEASURE TO BE BACK
EVEN IF I'M ONLY BACK VIRTUALLY.
SORRY I COULDN'T BE THERE IN
PERSON.
AND DAVE WAS A FACULTY MEMBER
AND I WAS A ONE OF HIS FELLOW
AND LATER HAD THE PLEASURE OF
BEING HIS COLLEAGUE AND
COLLABORATOR.
SO SOME OF THE WORK IS SOME OF
THE WORK THAT WE DID TOGETHER
AND DAVE DID SUBSEQUENTLY.
SO WHAT I'M GOING TO TALK TO
YOU ABOUT TODAY IS ETHICAL
INCLUSION OF CHILDREN IN
RESEARCH AND THE GOAL IS TO
REALLY SHOW YOU HOW WE SHIFTED
OVERTIME TO RECOGNIZING THE
IMPORTANCE OF RESPONSIBLE
INCLUSION OF CHILDREN INSTEAD
OF JUST FOCUSING ON THEIR
PROTECTION.
FOCUS ONING IF YOU JUST FOCUS
ON PROTECTION, THEN YOU MISS
OUT ON MANY POTENTIAL BENEFITS
FOR CHILDREN AS A GROUP AND
EXPOSE THEM TO RISK IN CLINICAL
CARE.
SO THED BIG MOTIVATION BEHIND
PEDIATRIC RESEARCH, WHICH A LOT
OF PEOPLE DON'T REALIZE IS THAT
THERE IS A GREAT NEED TO FIND
INTERVENTION SXZ DOSES THAT
WORK FOR CHILDREN GIVEN THAT
THEY'RE NOT JUST SMALL ADULT.
THIS STUDY WAS DONE TO SHOW
EVEN ENORMOUS DIFFERENCES
BETWEEN ADULTS AND HEAT IN
RELATION TO HEAT PERCEPTION.
KIDS EVEN THAT THEY'RE HEIGHT
IS LOWER AND CLOSER TO THE
GROUND.
SO ALL OF THESE THINGS, IN MANY
CASES, NOT ALL, SUGGESTS THAT
THERE NEEDS TO BE A WAY TO DO
RESEARCH ON CHILDREN AND
INTERVENTIONS.
AND THIS QUOTE SUMS IT NICELY,
THE VAS MAJORITY OF OF DRUGS
WERE NOT DESIGNED OR DEVELOPED
FOR PEDIATRIC OR INFANT
POPULATIONS.
WHAT I WOULD LIKE TO TALK ABOUT
WHEN TO EN ROLL CHILDREN IN
RESEARCH WITH RESPECT TO OTHER
TYPES OF RESEARCH, PARTICULARLY
RESEARCH IN ADULTS.
AND THEN WE'LL TALK ABOUT RISK
SXZ BENEFITS AND TURN TO
DECISION MAKING FOCUSING ON THE
CONSENT AND DIS CONSENT.
SO FIRST WHEN WE WE EN ROLL
CHILDREN IN RESEARCH.
THE FIRST QUESTION IS WHO IS
THE CHILD?
AND THAT VARIES QUITE A BIT
FROM PLACE TO PLACE.
THE TYPICAL DEFINITION IS
CHILDREN IT ARE TOO YOUNG TO
GIVE THEIR OWN CONSENT.
AND IN THE UNITED STATES, EVEN
IN THE UNITED STATES IT VARIES
TWO STATES WHERE YOU DON'T HAVE
THE ABILITY TO GIVE CONSENT
UNTIL YOU'RE 19, YOU'RE A MINOR
UNTIL YOU'RE 19.
AND AROUND THE WORLD THIS
VARIES AS WELL, THERE IS A
COUNTRY WHERE YOU NEED TO BE 21.
AND WE'LL TALK MORE ABOUT
CONSENT BUT PROBABLY THE
PROBLEM THAT ARISING, BECAUSE
CHILDREN CAN'T GIVE THEIR OWN
CONSENT AND LACK HUMAN CAPACITY
TO GIVE CONSENT, THERE ARE A
LOT OF REASONS WHY YOU MAY WANT
TO STUDY ADULTS.
CHILDREN ARE MORE VULNERABLE TO
RISKS INSTEAD OF ADULTS.
BECAUSE CHILDREN MAY HAVE LESS
IMMUNITY TO THINGS OR BE MORE
FRAGILE IN CERTAIN RESPECTS
THAN ADULTS.
ADDITIONALLY BECAUSE CHILDREN
CAN'T GIVE THEIR OWN CONSENT,
THEY CANNOT PROTECT THEIR OWN
INTEREST.
AND FINALLY, THERE IS A GREATER
POTENTIAL FOR NEGATIVE REACTION
IF SOMEBODY GOES WRONG.
IF YOU'RE RELYING ONLY ON
CONSENT OR PERMISSION TO EN
ROLL A CHILD IN RESEARCH, YOU
MAY NOT BE GETTING THE SAME
LEVEL OF MORAL CONSERVATION
WHEREFORE THEIR OWN
PARTICIPATION.
HOWEVER, THERE ARE LOTS OF
REASONS TONE ROLL CHILDREN
SOONER.
SOMETIMES CHILDREN CAN RECEIVE
IMPORTANT BENEFITS DIRECTLY
FROM RESEARCHERS, THIS IS OFTEN
THE CASE IN LATER STAGE
TREATMENT TRIALS PARTICULARLY
TRIALS ON RARE CONDITIONS.
SOME DISEASES ARE CONDITIONS
ONLY AFFECT CHILDREN OR AFFECT
CHILDREN DIFFERENTLY.
SO, FOR INSTANCE TUBERCULOSIS
IS IN CHILDREN UNDER 10, VERY
DIFFERENT FROM ADULT
TUBERCULOSIS.
AND ONCE CHILDREN REACH THE AGE
OF 10, AGENTLY SIMILAR
CONDITION TO HOW IT'S
EXPERIENCED IN ADULTS.
BUT ALSO THE ISSUE LIKE MALARIA
WHICH AFFECTS PEOPLE OF ALL
AGES BUT CHILDREN UNDER 5 CAN
HAVE MORE SEVERE CONDITIONS.
FINALLY, THERE IS A IF YOU
DELAY, PEDIATRIC TESTING THAT
CAN LEAD TO SORT OF DOMINO
AFFECT WHERE AVAILABILITY OF
THE INTERVENTION IS ALSO
DELAYED FOR CHILDREN SO. WHEN
YOU TURN TO ETHICAL GUIDANCE TO
FIGURE OUT HOW WE BALANCE THESE
REASONS, AND RESEARCH, THE
WORLD HEALTH ORGANIZATION HAS
THE COUNCIL FOR INTERNATIONAL
MEDICAL SCIENCE AND YOU'VE
HEARD TALK ABOUT THIS GUIDANCE
THIS IS REALLY, GUIDANCE IN
2016, ADULTS SHOULD BE FIRST IN
ALL RESEARCH.
AND THE DECLARATION, THE 2013
VERSION SAID THE PEOPLE WHO
CANNOT CONSENT SHOULD NOT BE
ENROLLED IN RESEARCH UNLESS
THERE IS A PROSPECT OF DIRECT
BENEFIT OR RESEARCH IS DESIGNED
TO PROMOTE THE GROUP AND
INVOLVES MINIMAL RISK OR BURDEN
AND CANNOT BE PERFORMED WITH
PEOPLE WHO CAN'T CONSENT.
SO MANY ARE RESTRICTIVE ABOUT
WHEN CHILDREN CAN BE ENROLLED
IN RESEARCH.
THERE IS THE MOST SYSTEMATIC
APPROACH THAT I FOUND ON THIS
WAS AS FAR BACK AS IN 2004.
SO THIS IS A GROUP EUROPEAN
SPECIALIST IN PEDIATRICS WHO
CAME TOGETHER AND SAID WHEN
SHOULD WE EN ROLL CHILDREN IN
RESEARCH.
OF COURSE PHASES AND RESEARCH
WHICH YOU HEARD IN OTHER
CLASSES AS WELL, THEY'RE NOT
ALWAYS APPLICABLE TO ALL TYPES
OF RESEARCH.
BUT THE WAY THEY THOUGHT ABOUT
IT, WAS IF A DISEASE WAS ONLY
AFFECTING CHILDREN, THEN YOU
NEEDED TO HAVE SAFETY DATA
FIRST, BUT YOU CAN GO DIRECTLY
TO EN ROLL CHILDREN IN RESEARCH.
A SECOND CATEGORY, WOULD BE
DISEASES TO MAINLY AFFECT
CHILDREN OR VERY SERIOUS IN
CHILDREN OR WHERE THERE IS NO
OR LIMITED TREATMENT AND THERE
THERE WAS A NEED FOR SOME DATA
AND SOME ADULT ETHICACY DATA
BEFORE ENROLLING CHILDREN.
NOW WHEN YOU TURN TO DISEASES
WHERE THERE IS TREATMENT
OPTIONS THEN THE IDEA WAS THAT
YOU WOULD ACTUALLY GO ALL THE
WAY THROUGH, ALL THE RESEARCH
ON ADULTS BEFORE TURNING TO
CHILDREN.
AND THIS I THINK IS REALLY AT
LEAST ONE OF THE MOST SUSTAINED
EFFORTS TO BE MORE SYSTEMATIC
ABOUT WHEN TO EN ROLL CHILDREN
IN RESEARCH.
HOWEVER, THESE RECOMMENDATIONS
DON'T FOCUS DIRECTLY ON THE
RISK AND BENEFITS OF A GIVEN
TRIAL.
THEY SORT OF ASSUME THE RISK
AND BENEFITS BASED ON WHETHER
THERE ARE TREATMENT OPTIONS AND
WHETHER THE DISEASE ONLY AFFECTS
CHILDREN OR ADULT.
THEY ALSO DON'T FOCUS ON THE
VALUE AND THEY DON'T FOCUS ON
THE DIFFERENCES BETWEEN
PREVENTION AND TREATMENT.
THEY'RE REALLY JUST FOC USED ON
TREATMENT AND NOT RESEARCH LIKE
VACCINES TO PREVENT CHILDREN
FROM BEING INFECTED WITH A
PARTICULAR DISEASE.
SO IT MAY REALLY MAKE MORE
SENSE TO FOCUS ON THE RESEARCH
GIVEN THE ALTERNATIVES AND GET
MORE GRANULAR TO DECIDE WHEN TO
EN ROLL CHILDREN.
SO I THINK THIS IS A HELPFUL
PIECE OF GUIDANCE THAT CAN HELP
WHEN YOU'RE THINKING ABOUT
TREATMENT TRIALS.
AT LEAST ONE OF THE FIRST
APPROACHES TO APPROACH THIS
SYSTEMATICALLY.
THERE IS ALSO A ADDITIONAL
PROTECTION THAT PEOPLE TALK
ABOUT AGE DECALATION.
AND THE IDEA IS FIRST YOU HAVE
TO DECIDE WHEN YOU EN ROLL
CHILDREN IN GENERAL AND THEN
HOW YOU PROTECT THEM WHEN YOU
START TO ADD CHILDREN.
AND YOU START WITH OLDER
CHILDREN AND THEN WORK YOUR WAY
DOWN TO THE YOUNGEST CHILDREN.
THIS IS BEEN USED IN RESEARCH
ON TREATMENTS FOR MALARIA
CANCER AND FLU AND VACCINE
TRIALS ON ANTHRAX AND A NUMBER
OF OTHER CONDITIONS.
WHAT IS INTERESTING IS THAT IS
OFTEN PRESUMED SOB TO BE A
VALUABLE SAFEGUARD AND ETHICS
THINKS ABOUT BIOMEDICAL
MEASURESES ONE OF THE WAY TO
JUSTIFY RESEARCH IN CHILDREN
SO. THERE MAY BE SPECIAL CASES
WHERE IT'S REALLY IMPORTANT.
BUT WHAT IS INTERESTING, I
THINK IS FOR A LONG TIME PEOPLE
SORT OF TREATED DEESCALATION AS
IF IT WAS THE APPROACH THAT YOU
SHOULD USE WITHOUT QUESTIONING
IT.
AND MORE RECENTLY ESPECIALLY
DURING THE COVID PANDEMIC,
PEOPLE START TO QUESTION
WHETHER DECALATION IS THE BEST
IDEA.
SOL THIS TALKS ABOUT HOW AGE
ESCALATION IS USED DURING THE
COVID PANDEMIC LEAD TO HARMS
AND REALLY DIDN'T ADDRESS THE
POTENTIAL BENEFIT FOR CERTAIN
GROUPS OF KIDS.
NOTED THAT ALTHOUGH YOUNG
CHILDREN HAD LOWER RISK FROM
COVID INFECTION, THERE WERE
STILL 650 DEATHS AND OVER 2000
CASES OF A MULTI SYSTEMIC
INFLAMMATORY SIN DRONE
--SYNDROME UNDER THE AGE OF 5.
AND IN 2021, THE CHILDREN HAD
THE LARGEST INCREASE OF
HOSPITALIZATIONS AT THE TIME
FOR CHILDREN UNDER FIVE.
SO WHAT THESE AUTHOR CONCLUDE
IS WE SHOULD THINK ABOUT
DEESCALATION MORE CAREFULLY AND
RECOGNIZE THAT IT CAN BE
PROBLEMATIC IN A NUMBER OF
CASES.
BUT I THINK THE ONE THAT IS
DIFFERENT FROM THE COVID-19
EXAMPLE IF YOU HAVE A NARROW
CONCEPTION OF BENEFITS FOR
CHILDREN TO BE INVOLVED IN
RESEARCH, THEN YOU MAY FIND
THAT AGE DEESCALATION CAN
BENEFIT.
THERE WERE TWO WAY THAT THIS
PLAYED OUT.
THERE WAS A LACK OF
APPRECIATION THAT EVEN YOUNG
CHILDREN COULD HAVE SERIOUS
RISK FROM COVID INFECTION.
AND THE SECOND IS THAT THE FACT
THAT CHILDREN COULD BECOME
INFECTED AND MISS TIME FROM
SCHOOL AND NOT BE IN DAYCARE
THAT ALL OF THOSE THINGS WERE
SIGNIFICANT INDIRECT HARMS THAT
COULD APPLY TO CHILDREN.
IT WAS NOT JUST THE STANDARD
WAY THAT WE CALCULATE RISKS.
AND THOSE THINGS WERE NEGLECTED
AS PEOPLE CONSIDERED WHEN TO
INVOLVE CHILDREN IN RESEARCH.
SO I THINK THE LESSON IN
COVID-19 IN GENERAL, CHILDREN
WERE OFTEN AFTERTHOUGHT IN
THESE DECISIONS AND WE NEED TO
DO A BETTER JOB OF TRYING TO
BENEFIT CHILDREN IN FUTURE
PANDEMICS AND TO THINK MORE
COMPREHENSIVELY OF ENROLLMENT
AND RESEARCH CAN LEAD TO WITH
CHILDREN IN THIS GROUP.
AND WITH MY SEVERAL OF MY
COLLEAGUES FROM FORMER
COLLEAGUES FROM THE DEPARTMENT
OF BIOETHICS, WE WROTE THIS
PAPER ON WHEN TO EN ROLL MINORS
IN COVID VACCINE TRIALS.
AS AN ATTEMPT TO LEARN FROM
THAT EXPERIENCE.
OKAY, SO WE TALKED ABOUT THE
RISKS AND BENEFITS.
WHAT DOES THAT MEAN?
HOW DO WE FOCUS ON RISK AND
BENEFITS AND RESEARCH IN
CHILDREN?
SO MOST REGULATIONS INCLUDING
THE COUNSEL OF EUROPE, UGANDA,
AFRICA AUSTRALIA, THEY ALL
PERMIT RESEARCH IN TWO
CATEGORIES.
FIRST, RESEARCH THAT OFFERS A
PROSPECT OF DIRECT BENEFIT TO
THE CHILD THAT OUT WEIGHS THE
RISK ESPECIALLY IN COMPARISON
TO THE ALTERNATIVES.
AND THEN THE SECOND CATEGORY IS
RESEARCH THAT POSES MINIMAL
RISK.
SO IT'S NOT SUPPOSE TO BE THE
BENEFIT THE CHILD BUT THE RISK
IS JUST MINIMAL.
U.S. REGULATIONS, THERE ARE
COUNTRIES THAT ADOPTED OUR
REGULATIONS AND CODIFIED THEM
INTO THEIR OWN LAWS.
SO OUR REGULATIONS HAVE FOUR
CATEGORIES OF PROTECTION WHICH
INCLUDE THE FIRST TWO THAT WE
TALKED ABOUT, THAT EXIST AROUND
THE WORLD AND TWO OTHERS THAT
ARE MUCH LESS COMMON.
SO YOU CAN DO RESEARCH WITH
MINIMAL RISK, RESEARCH THAT
OFFERS A DIRECT BENEFIT THAT
OUT WEIGHS THE RISK AS PRETTY
MUCH ANYWHERE IN THE WORLD.
AND YOU CAN ALSO DO RESEARCH IN
THE UNITED STATES, IF IT'S A
APPROVED BY AN INSTITUTION
REVIEW BOARD BECAUSE IT POSES A
MINOR INCREASE OF MINIMAL RISK
AND THAT'S OKAY EVEN IF THERE
IS NO DIRECT BENEFIT.
BUT IN THIS CATEGORY, THE
RESEARCHER HAS TO BENEFIT THE
GROUP OF PARTICIPANTS FROM
WHICH THE PARTICIPANTS ARE
COMING FROM AND BENEFIT THEIR
CONDITION OR DISORDER.
AND FINALLY, THERE IS A SORT OF
CATCH-ALL CATEGORY WHERE
RESEARCH DOESN'T FIT INTO ANY
OF THESE CATEGORIES IT CAN BE
TAKEN TO A SPECIAL PANEL AND
APPROVED BY THAT SPECIAL PANEL
WHICH IS APPOINTED BY THE
SECRETARY OF HEALTH AND HUMAN
SERVICES.
SO WHEN WE LOOK AT THE
REGULATIONS AN IMPORTANT
QUESTION IS WHAT DO ALL OF
THESE WORDS MEAN?
AND HOW ARE THEY DEFINED?
AND DEFINITIONS ARE NOT AS
ROBUST.
SO MINIMAL RISK, I THINK THIS
DEFINITION HAS BEEN
OPERATIONALIZED BY MANY
SCHOLARS.
SO MINIMAL RISK INVOLVES A RISK
OF DAILY LIFE OR ROUTINE OF
EXAMINATIONS AND TESTS.
BUT THERE IS NO DEFINITION FOR
WHAT A MINOR INCREASE OVER
MINIMAL RISK IS IN THE
REGULATIONS.
AND WE DID A SURVEY OF U.S.
CHAIR PERSONS OF INTUITION AL
REVIEW BOARDS AS RESEARCH
COMMITTEES, MANY YEARS AGO NOW,
SO IT'S BACK IN 2004 THAT WE
PUBLISHED THIS DATA AND FOUND
LIABILITY ON HOW PEOPLE ON IRBs
ACCOUNTED SO THEY CAN--ONLY
AGREE ON THE EXTREMES BOTH ENDS
OF THE SPECTRUM, A 10 WITH CC
BLOOD DRAW AND A LUMBAR
PUNCTURE IN THAT HEALTHY
11-YEAR-OLD.
IT WAS JUST MINIMAL RISK.
AND EVERYWHERE ELSE, IT WAS
SPLIT AND ACTIVITY AND WE ALSO
FOUND THAT ALLERGY SKIN TESTING
PEOPLE, DON'T SEEM TO SHOW THIS
HERE BUT THERE IS A THIRD IN A
EACH CATEGORY.
SO WHAT I THINK THIS TELLS US
IS OFTEN REVIEW COMMITTEE
ASSESS RISK BASED ON THEIR
INTUITION AND THEIR JUDGMENT
AND THIS MAY LEAD TO RISK AND
ALSO INCORPORATING BIAS INTO
THEIR BIAS.
AND ESPECIALLY IF YOU HAVE A
STUDY BEING DONE IN MULTIPLE
SITES AND DIFFERENT SITES HAVE
DIVA SESMENTS OF WHAT THE RISK
ENTAIL.
THIS LEADS INTO OTHER ISSUES
WHERE THE PERMISSION THAT IS
REQUIRED CAN BE DIFFERENT IN
DIFFERENT SITES.
SO IF THE STUDY IS IN THAT
THIRD CATEGORY, YOU NEED BOTH
PARENTS TO GET THEIR CONSENT.
AND THAT MAY LEAD TO
COMPLICATIONS IN TRYING TO PLAN
OUT THE STUDIES.
SO IT'S BETTER TO USE THE DATA
ON RISK OF PROCEDURES AND RISK
OF DAILY LIFE AND COMPARE THE
TWO.
AND DAVE AND OTHERS HAVE WORKED
ON TRYING TO DO THIS MORE
SYSTEMATICALLY AND SHOW HOW IT
CAN BE DONE.
IN MUCH WIDE RANGE OF
PROCEDURES.
OKAY, SO LET'S TURN NOW TO
DECISION.
FIRST WHEN YOU THINK ABOUT
PARENTAL CONSENT, IT'S
IMPORTANT THAT CHILDREN SHOULD
BE ENROLLED ONLY WITH THE PERM
PISSING OF THEIR LEGAL GUARDIAN
WHICH IS TYPICALLY THEIR PARENT
AND IT CAN BE OTHER CAREGIVER.
AND WHO CAN CONSENT IS LOCAL
LAW.
MOST GUIDELINES AROUND THE
WORLD ALLOW WAVING PARENTAL
CONSENT AND COMMON EXAMPLE IS
GIVEN, THAT SOMETIMES PARENTAL
CONSENT IS NOT A PROTECTION.
SO WHEN YOU THINK OF A CASE
WHERE PARENTS SUSPECTED OF
CHILD ABUSE, THERE MAY BE A
CONCERNS THAT A PARENT DOES
NOT WANT TO BE PART OF THAT
RESEARCH BECAUSE THEY'RE NOT
REALLY NOT PROTECTING THEIR
CHILDREN IN A WAY THAT THEY
SHOULD BE.
SO THAT MAY BE AN EXAMPLE WHERE
WAIVER PARENTAL CONSENT CAN BE
JUSTIFY.
ALSO A NUMBER OF LOCAL AND
STATE LOCAL LAWS THAT ALLOW
MINORS TO CONSENT FOR
THEMSELVES AND THIS CAN BE
BASED ON THE STATUS.
OF THE MINOR FOR INSTANCE IF
THAT MINOR IS MARRIED.
THEY'RE MATURITY IF THEY'RE
DETERMINED TO BE A MATURE MINOR.
OR THEIR CONDITION.
SO FOR TREATMENT FOR
TRANSMITTED INSPECTIONS AND
I'LL TALK ABOUT THIS MORE LATER.
I PROVIDED A MAP HERE WHICH
LAYS OUT WHEN MINORS CAN OBTAIN
CONTRACEPTIVE SERVICE.
AND THEY'VE DONE A LOT
PROVIDING INFORMATION FOR WHAT
THE CURRENT LAW IS, SO IT'S A
GOOD RESOURCE TO HAVE IN MIND.
SO IN THE U.S. REGULATIONS
REQUIRE THAT BOTH PARENTS GIVE
CONSENT IN RISKY OR NON
BENEFICIAL RESEARCH LIKE THE
THIRD CATEGORY I WAS JUST
TALKING ABOUT.
A LOT OF EMPHASIS REALLY WANT
TO POINT OUT SOMETHING IS IS
NOT IN THE REGULAR REGULATIONS
BUT SHOULD BE.
THAT REALLY WHEN WE'RE TALKING
ABOUT WHAT PARENTS ARE DOING,
THEY'RE GIVING PERMISSION AND
THAT'S DIFFERENT THAN GIVING
CONSENT.
SOL IF YOU THINK ABOUT, WHEN A
CHILD IS GOING TO SCHOOL, THEY
SIGN A PERMISSION NOT A CONSENT
FORM.
AND CONSENT IS WHAT YOU GIVE
PERMISSION TO DO SOMETHING TO
YOU.
SO REALLY WHAT PARENTS ARE
DOING IS GIVING THEIR
PERMISSION FOR THEIR CHILDREN
TO BE ENGAGED IN ACTIVITY OR
RESEARCH IN THIS CASE.
AND THE REASON I WOULD LIKE TO
MAKE THIS DISTINCTION IS THAT
THERE IS A NOTION THAT CONSENT
ITSELF IS ONLY, IS MORALLY
TRANSFORMATIVE SO IT TURNS IT
INTO SOMETHING PERMISSIBLE THAN
PERMISSION.
SO PARENTS HAVE LESS DISCRETION
AND AUTHORITY TO CONSENT FOR
THEIR CHILDREN TO BE INVOLVED
IN A RANGE OF ACTIVITY AND
ESPECIALLY BECAUSE PARENTS ARE
SUPPOSE TO KEEP THEIR CHILDREN
BEST INTEREST, THEY CANNOT GIVE
PERMISSION FOR CHILDREN TO BE
EXPOSED TO SUBSTANTIAL RISK.
IN ADDITION TO THIS NOTION, THE
PARENTS HAVE TO GIVE PERMISSION
AND CONSENT.
THE REGULATIONS ALSO REQUIRE
THAT INSTITUTIONAL REVIEW
BOARDS MAKE REVIEWS FOR
CHILDREN THAT ARE CAPABLE.
NOW THEY ONLY DEFINE IN THIS
WAY NOT JUST THE OWNER.
NOW THIS IS NOT THE JUST
HOPEFUL DEFINITION BECAUSE IT'S
A DEFINING A CONSENT AS WHAT IT
IS NOT.
HOWEVER THE BETTER WAY TO THINK
ABOUT IT IS THAT THERE SHOULD
BE AGREEMENT BASED ON THE
CHILD'S UNDERSTANDING AS MUCH
AS SHE IS CAPABLE OF
UNDERSTANDING, EVEN IF THAT
CHILD CAN'T UNDERSTAND ENOUGH
TO GIVE CONSENT.
IN SOME CASES IT COULD BE
SUBMITTED INFORMATION LIKE
YOU'LL HAVE TO COME TO THIS
RESEARCH SITE THREE TIMES AND
THAT IS PRETTY MUCH ALL THAT
THE CHILD UNDERSTAND.
BUT IN OTHER CASES, IT MAY BE
MORE SUBSTANTIAL.
NOW, IT'S IMPORTANT TO
RECOGNIZE HOWEVER, THAT THE
REASON FOR FIRING CONSENT CAN
ALSO SHAPE WHAT IT IS AND ASKED
WHAT IT'S BEING ASKED.
SO WHEN WE INVOLVE CHILDREN IN
DECISION-MAKING, IT CAN BE
GIVING THEM A SENSE OF CONTROL
OVER WHAT IS ABOUT TO HAPPEN TO
THEM.
HAVING, GIVING THEM THE
OPPORTUNITY TO PREPARE FOR WHAT
THEY ARE GOING TO HAVE TO DO.
SO CHILD STAY OVERNIGHT IN THE
HOSPITAL.
IT MAY BE IMPORTANT FOR THE
CHILD THAT THAT IS COMING UP
AND TO BE ABLE TO PACK A BAG
AND BRING ALONG THEIR FAVORITE
STUFFED ANIMAL.
IT'S ALSO IMPORTANT TO SHOW
RESPECT FOR THEIR GROWING
AUTONOMY.
SO AS A PARENT OF A PRETEEN, I
CAN TELL YOU THAT I CANNOT
GETAWAY WITH MAKING DECISIONS
FOR MY PRETEEN IN THE WAY THAT
I USED TO.
I HAVE TO ENGAGE HER BECAUSE
SHE HAS INCREASING CAPACITY IN
MAKING DECISIONS AND JUST A
CONCERN FOR HER OWN AUTHORITY.
SHE DOESN'T LIKE TO BE ENGAGED
IN THINGS WITHOUT SOME ABILITY
TO WEIGH IN.
SO RESPECTFUL PROCESS THEREFORE
WOULD INVOLVE DIFFERENT STAGES.
IT CAN BE INFORMING THE CHILD
ABOUT INFORMATION, ENGAGING
THEM SEEING IF THEY HAVE
QUESTIONS AND CONCERNS.
AND ASKING FOR CONSENT AND
FINALLY RESPECTING ANY DISTANT,
SO THIS IS DISCOMFORT ANY
PROBLEMS THAT THEY'RE HAVING
AND ANY OBJECTIONS.
NOW ALL OF THESE THINGS ARE
IMPORTANT TO THE EXTENT THAT A
CHILD HAS FULL CAPACITY.
HOWEVER IF A CHILD HAS LESS
CAPACITY IT MAY BE THAT NOT ALL
OF THESE THINGS CAN BE DONE.
SO IF A CHILD CAN'T UNDERSTAND,
ASKING THEM TO PARTICIPATE IN
RESEARCH IS ESSENTIALLY ASKING
THE QUESTION THAT DOES NOT MAKE
ANY SENSE TO THEM.
SO IT MAY BE MORE IMPORTANT FOR
YOUNG CHILDREN TO REALLY FOCUS
ON INFORMING THEM ABOUT THE
RESEARCH ENGAGING THEM SEEING
IF THEY HAVE ANY QUESTIONS OR
WORRIES.
AND THEN CHECKING FOR THEIR
DISCOMFORT AS STUDIES IS COMING
ON TO SEE IF THAT'S AN
INCREASING WAY OF RESEARCH.
WHEN WE THINK ABOUT WHO CAN
CONSENT, MOST GUIDELINES DON'T
SPECIFY.
THE U.S. FEDERATIONS ONLY STIPT
THAT DETERMINATION OF CONSENT
SHOULD BE TAKEN INTO ACCOUNT,
THE CAGE MATURITY AND
PSYCHOLOGICAL STATE.
WE DID A STUDY LOOKING AT THIS
AND FOUND THAT ANY IRBs USE THE
RULE OF 7.
BUT IT'S INTERESTING BECAUSE
THIS RULE IS UNDER THE CHILD
UNDER THE AGE OF 7 CAN REALLY
GIVE A SENT.
AND BUT INDIVIDUAL CHILDREN CAN
HAVE VERY DIFFERENT CAPACITIES
FOR DECISION MAKING.
SO IF YOU CONSIDER CHRONICLELY
ILL CHILDREN.
AND OTHER CHILDREN WHO HAVE
BEEN CHRONICLELY ILL.
SO IT REALLY IS HOW EVEN ONE
FACTOR CAN CUT IN EITHER
DIRECTION.
MOST OF THOSE USE AGE CUT OFF
AND MAJORITY USED THE AGE OF 7
WHERE CONSENT WAS REQUIRED
AFTER THE AGE OF 7 AND THE REST
OF THE OTHER HALF OF IRB CHAIRS
LEFT IT UP TO THE INVESTIGATOR.
THIS REALLY RAISES THE QUESTION
THE ABILITY TO CONSENT WITH
DIFFERENT AGES, SHOULD CHILDREN
BE GIVING CONSENT SENT OR.
THE CHILDREN MAY BECOME LEGALLY
TO CONSENT.
SO THE GUIDANCE I REFERRED TO
EARLIER, IF A CHILD BECOMES
CAPABLE DURING THE RESEARCH,
RESEARCHERS SHOULD OBTAIN THE
CONSENT TO CONSIDER
PARTICIPATION AT THE TIME.
AND IF A CHILD SAMPLES ARE HELD
IN A DATABASE FOR STORED SAMPLE
RESEARCH, OVER THE COURSE OF
THE RESEARCH AND IN GENERAL, A
LOT OF BE RECONSENTED AT THAT
POINT.
THERE ARE SOME PEOPLE WHO ARE
ARGUED TO THE CONTRARY, HAS
ARGUED THAT REALLY THERE ARE A
LOT OF THINGS THAT PARENTS
DECISIONS THE CHILDREN MAKE
ABOUT THEIR CHILDREN AND
CHILDREN DON'T NECESSARILY GET
TO REVISIT ALL OF THEM AT THE
AGE OF 18 SO IT'S NOT CLEAR
THAT THIS IS ONE OF THOSE CASES
WHERE WE SHOULD ALWAYS GO BACK
AND ASK CHILDREN FOR THEIR
CONSENT.
AND ADDITIONALLY AS MENTIONED
EARLIER, DIFFERENT STATES AND
COUNTRIES ALLOW CHILDREN.
THIS INCLUDES MATURITY.
SO SOME COUNTIES CAN HAVE
DIFFERENT AGES AND THIS CAN
VARY BETWEEN THE AGE OF 14 AND
21.
A MINOR WHO IS MINOR AND
PREGNANT AND IN THE MILITARY
CAN HAVE THE ABILITY TO CONSENT
FOR THEMSELVES.
SOME HAVE STRANGE THAT THEIR
CAN HAVE THEIR OWN MEDICAL CARE
IF THEY'RE PREGNANT BUT ONCE
THE CHILD IS BORN, AND THEY'RE
NO LONGER PREGNANT, THEY CAN
CONSENT FOR THEIR CHILD BUT NOT
FOR THEMSELVES.
AND SOME IS MATURITY, THAT CAN
BE BASED ON EITHER A CLINICIAN
EVALUATING THE MINOR AND
DECIDED THAT THEY HAVE THIS
MATURITY OR BASED ON A COURT
PROCESS WHERE COURT DETERMINES
THIS.
AND FINALLY, MANY CASES WHERE
CHILDREN CAN CONSENT TO CARE
FOR HAVING CERTAIN CONDITIONS.
FOR INSTANCE, THERE ARE LAWS
THAT ARE BASED ON A CONCERN
THAT ADOLESCENT FAILED TO
RECEIVE THE TREATMENT BECAUSE
IT WOULD REVEAL RISKY SEX
PRACTICES THAT WOULD INCLUDE
GETTING TREATMENT FOR.
THIS IS NOT ABOUT OH THIS MINOR
HAS A GREATER AUTONOMY BUT IF
WE LET PARENTAL PERMISSION BE A
BARRIER, WE MAY HAVE SEXUAL
TRANSMITTED DISEASES GO
UNTREATED.
SO WHEN WE'RE ASKING A QUESTION
ABOUT WHETHER CHILDREN CAN GIVE
ASSENT OR CONSENT, THERE IS
BEEN A STUDIES ON H.I.V.
RESEARCH.
AND THESE STUDIES HAVE SHOWN
THAT THERE ARE A LOST REASONS
TO QUESTION THE DEFAULT THAT
CHILDREN CAN'T GIVE CONSENT
UNTIL THEY REACH THAT LEGAL AGE
WHERE THEY'RE NOW ABLE TO
CONSENT FOR MANY THINGS.
SO FIRST, ONE CITY INVOLVED
USING A CONSENT FORM AND
TESTING ADOLESCENTS TO SEE HOW
WELL THEY UNDERSTOOD WHAT THEY
NEEDED TO KNOW AND OVER THE
HALF OF THE ADOLESCENTS
ANSWERED ALL THE QUESTIONS
CORRECTLY.
ANOTHER STUDY THAT I
PARTICIPATED IN, DID SOMETHING
TO TAKE THIS A STEP FURTHER.
SO WE COMPARED ANALYST TO ADULT
AND TESTED THEM AND FOUND NO
SIGNIFICANT DIFFERENCE BETWEEN
ADULTS AND AGE THE AGE OF 14.
WE DID FIND A RIL YOUNGER THERE
WERE CERTAIN DIFFERENCES IN
THEIR COMPREHENSION.
SO THIS SUGGESTED THAT HAVING A
CUT OFF COULD WORK AT LEAST IN
THIS CASE ALL THOET TESTS WERE
PRETTY SIMPLE SO THEY WERE NOT
DELVING DEEP AND UNDERSTANDING.
FINALLY UNDERSTOOD PLACEBO AND
CLINICAL TRIALS BUT DID LESS
WELL WITH THINGS LIKE RISK AND
RAMIFICATION OR A PARTICULAR
RISK THAT OCCURS IN H.I.V.
RESEARCH WHERE IF YOU RECEIVE A
H.I.V. VACCINE, YOU MAY HAVE
FUTURE FALSE POSITIVE UNCERTAIN
H.I.V. TESTS HA ARE DONE AND IT
LOOKS LIKE, UNLESS A BETTER
TEST IS DONE, YOU DON'T KNOW
WHETHER OR NOT YOU HAVE H.I.V.
SO. THAT IS SOMETHING THAT THEY
DIDN'T UNDERSTAND VERY WELL.
SO WE DID A STAKEHOLDERS ON
ADOLESCENT CONSENT TO TRY TO
UNDERSTAND HOW DO WE MAKE SENSE
OF ALL OF THESE ROLES AND LAWS
TO REALLY DO A BETTER JOB OF
ADDRESSING ADOLESCENT NEEDS AND
RESEARCH.
REDID SEMI STRUCTURE NEEDS FOR
PROPOSED SAMPLING OF 15
POLICIES STAKEHOLDERS WHICH
INCLUDED LAWYERS AND SCHOOL
ADMINISTRATORS AND POLICY
MAKERS AND THEN WE CONDUCTED
THE ANALYSIS.
AND WE FOUND THREE THINGS, THE
FIRST WAS THAT AGE IS A PROXY
FOR DECISION MAKING CAPACITY.
AND PEOPLE THOUGHT THAT
MATURITY AND CONTEXT AND RISK
RATIO MATTERED MORE.
THE SECOND THING IS THAT POLICY
COULD EVOLVE, AND THE THIRD IS
THAT ADULTS SHOULD BE FOCUSED
ON EMPOWERING IN
DECISION-MAKING TO MOVE THEM
TOWARDS OWNERSHIP OVER THEIR
OWN HEALTH OVERTIME.
SO FOR THE FIRST THING, I WANT
TO GIVE YOU A COUPLE OF
REPRESENTATIVE QUOTES.
ONE PERSON POINTED OUT, PEOPLE
DON'T MATURE THE SAME WAY.
AND YOUNGER ADOLESCENT THAT CAN
BE QUITE MATURE AND IT JUST
DEPENDS.
THEIR VIEW IS A AGE IN GENERAL
IS A CORE PROXY.
THE SECOND THEME THAT I HAD
MENTIONED POLICY SHOULD EVOLVE
WITH SOCIETAL VIEWS.
THIS PERSON, WHO IS IT HELPING
IS THE POLICY FOR US TO HELP
RIGHT AND RELIGIOUS AND MORAL
OR IS IT TO PROTECT FOR WORK
FOR OUR ADOLESCENT.
FOR ME, I THINK THE POLICIES
NEED TO CHANGE AND EVEN THE
LAWS NEED TO CHANGE TO REFLECT
CURRENT SOCIETY.
AND WITH ACCESS TO SOCIAL
MEDIA, THE THINGS THAT
ADOLESCENT KNOW HAS REALLY
INCREASED, THEY KNOW NOW THAN
PREVIOUS GENERAL RAISESING.
FINALLY WITH THE THIRD THEME,
THERE WAS REALLY THE SENSE THAT
IT'S IMPORTANT FOR ADULTS TO
STILL BE INVOLVED IN DECISIONS
IN ADOLESCENTS WHEN THAT'S
POSSIBLE AND WHEN THAT'S A
PROTECTION.
BUT IT'S REALLY A SHIFT FROM
MAKING DECISIONS IN
AUTHORATVIVE.
FOCUSED ON EAST AFRICAN CONTEXT
BUT WHAT WE FOUND.
BUT FIRST LAWS WITHOUT AGE CUT
OFF WHICH IS MATURE MINOR LAWS
WHERE A CLINICIAN CAN DETERMINE
WHETHER A MINOR HAS THE ABILITY
TO MAKE DECISIONS FOR
THEMSELVES.
THAT MAY HELP ADDRESS DIVERSION
AND ALLOW CLINICIANS TO REALLY
DETERMINE, IF THEY HAVE A LOT
MORE MATURITY OR LESS MATURITY
BASED ON THEIR AGE.
ADDITIONALLY, THERE IS A NEED
ON CONTINUED RESEARCH IN
WORKING TOGETHER TO MAKE
DECISIONS.
SO THIS COULD EVOLVE TRAINING,
CARE GIVERS ON HOW TO GUIDE AND
FIGURING OUTWEIGHS TO SUPPORT
ADO LESS EPT WITH INTERVENTION
TO ADDRESS LIMITATIONS.
THE LATTER RESEARCH SHOWN THAT
THEY CAN UNDERSTAND SOME OF THE
IMPORTANT CONCEPT.
BUT THERE MAY BE OTHER
LIMITATIONS, WE KNOW THAT THE
ADOLESCENT BRAIN IS ONE THAT
HAS TROUBLE RESISTING PRESSURE
AND MAYBE THERE IS A WAY TO
REALLY JUST ADDRESS THOSE
DEVELOPMENTAL LIMITATION TO SEE
HELP ADOLESCENTS MAKE BETTER
DECISIONS BY THEMSELVES.
SO THIS IS THE PAPER THAT TRIES
TO ILLUSTRATES, THE RESEARCH
THAT I WAS JUST TALKING ABOUT.
SO FINALLY DISTANT IS ANOTHER
IMPORTANT CONSIDERATION AND
MANY GUIDELINES MENTION THAT A
CHILD'S DISSENT SHOULD BE NOTED
AND A CHILD AND/OR PARENT
SHOULD BE ABLE TO WITHDRAWAL AT
ANY TIME.
HOW DO WE KNOW IF A CHILD IS
DISSENTING FROM A RESEARCH.
AGE IS A FACTOR, SO A CRYING
CHILD WHO IS THREE MAY JUST BE
HAVING A TANTRUM OR HUNGRY AND
THAT DOES NOT MEAN THAT THE
CHILD IS DISSENT.
BUT WE SHOULD RESPECT DIS
STAINED DISSENT WHO UNDERSTAND
WHAT HE OR SHE IS DOING.
IT MAY BE A CONTRARY TEENAGERS
THAT IS SAYING YES TO
EVERYTHING.
IF A CHILD DOESN'T HAVE
CAPACITY OR MAKING CONTRARY
DECISIONS, REALLY DOESN'T WANT
TO DO SOMETHING, WE HAVE TO
THINK ABOUT THE PRACTICALITY OF
GET THATING CHILD TO
PARTICIPATE IN RESEARCH.
THEY HAVE TO BE DRAGGED TO THE
SITE AND HELD DOWN, THAT'S NOT
SOMETHING THAT I THINK IS GOOD
FOR EITHER THE RESEARCH STAFF
OR THAT CHILD.
SO THERE MAY BE CASES WHERE
EVEN IF THERE IS AN AUTONOMY
REASON OR THERE IS NOT A REASON
BASED ON THINKING THAT, THE
CHILD IS NECESSARILY GOING TO
BE HARMED, THAT ACTUAL
PRACTICALITY OF IT YOU JUST
DON'T EN ROLL THAT CHILD
ANYMORE.
AND DISSENT IS DIFFERENT FROM
DISTRESS.
AND THE IT MAY BE CONTROLLER TO
EXPRESS SOMEBODY'S AUTONOMY BUT
DISTRESS IS WHEN A CHILD IS
EXPERIENCING PSYCHOLOGICAL HARM.
LIKE IF THERE IS A CHILD WHO IS
TERRIFIED OF INJECTIONS AND THE
RESEARCH INVOLVES AN INJECTION,
THAT MAY INCREASE THE RISK OF
RESEARCH PARTICIPATION FOR THAT
CHILD BECAUSE OF THE
PSYCHOLOGICAL HARM THAT THEY
MAY EXPERIENCE.
THAT MAY BE DIFFERENT OR HIGHER
THAN WHAT OTHER CHILDREN
EXPERIENCE.
AND IMPORTANTLY, THERE ARE
TIMES WHEN EVEN IN RESEARCH, IT
COULD BE ETHICALLY JUSTIFIABLE.
FOR INSTANCE, IF THE CHILD CAN
BENEFIT FROM THE RESEARCH THAT
THEY COULD NOT OBTAIN OTHERWISE
AND THE HARMS ARE OUT WEIGHED
BY THAT.
BUT IT'S IMPORTANT TO THINK OF
THE LEVEL OF RISK IS THAT IS
BEING ADDED TO THE RESEARCH AND
DETERMINING WHETHER THE HARMS
FROM THAT RESEARCH
PARTICIPATION ARE OUT WEIGHED
BY THE POTENTIAL RISKS.
OKAY, SO IN SUM, RESEARCH CHILD
ABOUT TREATING CHILDREN AS A
GROUP.
AND MOST ALLOW CHILDREN TO
PARTICIPATE IN RESEARCH THAT
BENEFITS THEM AND MINIMAL RISK
RESEARCH IF THERE IS NO
PROSPECT OF BENEFIT.
I REALLY WANTED TO ENCOURAGE TO
YOU RECOGNIZE THAT ALTHOUGH
THERE IS LONG BEEN THIS DEFAULT
FOR THINKING ABOUT THE
PROTECTION OF CHILDREN, THERE
ARE MANY CASES WHERE WE NEED TO
GIVE CONSIDERATION TO ENROLLING
CHILDREN IN RESEARCH EARLIER.
AND THE COVID-19 PANDEMIC
REALLY TAUGHT US THAT SORT OF
THINKING REFLECTIVELY AND NOT
SPECIFICALLY ABOUT CHILDREN CAN
REALLY HURT THEM IN PANDEMIC
RESPONSE.
BUT IN MANY CASES, HOWEVER, TO
ENSURE THAT EARLIER INCLUSION
OF CHILDREN IS ETHICAL, IT'S
IMPORTANT TO ENSURE THAT THERE
IS A STRONG EXPECTATION AND
THERE IS A RESPECTFUL
PERMISSION IN A PROCESS.
FINALLY, WE REALLY DO NEED BARE
GUIDANCE ON WHEN CHILDREN
SHOULD DECIDE ON THEIR OWN ON
HOW TO PARTICIPATE ON THEIR
RESEARCH AND HOW CARE GIVERS
CAN MAKE GOOD RESEARCH
DECISIONS.
: AND A LOT STRUGGLE WITH
CHILDREN GAIN AUTONOMY AND GO
THROUGH ADOLESCENT AND IT
DESERVES MORE ATTENTION TO GET
THAT RIGHT.
THANK YOU VERY MUCH, AND I
WOULD LOVE TO HEAR FROM YOU AND
TURN THE TABLES AND SEE IF YOU
HAVE ANY QUESTIONS OR COMMENTS
BASED ON YOUR EXPERIENCE.
>> GREAT, SEEMA, THANK YOU SO
MUCH FOR YOUR LECTURE, I JUST
WALKED AWAY FROM MY COMPUTER
WHERE THERE MAY BE SOME
QUESTIONS.
WE HAVE A NUMBER OF PEOPLE HERE
IN THE AUDIENCE, THEY'RE GOING
TO WALK TO THE MICROPHONES IF
THEY HAVE A QUESTION.
AND I'M GOING TO SEE IF THERE
ARE QUESTIONS ONLINE.
BRITNEY AS A QUESTION.
>> THANKS SO MUCH FOR THIS
PRESENTATION, I WAS WONDERING
IF LAW ABOUT THE AGE OF CONSENT
TO RESEARCH ARE CHANGING
ALONGSIDE LINES OF AGE CONSENT
FOR OTHER THINGS.
I KNOW VIRGINIA RAISED THEIR
MARRIAGE AGE TO 18, THAT
AFFECTING RESEARCH OR LEFT UP
TO IRBs AND RESEARCHERS TO
DECIDE?
>> YEAH, GREAT QUESTION.
SO THERE IS THIS INTER PLAY
BETWEEN GENERAL LAWS ABOUT WHEN
ADOLESCENTS CAN GIVE CONSENT IN
RESEARCH WHEN THEY CAN GIVE
CONSENT IN RESEARCH.
SO I THINK AN EXAMPLE YOU GET,
BECAUSE A CHILD CAN'T MARRY
UNTIL THEY'RE 18, THAT CHILD
COULD NOT MAKE DECISIONS BASED
ON THEIR STATUS, IS IT EARLIER?
SO IT MAY BE BEEN EARLIER AND
THEN MADE DECISIONS AND THAT
WOULD NO LONGER BE THE CASE.
BUT THERE ARE A LOT OF OTHER
EXAMPLES THAT RAISE QUESTIONS.
SO FOR, VACCINATIONS SOME
STATES ARE TRYING TO LOWER THE
AGE AT WHICH, SOME CITIES ARE
TRYING TO LOWER THE AGE WHERE
THEY CAN GIVE CONSENT GIVING
THAT THERE IS ADO LESCENT HAVE
STRONG VACCINE USE.
WE HAD CONSULTS ABOUT THAT,
WHERE A CHILD HAD GOTTEN INTO
SUMMER CAMP AND HAD TO GET
VACCINATIONS.
AND IT WAS A PRESTIGIOUS CAMP
SHE WANTED GET TO HER MOM WAS
AGAINST VACCINE AND THEY WANTED
TO GET VACCINES WITHOUT HER
MOTHER'S CONSENT AND THERE WAS
NO WAY.
SO IT'S UP TO IRBs TO DECIDE IS
THE LAW TO CONSENT THE
PARTICULAR TREATMENT OR
INTERVENTION APPLICABLE TO THIS
PARTICULAR RESEARCH STUDY?
AND THEY SAID THE RESEARCH
STUDY INVOLVED THAT SPECIFIC
INTERVENTION LIKE GIVING A
VACCINE, OR TREATING A CHILD
FOR SEXUALLY TRANSMITTED
INFECTION, IT CAN MOVE FORWARD
AND THERE IS GOOD GUIDANCE NOW
FROM THE FDA ON THIS.
BUT MANY INTERVIEWS ARE STILL
RELUCTANT.
AND PASTER RELUCTANCE IS THAT
RESEARCH DOES NOT JUST IN VOLVE
INTERVENTION IT'S GOING TO
INVOLVE SURVEYS AND BLOOD DRAWS
AND OTHER THINGS TO GATHER THE
DATA THAT YOU NEED.
SO THAT'S WHY WHERE IT BECOMES
A LITTLE GRAY AND DEFAULT
CONSERVATIVE JUDGMENT THAT
CHILDREN CANNOT MAKE THESE
DECISIONS ON THEIR OWN.
FINALLY, I WILL SAY IN CERTAIN
COUNTRIES WHERE THERE IS A LOT
OF RESEARCH GOING ON, STATES
HAVE ACTUALLY CREATED LAWS THAT
FOCUS ON RESEARCH SPECIFICALLY
AND ALLOW CHILDREN UNDER THE
AGE OF 18 TO CONSENT TO
RESEARCH AND IT'S IMPORTANT IN
CASES WHERE CHILDREN MAY BE
GOING TO A CLINIC SITE, GETTING
TREATMENT FOR H.I.V. AND GOING
BY THEMSELVES AND FOR THEM TO
EN ROLL IN RESEARCH WITH THEIR
PARENTS PERMISSION MAY MAKE IT
POSSIBLE FOR THEM TO EN ROLL
FROM A PRACTICE PERSPECTIVE.
GETTING CARE AND SORT OF BEING
ABLE TO MAKE THAT DECISION
RESEARCH AND THAT IS PERMITTED
FOR INSTANCE IN TEN I CAN'T.
CAN --KENYA.
GREAT QUESTION, I HOPE TO
ELABORATE IF I MISSED THE
INTENT OF YOUR QUESTION.
>> SO I DON'T HAVE ANY NEW
QUESTIONS FROM THE WEB FOR
THOSE OF WHO ARE STILL OUT
THERE, YOU CAN GO TO THE
DISCUSSION BOARD, THERE IS A
PLACE FOR SESSION 3, BUT I HAVE
A QUESTION.
I WANT TODAY FOLLOW-UP ON YOUR
LAST SLIDE, ON THE LAST BULLET
ABOUT HOW BEST TO THINK ABOUT
UNDER WHAT CIRCUMSTANCES OR HOW
BEST TO SUPPORT THE ADOLESCENT?
SO AS YOU WERE TALKING AND YOU
KNOW, WE'RE JUST NOW TALKING
ABOUT WHEN IS IT OKAY FOR AN
ADOLESCENT TO DO THIS ON THEIR
OWN.
AND I'M THINKING ABOUT THE FLIP
SIDE, WHEN WOULD IT BE BETTER
OR WHEN WOULD BE BEST TO HAVE
THE WHOLE FAMILY INVOLVED?
OR AT LEAST A PARENT INVOLVED
TO SUPPORT THE ADOLESCENT IN
TAKE MAKING THE DECISION.
I GUESS TO SAY, IT SEEMS LIKE
THERE IS ROOM FOR HAVING
RECOMMENDATIONS THAT MAYBE NOT
DEFAULT BUT DEFAULT TO THERE IS
JUST SOMETHING, THIS IS A
DECISION YOU SHOULD BE MAKING
WITH YOUR PARENTS.
NOT THE PARENT PROVIDE
PERMISSION EXAMINE WE GET
ASSENT FROM YOU BUT THAT'S A
JOINT ENDEAVOR.
AND I DON'T KNOW IF THERE IS
ANY RESEARCH ON THAT SPACE OR
ANY WORK THAT YOU'RE DOING ON
THAT SPACE?
>> YEAH, THAT'S A GREAT
QUESTION.
SO WE DID ONE STUDY WORD AND IT
WAS REALLY INTERESTING BECAUSE,
CAREGIVER--SO CLINICIAN REALLY
FOCUS AGO NOT IDEA OF JOINT
DECISION MAKING AND TRYING TO
WORK WITH THE ADOLESCENT
TOGETHER.
THEY REALLY FOCUS ON SORT OF
ONE PERSON MAKING THE DECISION.
SO IT WAS EITHER, ADOLESCENT OR
PARENTS MAKE IT BY THEMSELVES
AND THEY CHOOSE BOTH OPTIONS IN
DIFFERENT CASES.
SO IT WAS REALLY INTERESTING
BECAUSE IN SOME WAYS, I DON'T
THINK WHAT REALLY DROVE THIS
FINDING AND SOMETHING I WANT TO
EXPLORE MORE BUT ALMOST LUKE A
LACK OF APPRECIATION FOR THE
ABILITY TO RALLY MAKE THESE
DECISIONS TOGETHER.
SXL YOU KNOW, NOW THAT I HAVE
TO SAY, I SORT OF UNDERSTAND
THAT IT'S IT'S OFTEN A FRAUGHT
TIME WHEN YOU'RE TRYING TO MAKE
DECISIONS WITH YOUR ADOLESCENTS
AND MANY TIMES THEY REJECT THAT
AND DON'T WANT TO MAKE THOSE
DECISIONS WITH YOU, MY PRETEEN
IN MY CASE.
SOMETIMES IT'S CLEANER TO HAVE
THE DECIDER.
BUT I DON'T THINK IN MOST CASES
IS BETTER AS YOU WERE ALLUDING
TO.
>> YEAH.
>> SO WE DID ANOTHER STUDY
WHERE WE WERE REALLY TRYING TO
USE THE WISDOM OF CROWD SOURCES
TO UNDERSTAND WHERE PEOPLE FROM
LOW AND MIDDLE INCOME COUNTRIES
WHAT IS IT THAT WE SHOULD DO TO
TRY AND GET BETTER DECISIONS
FOR ADOLESCENTS AND MORE
ETHICAL RESEARCH.
AND ONE OF THE QUESTIONS WE
ASKED ABOUT WAS PART WAIVERS,
WHAT IF YOU JUST GET THE PARENT
OUT OF THE EQUATION.
AND THAT WAS THE ONE THING MOST
PEOPLE OBJECTED TO.
WE COULD NOT GET WAIVERS
BECAUSE POEM HAD THIS INSTINCT
THAT FIRST AND IN MANY CASES
IT'S IMPORTANT FOR PARENTS TO
BE INVOLVED AND THEY ALSO FELT
THAT IF PARENTS ARE SORT OF,
THEY'RE STUCK THEY HAVE THIS
ADOLESCENT AT HOME AND THEIR
ADOLESCENT IS GOING TO HAVE TO
GO TO THE RESEARCH SITE IF
THERE IS A ROIFP AND A PARENT
HAS TO DEAL WITH IT, IT DOES
NOT MAKE SENSE TO TAKE THE
PARENT OUT OF THE EQUATION
WHOLELY OUT.
I THINK THE CHALLENGE, RIGHT IS
THERE IS A LOT OF DIFFERENT
KIND OF PARENTAL CAN SENT.
AND WHAT WE NEED TO DO A BETTER
JOB I THINK IS FIRST BEING ABLE
TO DISTINGUISH WHEN IT'S NOT A
GOOD IDEA WHEN TO INVOLVE TO
THE PARENT, MAYBE THE PARENT
HAS BEEN CHECKED OUT OR THEY
WOULD REACT NEGATIVELY AND
WAIVER IS THE ONLY OPTION.
IN OTHER CASES, YOU MAY NEED TO
FIGURE OUT HOW CAN THE RESEARCH
TEAM ENGAGE THE PARENT OR HELP
THE ADOLESCENT AND CHAIR
INFORMATION THAT THEY MAY WANT
TO SHARE WITH THEIR PARENTS SO
THEY CAN WORK TOGETHER AND MAKE
THAT DECISIONS AND MAYBE
FACILITATE THAT DECISION.
SO I DO THINK THAT TO ME IS
MAYBE IT'S DEPENDS ON WHO IS
SHOWING UP TO THE RESEARCH SITE
AND IF THE ADOLESCENTS IS THERE
BY THEMSELVES AND WORKING WITH
THEM TO GET THEIR PARENTS
INVOLVED IF THE ADOLESCENT IS
THERE WITH THEIR PARENTS AND
DOING THIS DELICATE DANCE OF
HAVING THAT CONVERSATION.
BUT WHAT I UNDERSTAND RIGHT NOW
IS THAT, IT'S JUST KIND OF NOT
A DREDS SYSTEMATIC AND THERE IS
NOT A LOT OF WIDE ANS FORERS TO
INVESTIGATE.
WHERE ADOLESCENT MAY BE
RELUCTANT TO INVOLVE THEIR
PARENTS.
>> YEAH, YEAH.
FRAUGHT AND ALSO THEN HARD FOR
IRBs RIGHT TO SAY OH THEY SAY
THEY'RE GOING TO DO XY AND Z, I
GUESS WE HAVE TO TRUST THEM.
BUT WOULD LIKE THEM FOR MAYBE
HAVE SOME SECOND OR THIRD
THOUGHTS.
SO FOR EXAMPLE, YOU MENTIONED
THAT SOME STATES WELL IT'S TRUE
IN THE STATE OF MARYLAND FOR
EXAMPLE, THAT A SOMEBODY WHO IS
UNDER THE AGE OF 18 WHO HAS AN
S T.D., CAN GO AND SEEK
TREATMENT FOR THEMSELVES.
THEY'RE ALSO ABLE TO PROVIDE
PERMISSION TO EN ROLL IN
RESEARCH DIRECTLY.
NOW IF I WAS THE COLIN KISSING
OR IF --I WAS THE CLINICIAN, I
KNOW THE ADOLESCENTS CAN COME
TO YOU BY THEMSELVES BUT IT
WOULD BE GREAT IF YOU TALK TO
THEM ABOUT WHY THEY DON'T WANT
TO ENGAGE THEIR PARENTS AND
WHAT THE RISK RIGHT SIDE IN
ENGAGING WITH THIS RESEARCH
WITHOUT YOUR PARENT'S KNOWLEDGE.
WE'RE GOING TO DO THE BEST WE
CAN TO ENSURE THAT THE
INSURANCE COMPANY ISN'T.
THERE ARE ALL SORTS OF THINGS
THAT SHE SHOULD BE CONSIDERING.
AND IF THEY SAY NO NO NO, THIS
IS TOTALLY COOL FOR THEM.
IT'S EASIER FOR ME TO BE MY BY
SELF, JUST ONE MORE QUESTION OR
ONE MORE ENGAGEMENT.
IT FEELS LIKE IT WOULD MAKE
SENSE.
>> I AGREE WITH THAT.
AND I THINK SOME IS HELPING
ADOLESCENTS.
SO I THINK THE EXAMPLE YOU'RE
ALLUDING TO IS THERE CAN BE
SOME CASES WHERE TREATMENT,
THEY'RE ABLE TO GET
CONFIDENTIAL TREATMENT THAT THE
EXPERIENCE COMPANY IS BUILD AND
THEY SEND A EXPLANATION OF
BENEFITS AND PARENTS GETS THAT
IN THE MAIL AND SEE THAT THEIR
ADOLESCENTS WAS ENGAGED AND
GETTING CARE FOR SOMETHING.
THAT COULD BE ONE WAY TO TALK
OUT OF ADOLESCENTS, MAY NOT
APPLY TO THE RESEARCH CONTRACT
AND INTERVENTIONS ARE NOT.
BUT STILL I THINK, THE ISSUE
MIGHT BE SORT OF FROM AN IRB
PER RESPECT PIF HOW DO YOU, HOW
CAN RESEARCH DEMONSTRATE THAT
THEY GOT THE RIGHT.
>> YEAH.
>> FOR TRYING TO ENGAGE PARENTS.
AND MAYBE HAVE, YOU KNOW, A
SORT OF COMMON SET OF QUESTIONS
THEY ASK OR DIFFERENT SOURCES
OF GUIDANCE THAT THEY CAN
PROVIDE TO ADOLESCENTS TO TRY
TO GET THEIR PARENTS TO BE
ENGAGED.
AND THAT MAY BE I THINK, OF
THINGS THAT ARE LIKE THIS GRAY
AND COMPLICATED ARE HARD TO
REGULATE BUT MAYBE ONE WAY TO
DO IS JUST REALLY HAVE SOME
GREATER DETAIL ABOUT THAT
PROCESS.
>> YEAH, I COMPLETELY AGREE AND
I THINK I COMPLETELY AGREE AS
IT RELATES TO CONSENT GENERALLY
AND ESPECIALLY IN THIS CONTEXT.
ALEX HAS A QUESTION.
>> THANK YOU FOR THIS.
I WANTED TO ASK ABOUT WHAT YOU
THINK SOME GOOD STRATEGIES
WOULD BE FOR NOT SYSTEMATICALLY
EXCLUDING CHILDREN WHO'S
PARENTS ARE MAYBE HARD TO REACH
OR HARD TO GET CONSENT FROM.
IT SEEMS LIKE THERE MAY BE
PATTERNS WITH PARENTS THAT ARE
HARDER TO ENGAGE.
WHAT DO YOU THINK ARE SOME GOOD
WAYS?
>> GREAT QUESTION.
SO WHEN THE STUDY WE DID,
LOOKING AT THE STEP HERE FOR
ADOLESCENTS IN KENYA.
ONE OF THE THINGS WE FOUND
THERE WERE A LOT OF ADOLESCENTS
WERE SHOWING UP FOR CARE AND
THEY WERE SHOWING UP BY
THEMSELVES AND WITH THOSE
ADOLESCENTS, IT WAS
EXCEPTIONALLY HARD TO GET THEM
TO GET THEIR PARENTS ENGAGED.
BECAUSE THEIR PARENTS WERE NOT
ROUTINELY ENGAGED IN A LOT OF
DECISIONS.
SO WE HAVE APPLIED FOR A WAIVER
FROM THE IRB SPECIFICALLY FOR
THOSE ADOLESCENTS.
WHO THOSE WHO SAID THEY
COULDN'T GET THEIR PARENT'S
PERMISSION.
WE TRIED TO DO REALLY FOR THE
OLDER ADOLESCENTS THAT WERE
SHOWING UP FOR THEIR OWN CARE.
SO I THINK PARENTAL WAIVER IS
ONE OF THE BEST TOOLS.
ANOTHER WAY OF DOING IT, IF
THERE IS A WAY TO GET PARENTAL
PERMISSION THAT IS ELECTRONIC
OR OVER THE PHONE, THAT MAY BE
ANOTHER WAY, IF A PARENT IS
JUST NOT ABLE TO BE PHYSICALLY
PRESENT, THAT THEY CAN STILL BE
THERE ENROLLED.
AND SOMETIMES THAT'S IMPORTANT
FROM THE PERSPECTIVE OF
WORRYING ABOUT SCUING RESEARCH
PARTICIPATION.
SO THERE IS A GREAT STUDY BY
LIEU AND COLLEAGUES WHO DO YOU
LEAVE OUT OF THE RESEARCH
STUDIES?
AND THEY FOUND THAT OLDER
ADOLESCENT, BLACK ADOLESCENT,
ADOLESCENT OF SUBSTANCE USE
WERE LESS WELL REPRESENTED IN
THE STUDIES.
SO I THINK IN SOME WAYS, I HOPE
THAT GETS TO YOUR QUESTION BUT
STRONG REASONS TO GET A WAIVER
AND SOMETIMES IT'S IMPORTANT TO
GIVE THEM THAT DATA TO SHOW
THEM I COULDN'T NEED A WAIVER.
>> GREAT, THANK YOU.
>> SURE, THANK YOU.
>> GREAT, WELL THANK YOU SO
MUCH SEEMA FOR JOINING US.
IF ADDITIONAL QUESTIONS COME
IN, I WILL TRY TO ANSWER THEM
OR MIGHT FORWARD THEM TO YOU.
AND THANKS AGAIN.
>> OF COURSE, IT'S MY PLEASURE
TO COME AND HOPEFULLY NEXT YEAR
I CAN COME IN-PERSON.
>> THAT WOULD BE GREAT.
THANK YOU.
[APPLAUSE]
>> ALL RIGHT, THANK YOU.
>> SO NEXT WEEK, WE'RE GOING TO
BE TALKING ABOUT DIVERSITY AND
INCLUSION IN CLINICAL TRIALS.
UKEKO WHO IS ALSO FROM OUR
DEPARTMENT WILL JOIN US, YOU'LL
HEAR FROM ME AGAIN AND THEN
WE'LL HAVE A GUEST, IESHA WHO
IS AN EXPERT IN RECRUITMENT AND
RETENTION.
SO THAT'S IT FOR TODAY.
THANK YOU.