SO LET ME SAY A WORD ABOUT

HOW THIS UPON UNFOLD WHILE

PEOPLE ARE FILTERING IN.

WE HAVE 3 VERY DISTINGISHED AND

ANSWER EXPERIENCED AND

THOUGHTFUL INVESTIGATORS SITTING

IN FRONT OF YOU.

THERE WILL BE A FOURTH 1

HOPEFULLY COMEING IF HE CAN

BEFORE THE PANEL IS OVER.

I'VE ASKED THEM TO THINK ABOUT

THE ETHICAL CHALLENGES THEY FACE

AS PHYSICIAN INVESTIGATORS AND

SO THEY'RE GOING TO DEEP SAY A

COUPLE OF WORDS THAT YOU ABOUT

WHO THEY ARE, WHAT THEY DO, WHAT

KINDS OF CHALLENGES THEY FACE

AND THEN THE REST OF THE HOUR

WILL BE AN OPPORTUNITY FOR TO

YOU ASK THEM QUESTIONS.

THINGS WE'VE ALREADY TALKED

ABOUT IN THE CLASS OR THINGS

THAT YOU THINK THAT YOU WOULD

LIKE TO HEAR FROM THE MOUTH OF

SOMEBODY EXPERIENCED IN„i THESE

ISSUES.

SO WITH THAT BRIEF INTRODUCTION,

I WANT TO FIRST THING C

PANELISTS FOR COMING.

I KNOW THEY'RE INCREDIBLY BUSY

AND I REALLY APPRECIATE TAKES

THE TIME TO COME AND BE PART OF

THIS COURSE AND I WILL BRIEFLY

INTRODUCE EACH 1 AND THEN YOU'LL

HEAR MORE FROM THEM.

>> CLOSEST TO ME IS DR. MONICA

KCULIOUS, WHO IS CHIEF THE

BRANCH OF THE NIDDK.

NEXT TO HER IS BILL GAUL WHORKS

IS THE CLINICAL DIRECTOR OF THE

NATIONAL HUMAN GENOME AND

RESEARCH INSTITUTE, ALSO THE

CHIEF THE SECTION OF HUMAN AND

MEDICAL GENERATED FETTICS

BRANCH, ALSO LITTLE HEAD OF THE

UDP, UNDIAGNOSED DISEASES

PROGRAM.

AND RECENTLY 1 WON THE SAMMY

AWARD, SERVICE TO

AMERICAN--SERVICE TO AMERICA

MEDAL.

NEXT TO BILL IS MARILYN POWELL

OF THE DIRECTOR OF THE CLINICAL

ENS TUITION OF METROPOLITANNAL

HEALTH, CONSULTATION LIAISON

SERVICE AND ALSO A PREVIOUS

MEMBER CHAIR, EXCUSE ME OF AN

IRB.

SO WITH THAT INTRODUCTION I'M

GOING TO LET MONICA BEGIN AND

SAY A FEW WORDS.

>> THANK YOU KRISTIN.

SO I'VE NEVER DONE THIS PANEL

THING BEFORE LIKE OTHERS MAY

HAVE, BUT I WEAR A COUPLE OF

DIFFERENT HATS INCLUDING BEING A

PRINCIPLE INVESTIGATOR, AND

ASSOCIATE INVESTIGATOR ON NUMBER

OF TRIALS, I ALSO RUN A

SUBSPECIALTY TRAINING PROGRAM

WHERE WE HAVE FELLOWS WHO COME

TO SEEK CERTIFICATION IN

ENDOCRINOLOGY AND THEN ON TOP OF

THAT, I HAVE BEEN A VERY LONG

STANDING MEMBER OF THE NIDDK,

WITH CHRISTINE.

AND I'VE PARTICIPATED AND IN

MANY DIFFERENT KINDS OF STUDIES,

PHASE 1, PHASE 2, STUDIES,

PHYSIOLOGY STUDIES AND THEY RUN

THE GAMUT BUT AS I WAS REFLECT O

GBA MY EXPERIENCE, I THINK THAT

SOME OF MY MOST ETHICALLY

CHALLENGING EXPERIENCES HAVE

COMMON CONDUCT

NATURAL HISTORY PROTOCOLS AND

THESE PROTOCOLS HAVE MULTIPLE

AIMS AND IN OUR BRANCH, WE USE

THEM TO TO MAKE UNIQUE

OBSERVATIONS IN RARE DISEASES.

WE TRY NEW THERAPEUTICS AND

DIAGNOSICS OUT AND WE USE USE TO

TRAIN OUR PHYSICIANS.

EXAMPLE IS WHAT IS AND VERY MUCH

SO AT NIH, MAYBE MORE THAN OTHER

INSTITUTIONS, IS THAT IN THE

CONTEXT OF THESE TYPES OF

PROTOCOLS, THE MARGINS BETWEEN

RESEARCH STUDIES, AND ROUTINE

CLINICAL CARE CAN BE VERY, VERY

BLURRY AND SOMETIMES A SOURCE OF

GREAT CONFUSION ON BOTH THE

PARTS OF THE ASSOCIATE

INVESTIGATORS, THE TRAINEES AND

THE PATIENTS.

SO IN ORDER TO TELL YOU ABOUT

HOW I LOOK AT THIS CHALLENGE, I

THINK IT'S BEST TO START FROM

WOTHE BLURRINESS BEGINS AND I

BELIEVE THAT THAT ACTUALLY

OCCURS MOSTLY AT THE TIME OF THE

INFORMED CONSENT PROCESS.

SO HERE WE ARE AT A POINT WITH

WHEN A PATIENT IS BEING

RECRUITED INTO A STUDY WHERE

THEY MAY HAVE A RARE DISEASE

THAT PEOPLE IN OTHER CENTERS OR

PRIORITIZATIONS ARE NOT ENTIRELY

CLEAR WHAT TO DO WITH THEM AND

IT'S AT THAT POINT THAT WE

PRESENT WHAT WILL BE PERFORMED

AS PART OF THE STUDY, AND SOME

OF THE PROTOCOL SPECIFIC

PROCEDURES, MAY BE CLINICALLY

USEFUL TO THE PATIENTS BUT YET

SOME OF OF THEM MAY NOT BE.

AND IT IS VERY CLEAR THAT WE

HAVE A LOT OF DISCRETION WE AS

INVESTIGATORS HAVE AS WHAT WE

CAN DO TO ROUTINE CLINICAL CARE

IN ADDITIONITATION TO

ABNORMALITIES TANNING RESEARCH

SAMPLES, PERHAPS TISSUES DURING

THE COURSE OF AN OPERATION, OR

OTHER KINDS OF SAMPLES IN THE

PATIENT FOR OUR RESEARCH.

SO SO I THINK ABOUT 1 OF THE

DILEMMAS IN THAT SOMETIMES WE DO

NOT OFFER EACH AND EVERY PATIENT

ON THE HISTORY PROTOCOL THE SAME

ACCESS TO MEDICAL SERVICES THAT

MAY BE COMPLETELY UNRELATED TO

THEIR UNDERLYING CONDITION AND

IN NOT DISTRIBUTING THAT KIND OF

CAREUNE NORMALLY, THERE BECOMES

THIS SOME PATIENTS HAVE AN

ADVANTAGE OVER ANOTHER AND THE

QUESTION IS, THAT COMES TO MIND

IS WHAT MOTIVATES US AS AN

INVESTIGATIVE TEAM TO PRECEPT

THOSE TO SOME PATIENTS AND NOT

OTHERS AND IN DOING SO ARE WE

ABIDING BY THE PREACCEPTS THAT

WERE LAID OUT INITIALLY IN A

PROTOCOL CONSENT FORM?

DID WE MAKE THAT VERY CLEAR, AND

HOW DO WE DECIDE WITH WE OFFER

THESE KINDS OF BENYS AND WHY DO

WE DO IT?

ARE WE TRYING TO ENCOURAGE A

PATIENT TO COME BACK BECAUSE

WE'RE INTERESTED IN THEIR

PROBLEM, ARE WE TRYING TO OFFSET

THE INCONS CONVENIENCE TO THEM

FOR COMING TO THE NIH OR ARE WE

SORT OF EXERCISING THE PRINCIPLE

IN THAT THEY DON'T HAVE

RESOURCES IN THE COMMUNITY THAT

THEY NEED TO MAINTAIN THEIR

HEALTH.

SO I'M GOING ON, BUT I HAVE 5

MINUTES, I THINK I'M OKAY,

CORRECT?

SO I WAS TRYING TO COME UP WITH

SITUATIONS IN MY MIND WHERE THIS

MARGIN CAN GET BLURRED AND THE

FIRST THING IS I WOULD LIKE TO

DESCRIBE AN EXAMPLE OF WHERE THE

INFORMED CONSENT PROCESS CAN

BECOME DERAILED BECAUSE OF THE

ENTHUSIASM OF THE INVESTIGATOR.

AND THIS COULD LEAD TO AN

INABILITY OF THE PATIENT TO

UNDERSTAND WHAT PART OF A

NATURAL HISTORY PROTOCOL IS

ACTUALLY CLINICAL CARE RESEARCH

PURPOSES.

AND THIS HAPPENED MANY YEARS AGO

WHEN I WAS VERY YOUNG AND WE

WALK INTO THE ROOM OF A PATIENT

OF A HISTORY WHO WAS ENROLLING

IN A NATURAL HISTORY PROTOCOL

WHO HAD A RARE PITUITARY

INVESTIGATOR AND THE CLINICAL

INVESTIGATORS ANNOUNCED, HAVE

YOU A TIME BOMB IN YOUR HEAD.

WHICH COMPLETELY WAS THE WRONG

KIND OF ICE BREAKER TO USE WHEN

YOU'RE TRYING TO LAY OUT OF

PROTOCOL, THE RESEARCH AND

CLINICAL CARE STRATEGY TO THE

PATIENT.

THE PATIENT COULD NOT DISCERN

THE DIFFERENCE BETWEEN WHAT WE

WERE DOING FOR OUR GOOD AND WHAT

WAS BEING DONE FOR HER GOOD.

AND SO, WE NEED TO BE CLEAR, I

MEAN THIS IS A VERY, VERY,--YOU

MIGHT SEE EGREGEIOUS OR OVERLY

ENTHUSIASTIC INTRODUCTION TO THE

PROTOCOL BUT THAT'S SORT OF

SAYING--OCCURS ALL THE TIME.

THE INVESTIGATORRIVE TEAM HAS

THE ABILITY TO SET THE TONE FOR

THE PATIENT'S PARTICIPATION I

WANT TO MENTION ANOTHER TIME

I'VE SEEN THE MARGINS OF CARE

AND THIS IS JUST AND THIS IS IN

THE DISTANT PAST AND SOMEBODY

ENROLL INDEED A PROTOCOL IS THEN

SOMETHING TO IDENTIFY THE

EXAMPLE, IS A PATIENT, A MINOR,

A YOUNG MAN WAS ENROLLED IN A

PROTOCOL TO LOOK AT POSSIBLE

PHENOTYPES OF A RELATIVELY NEW

HER EDUCATIONALITTORY SYNDROME

AND THE INVESTIGATIVE TEAM DID

AN ULTRASOUND OF THE THYROID,

NOW THIS IS PART OF MY WORLD,

THE THYROID AND THEY CALLED A

CONSULT FOR A TINY, AND I'M

TALKING 2-MILLIMETER LITTLE

VISESLE IN THE THYROID WHAT TO

DO SO THE CONSULT WENT AS IT

WOULD NORMALLY DO, WE ASK THE

FAMILY HISTORY AND ALL THIS

OTHER STUFF AND WE DETERMINE

THAD THE LESION WAS TOO SMALL TO

BIOPSY, THAT THE BEST COURSE OF

ACTION WAS TO OBSERVE THIS AND

WE KNEW THAT WOULD HAPPEN

BECAUSE THIS PATIENT WAS COMING

BACK PRE--FREQUENTLY AS PORT OF

THIS PROTOCOL.

Y OTHER INVESTIGATION TEAM

DECIDED TO REMOVE THE THYROID IN

TOTAL AND PUT THE PATIENT ON

THYROID MEDICATION FOR THE REST

OF HIS LIFE, AND EAR HERE WE

HAVE THE QUESTION, WE WHO-FIC WE

GO BACK, WHY WAS THAT DECISION

MADE, IT WAS PERHAPS MADE ON

WHAT IS SEEMINGLY SOUND

FUNDAMENTAL CLINICAL, YOU KNOW

FACTS.

THE PATIENT WAS A YOUNG MAN HAD

A THYROID ABNORMALITY MAY HAVE

HAD A HISTORY OF THOI ROADWAY

CANCER BUT IN FACT THE

PENNISHMENT TO THE THYROID

WASN'T REALLY WELL DESERVED SO

THE QUESTION WHAT MOTIVATES THE

INVESTIGATOR TO DO SUCH A THING.

SO, YOU KNOW THIS IS A RARE

EXAMPLE, BUT IT WAS 1 THAT

CERTAINLY MADE ME TAKE PAUSE AS

A YOUNGER INVESTIGATOR TO SAY

THAT THESE MARGINS BETWEEN

RESEARCH AND CLINICAL CARE ARE

SOMETIMES BLURRY AND WE NEED TO

CONSTANTLY BE LOOKING AT OUR

MOTIVATION FOR THE DELIVERY OF

CLINICAL CARE IN THE CONTEXT OF

RESEARCH SETTING, SO, THANK YOU.

>> WELL IT'S INTERESTING MONICA

THAT THERE'S SOME OVERLAP

BETWEEN WHAT YOU WERE KNOWING

ABOUT AND WHAT I WAS THINKING

ABOUT, TOO.

I WAS THINKING ABOUT ALLOCATION

OF RESOURCES IN TERMS WHAT HAVE

STUDIES WE'LL BE WILLING TO

PURSUE ARE.

I STUDY RARE DISEASES SOME OF

THEM NEW DISEASES AND REALLY

HOLD A LOST RESOURCES, AND I'M

NOT REALLY TALKING SO MUCH ABOUT

MONITORITARY RESOURCES AS SORT

OF THINKING RESOURCES AND PEOPLE

SURROUNDING ME WHO KNOW WHAT

THEY'RE DOING IN TERMS OF

PURSUING A PARTICULAR DISORDER.

AND 1 OF THE CONSIDERATIONS IN

DECIDE WAG YOU'RE GOING TO

PURSUE AND WHAT YOU CAN ACTUALLY

ACCOMPLISH.

I THINK THE ABILITY TO AKOCHLISH

SOME OF THESE THINGS DEPENDS

UPON HOW THEY'RE RECEIVED BY

OTHERRENTITYS AT THE FEDERAL, AT

THE INSTITUTIONAL LEVEL AS WELL

AS AT THE SINGLE PERSON LEVEL.

AND 1 CONSIDERATION THAT I FIND

MISSING THIS THIS IS THE

NOVEMBER NOVEMBER THIS THIS IS

THE CONSIDERATION OF THE SENSES

OF OMISSION.

IN OTHER WORD WHEN IS PEOPLE

LOOK AT THE RISKS OF A COAT

COLOR INVOLVEMENT OF PATIENTS IN

A PROTOCOL WHAT'S THE RISK OF

NOT DOING THE PROTOCOL AND

SOMETIMES THAT RISK IS CERTAIN

DEATH.

AND YET THAT CONSIDERATION IS

NOT PART OF THE THINKING OF MANY

PEOPLE IN INSTITUTIONS AT THE

FEDERAL LEVEL FOR EXAMPLE THE

REQUIREMENTS FOR PRECLINICAL

STUDIES LIKE ANIMAL STUDIES THAT

ARE HELD TO RIGIDLY, REGUARDLESS

OF WHETHER OR NOT ISSUES THE

PATIENT INVOLVED IS A CHILD WHO

HAS A CERTAIN NEUROLOGICALLY

FATAL DISORDER.

AT THE LEVEL OF THE

INSTITUTIONS, THE IRBs ALSO

FEEL THAT WAY MANY TIMES AND

MANY TIMES YOU HAVE TO DO, THIS,

THIS, THIS, THIS, AND THERE'S

LITTLE CONSIDERATION WHAT WILL

HAPPEN WHEN A PATIENT DOESN'T

GET ANY OF THE INVESTIGATIONAL

OR EXPERIMENTAL INTERVENTIONS

THAT MIGHT ACCRUE BY VIRTUE OF

THE APPROVAL OF A PROTOCOL AND

THEN THEIR PERSONAL LEVELS.

I'VE GIVE YOU AN EXAMPLE OF A

PATIENT WE HAD WHO HAD POTS, SO

IT WOULD BE ORTHOSTATICÖI

TACHYCARDIA AND SYNCOPI, IN

STANDING UP AND THEY HAD A

PROBLEM WITH CO LINE METABOLISM

AND 1 QUESTION WAS WHETHER IT

WOULD HELP THE INDIVIDUAL?

NOW WE WERE ADVICED--CAN YOU BUY

THIS IN STORES AND IT COMBINES

WITH B10 TO REMETHALATE HOME HOE

CYSTOLINE IN THE--I KNOW YOU

DIDN'T WANT TO KNOW THAT,

NONETHELESS, THE THING IS, THE

QUESTION IS WHETHER YOU COULD

GIVE CO LINE AND STUDY THIS

PATIENT AND PERHAPS HELP HER.

SO WE GO TO THE IRB, THE IRB

SAYS YOU NEED AN IRB, AND AN

IND, WE WILLET NOT GET 1 FOR CO

LINE, THERE ARE NOT ANIMAL

STUDIES THAT WILL TELL US HOW

MANY GRAMS OF COLLEEN WILL KILL

A MOUSE OR A RAT OR A DOG.

SO WE DON'T DO IT.

SUCH STUDIES NOT DONE, PATIENT

GOES ON WITH HER LIFE.

AND THE STUDY WILL ESSENTUALLY

NEVER BE DONE UNLESS IT'S DONE

OUTSIDE OF CURRENT REGS.

ANOTHER 1 MADE A DIAGNOSIS OF

THIS LITTLE BOYS IS 5 YEARS OLD

WHO TURNS OUT TO HAVE CLUB FOOT

ABDUCTED THUMB SYNDROME WHICH IS

A MUTATION IN A GENE THAT

ENCODES A 4 SULF ULTIMATELY

TRANSFER ACE, IT PUTS IT ON THE

SULFATE AND YOU MAY KNOW IT AS 1

OF THE GLIKE O GLYCANS, REMEMBER

HUNTER SYNDROME WHERE THERE

THESE ARE ACCUMULATED.

WELL, IN ANY EVENT THERE

THERAPIST IS A DISORDENER THE

SYNTHESIS OF THAT, NOT IN THE

DEGRADATION OF GLYCANS SO YOU

CAPTAIN MAKE THIS AND IT TURNS

OUT THIS THIS BOY AND PATIENT

WHO IS HAVE THIS ULTRA RARE

DISORDER HAVE A BLEEDING PROBLEM

BECAUSE„i TERMA TIN SULFATE IS

NEEDED FOR THE LYSIS.

SO THE RESOLUTION OF A CLOT, SO

HE FALLS OFF HIS SCOOTER AND HE

HAS A HEMATELOMERA THAT'S HUGE.

IT DOESN'T RESOLVE FOR A MONTH.

AND NOW HE'S A SORT OF ULTRA

PROTECTED AS WELL AND REALLY

DOESN'T HAVE A SIGNIFICANT LIFE,

COULD WE GIVE THIS PERSON DERMA

TIN SULFATE, REMEMBER IT'S 1 OF

THOSE THINGS THAT YOU CAN GET IN

HEALTH FOOD STORES SO YOU KNOW

IN COMBINATION WITH THE ACID AND

THINGS OF THAT SORT AND THE

ANSWER IS, NO.

NO TOO MUCH REGULATORY WORK

INVOLVEDDED IN THIS SO THIS

CHILD WILL GO WITHOUT

INTERVENTION AND I DON'T SEE

PEOPLE DOING THIS, IN THIS

COUNTRY.

THIS IS THE ONLY CHILD IN THIS

COUNTRY WITH THIS DISORDER,

THEY'RE PROBABLY ABOUT MAYBE 10

IN EUROPE AND I THINK THERE ARE

LIKE 15 OR SO REPORTED IN JAPAN

OR SOMETHING OF THAT SORT AND

THOSE COUNTRIES MIGHT DO THIS,

BUT, WE WON'T.

SO, THIS I CONSIDER A SORT OF A

MISSION AND IT'S DIFFICULT FOR

ME TO MAKE AN ETHICAL DECISION

ABOUT A CHILD LIKE THIS WHEN MY

TIME AND RESOURCES COULD BE

INVESTED IN INDIVIDUALS WHO I

KNOW CAN HELP RATHER THAN THIS

LITTLE BOY I DON'T KNOW IF I CAN

HELP AND THAT'S AN ETHICAL

DILEMMA WE PHASE EVERY DAY.

IT'S A LITTLE BIT LIKE TRIAGE.

THAT'S ENOUGH.

>> HARD TO FOLLOW THAT ACT, BUT,

SO I DO MENTAL HEALTH BOTH

CONSULTATION WORK AND LARGELY AS

AN ADMINISTRATOR AND SHOULD AS A

RESEARCHER, AND I CONFRONT

DIFFERENT ETHICAL ISSUES IN ALL

OF THOSE SETTINGS SO AS A

CONSULTANT MONICA ALLUDED TO

THAT, I HAVE HAD BEEN PLACED IN

THE POSITION WHERE A PATIENT

CONFESSS TO US THAT THEY'RE IN

FACT SUICIDAL AND WE CAME TO THE

REALIZE THAT IF WE WERE TO

DISCLOSE THAT INFORMATION THAT

THAT PERSON WOULD BE CONSIDERED

HAVING A GRADE 4 TOX ISOTOPE

IDENTITY IN THE CLINICAL TRIAL

THAT THEY WERE IN AND THEY WOULD

BE REMOVE FRIDAY THEIR TRIAL.

--REMOVED FROM THEIR TRIAL FOR

CANCER TREATMENT.

SO HERE WE HAVE A SERIOUS

CLINICAL PROBLEM THAT NEEDS TO

BE ADDRESSED AND THIS IS

SOMEBODY WHO HAD NO FINANCIAL

MEANS AND WAS COMING HERE FROM A

LONG DISTANCE AND WHAT WERE WE

SUPPOSED TO DO WITH THAT

INFORMATION?

NOW WE ENDED UP TELLING HER

TREATMENT TEAM, SHE DID END UP

GETTING REMOVED AND SHE WASN'T

DOING WELL IN THE TRIAL ANYWAY

SO AND SHE WENT HOME AND WE

FOUND HER RESOURCES FOR HER

TREATMENT AT HOME BUT IT WAS A

STRUGGLE DURING THAT PERIOD OF

TIME.

IF HE HAD BEEN SOMEONE WHO HAD

BEEN DOING WELL ON THE

TREATMENT, I'M NOT SURE HOW WE

VALID RESOLVED THAT.

SO THAT DOES HAPPEN AND I THINK

EVEN THOUGH WE'RE PROVIDING

STRAIGHT UP CLINICAL CARE, WE

NEED TO LET PEOPLE KNOW WHEN

THEY'RE ASKING FOR A CONSULT

THAT THERE COULD BE

CONSEQUENCES, IT'S AN INFORMED

CONSENT FOR THE CONSULT EVEN

THOUGH IT WAS CLINICAL CARE THIS

THIS COULD RESULT IN SOMETHING„i

THAT SHE DIDN'T WANT.

SO, THAT WAS A DIFFICULT TIME.

AS AN ADMINISTRATOR, OUR JOB IS

TO TOLERATE THE RISK THAT YOU

ALL AS INVESTIGATORS ARE

INCURRING AND THERE'S A LOT OF

RISK IN RESEARCH SO I WANT TO

EMPHASIZE, YOU KNOW WE PRIDE

OURSELVES ON DOING HIGH RISK,

HIGH YIELD AND WERE THAT GIVES

THE ADMINISTRATOR HEART BURN

EVERY DAY, BUT SO, YOU KNOW IN

OUR UNITS WE TAKE PEOPLE WITH

SCHIZOPHRENIA OFF THEIR

MEDICATION AND SOMETIMES, YOU

KNOW THEY'RE GOING TO GET WORSE

AND HOW DO WE JUSTIFY THAT.

NOW THIS IS THE ONLY HOSPITAL

THAT HAS THE LUXURY OF HAVING

PATIENTS BE ABLE TO STAY AND TRY

THEMSELVES ON ALL THEIR

MEDICATIONS AND IN IN MANY CASE

ESTIMATE THAD SPECS LEGAL IN THE

OFFICE OF SCHIZOPHRENIA, WE FIND

THEY DON'T HAVE SCHIZOPHRENIAIA

AND OFF THE MEDICATION, THEY

OFTEN LOOK BETTER THEY CAN COME

IN ON 4 OR 5 MEDICATION, SO WE

ARE A PLACE THAT ALLOWS THAT

KIND OF TIME AND MOST OF THE

TIME, THE PATIENTS ARE--OR THE

SUBJECTS SIGN ON TO THESE TRIALS

BECAUSE THEY WANT THE

OPPORTUNITY TO BE TRY TO BE OFF

MEDICATION BUT SOMETIMES WE

NECESSARILY MAKE SOMEONE WORSE

AND WE GET INTO HALLUCINATIONS,

BUT THE WAY WE COME TO DEAL WITH

THAT IN OUR HOSPITAL IS THAT WE

HAVE A SEPARATE TEAM OF HUMAN

SUBJECTS PROTECTIONS UNIT.

THESE ARE CLINICIANS WITH

MASTERS, SOCIAL DEGREES,

PSYCHEICOLOGY DEGREES WHO GO AND

MONITOR ALL OF OUR INPATIENTS

AND RESEARCH.

SEPARATE FROM THE RESEARCH, SO

THEY HAVE NO INVESTMENT IN THE

PIs, DETERMINATION OF WHETHER

THE PATIENT STAYS IN THE

RESEARCH OR NOT AND THEY'RE

SIMPLY THE PATIENTS ADVOCATE AND

SOMETIMES, YOU KNOW IT'S A FINE

LINE ON HOW--HOW DIFFICULT IS

THIS PERSON.

DO THEY STILL WANT TO BE IN THE

RESEARCH AND SO WE QUESTION THAT

EVERY DAY.

AND SOMETIMES WE DO TAKE

PATIENTS OUT OF RESEARCH.

THEY'RE TOO SICK.

SOMETIMES WE DON'T ARE THE

PATIENTS GET INTO RESEARCH IF

IT'S TAKEN THIS PERSON 2 YEARS

TO GET A STABLE TREATMENT

RECOMMENDATIONS, WE MIGHT TELL

THEM IT'S NOT SUCH A GOOD IDEA

TO COME IN RESEARCH TO BE TAKEN

OFF THE MEDICATION SO THAT WAS 1

OF THE QUESTIONS WE'RE ASKED.

HAVE WE EVER FELT IT WAS MORE IN

THE INTEREST OF THE PERSON NOT

TO BE IN THE TRIAL?

SO OCCASIONALLY THAT DOES

HAPPEN, I THINK THAT'S ABOUT--

>> I WANT TO START BY ASKING

QUESTIONS.

LET ME START BY SAYING, EACH OF

YOU IN A CERTAIN WAY, ALTHOUGH

SLIGHTLY DIFFERENT ANGLE, TALKED

ABOUT TO DO SOMETHING FOR A

PATIENT THAT ARE SOMETIMES

CHALLENGED EITHER BY THE

REQUIREMENTS IN RESEARCH OR

BEURRE COGNITIVE ROSEY OF

RESEARCH, THE NEEDS OF RESEARCH

SOMEBODY ELSE'S DECISION ABOUT

WHICH YOUR CLINICIANS AND

INTUITION GETS CAUGHT IS THE WAY

I WOULD SAY IT.

SO 1 QUESTION IS I HAVE IS WHAT

DO YOU THINK CAN BE DONE ABOUT

THAT?

SO, AS YOU MIGHT KNOW, THERE ARE

ROLES THAT ARE COMPLETE PLEA

SEPARATE WHAT--WHICH I THINK IS

UNREALISTIC BUT TO PLAY THE

SCENARIO OUT, THERE ARE PEOPLE

WHO SAY, YOU KNOW YOU SHOULD

HAVE CLINICIANS AND

INVESTIGATORS THEY CAN'T BE IN

THE SAME PERSON.

THERE ARE SOME WHO WRITE, YOU

SHOULD IDENTSIFY YOURSELF AS

DIFFERENT THERE.  'S A VERY

PROVOCATIVE ARTICLE THAT SAYS

YOU SHOULD WEAR A WHITE COAT

WHEN YOU'RE A CLINE EXCISION

WEAR A RED SCOT--COAT WHEN

YOU'RE BEING A RESEARCHER AND

YOU SAY I'M YOUR CLINICIAN AND

LATTER ON I'LL BE YOUR

RESEARCHER BUT THERE ARE THESE

KINDS OF, YOU KNOW SOME WAYS TO

SEPARATE THE ROLE SO THAT THE

TENSIONS ARE MITIGATED.

I THINK MOST OF THOSE ARE

UNWORKABLE AND PROBABLY BAD FOR

THE PATIENTS IN THE LONG RUN,

BUT I WONDER IF YOU HAVE

PERCEPTION O SINGLE HOW THIS

TENSION AND CONFLICT COULD BE

MITIGATE.

IS IT FINE THE WAY IT IS?

DOESN'T LIKE LIKE IT BUT LET

ME--KD LAUGHT SNEER.

>> FIRST OF--ALL BECAUSE I HAVE

A FEMME 9 SAID I WOULD--FEMININE

SIDE I WOULD WEAR A PINK COAT.

[LAUGHTER]

BUT I DON'T THINK THEY'RE

SEPARABLE BUT WE ALL HAVE

FRIENDS, COLLEAGUES AND

CONFIDANTES WHO ARE THINKING

PEOPLE WHO ARE HAVE AREA OF

EXPERTISES WHO CAN COVER THE

CLINICAL ASPECTS AND COVER THE

ETHICAL ASPECTS AND THAT TYPE OF

CONVERSATION THAT DOESN'T HAVE

TO BE FORMALIZED, THAT HELPS ME

ENORMOUSLY TO MAKE THIS

SEPARATION FOR INDIVIDUAL CASES.

I ACTUALLY DON'T BELIEVE THAT

THE BEST SCENARIO IS TO HAVE AN

INVESTIGATOR THAT'S ABSOLUTELY

INDEPENDENT OF THE CLINICIAN,

AND I HAVE SORT OF IDEAS ABOUT

THIS RIGHT NOW, BUT, I THINK THE

ROAD MAP FOR THE INVESTIGATION

REPRESENTS THE INVESTIGATOR.

AND THE INVESTIGATIVE TEAM WHO

IS WORKING OFF OF THAT ROAD MAP

AND SOME POKES WHO MAY AND MAY

NOT HAVE, SORT OF GOOD CLINICAL

EXPERIENCE AND EXPERTISE IN THE

DISEASE OF STUDY, HELP TO

PROMOTE THAT ROAD MAP.

I JUST THINK THAT IF YOU TAKE

THE CLINICIAN OUT OF THE

INVESTIGATOR THAT YOU

POTENTIALLY CAN RUN INTO VERY

BECAUSE THERE IS SOMETHING,

CALLED CLINICAL INTUITION.

I DON'T KNOW WHETHER THE

INVESTIGATOR IS THE LEFT SIDE OF

THE BRAIN OR AND THE CLINICIAN

IS THE RIGHT SIDE OF THE BRAIN,

BUT APPARENTLY, THERE'S A CORPUS

CO LOSS UMKC AND THEY'RE

CONNECTED, PRESUMABLY IN SOME

PEOPLE, MOST PEOPLE.

I'VE%Mk BEEN WONDERING, MANY OF
US

HAVE OUR FRONTAL LOBES GONE.

BUT BE THAT AS IT--I MEAN I JUST

REALLY HAVE A PROBLEM WITH THAT

BECAUSE I THINK THAT

THE--BECAUSE INVESTIGATION IS

SCIENTIFIC UNDOUBTEDLY BUT

CLINICAL INVESTIGATION IS

LATELYING.

>> I THINK COURSES LIKE THIS,

AND ATTENTION TO TRAINING

CLINICIANS WHO ARE BECOMING

INVESTIGATORS TO THE TENSION

BETWEEN THE ROLES, I MEAN,

FUNDAMENTALLY INVESTIGATION IS

ABOUT FINDING THE GREATER

KNOWLEDGE FOR THE GREATER GOOD

AND THAT SOMETIMES IS GOING TO

RUN INTO DO NO HARM.

YOU KNOW THEY'RE NOT GOING TO BE

THE SAME GOALS.

AND THAT'S TRUE ALWAYS.

SO, I--WE SPENT A LOT OF TIME

WITH OUR TRAINEES TALKING ABOUT

THESE ISSUES, PARTICULARLY DOING

RESEARCH IN MENTAL HEALTH WHERE

SUBJECTS ARE OFTEN VULNERABLE

AND WE--AND DOING RESEARCH IN

CHILDREN IS PARTICULARLY

CHALLENGING.

IF YOU HAVE FRAGILE X AND YOU

NEVER HAD CAPACITY BEFORE YOU

WERE 18, DIDy–Ö YOU HAVE
CAPACITY

BECAUSE YOU TURNED 18, CAN YOUR

PARENTS MAKE DECISIONS FOR YOU,

HOW ARE WE EVER GOING TO MAKE

ADVANCES IN FRAGILE X IF WE CAN

BE THE DO RESEARCH IN PEOPLE

WITH FRAGILE X WHO HAVE

DEVELOPMENTAL DELAY.

THESE ARE DIG CHALLENGES.

PEOPLE HAVE TO THINK HAVE

CREATIVE AND THOUGHTFULLY

TOGETHER WITH EMPHASIS AND AND

--I UNDERSTAND THAT WITH

PATIENTS.

>> THE INSTITUTE OF MEDICINE

RECENTLY STUDIED IN 1995 AND

THAT STUDY DISCUSSED THE

DISPARITIES THAT EXIST IN TERMS

OF RESEARCH FUNDING AND, 1

MENTIONED THE FACT HAD THAT HE

WORKS A LOT IN RARE DISEASES SO

CLEARLY THIS IS AN ETHICAL

DILEMMA NOW--WHAT DOES THE NIH

CURRENTLY DOING TO TACKLE THIS

DILEMMA OR IF SOMETHING

SUBSTANTIAL IS BEING DONE WHAT

CAN BE DONE TO OVERCOME THE

EXISTING DILEMMA.

>> SO YOU'RE REALLY TALK ABOUT

THIS DISPARITY BETWEEN LET'S SAY

APPROVAL OF INDs OR DRUGS FOR

RARE DISEASES COMPARED TO COMMON

DISEASES, IS THAT WHAT YOU'RE

TALKING ABOUT?

IN THAT DIFFICULTY?

>> YEAH.

>> WELL IT IS TRUE THAT

DR. COLLINS AND HAMBERG, HAVE

CREATED A LIAISON COMMITTEE AT

NIH, TO ADDRESS THIS AND I THINK

1 OF THE ISSUES IS TO MAKE

PEOPLE LESS RISK AVERSE AND

MORE, CONSIDERING MORE

CONSIDERATION FOR THE ETHICAL

DECISIONS TO BE MADE ON THE

BASIS OF RISK AND BENEFIT.

AND THAT'S SIMPLY RIGID

ADHERENCE TO RULES AND I THINK

THAT'S SOMETHING THAT BECAUSE

MANY OF THE DECISIONS ARE MADE

ON A FAIRLY--ON A BASIC LEVEL

AND NOT BASED ON PEOPLE WHO FEEL

THEY CAN MAKE THESE DECISIONS

AND USEW  THEIR DISKRUGZ THAT

RAISING UP THAT LEVEL A COUPLE

OF ECHELONS WITHIN THE HIERARCHY

CAN HELP AND AS I UNDERSTAND IT,

THE FDA IS INTERESTED IN DOING

THIS AND BEING EXTREMELY

CONCILIATORY OVER THIS ISSUE, SO

I THINK THAT THERE'S REAL HOPE

THAT THERE WILL BE PROGRESS MADE

IN THIS ISSUE.

>> I KNOW WE'VE GONE A LONG WAYS

TOWARD FULL DISCLOSURE OF

INTERESTS INVESTED BY CLINICAL

SCIENTISTS AND OTHERS AND

RESEARCH, THERAPEUTIC NATURE,

THERE'S STILL, I THINK A NUMBER

OF AREAS THAT RAISE SOME

CONCERN.

FOR EXAMPLE, I WONDER IF THE

FOLLOWING SCENARIO ACTUALLY

OCCURS AND IF SO WHETHER IT

RAISES POTENTIAL CONFLICT OF

INTEREST, ISSUES, RESEARCHER AT

A HYPOTHETICAL MEDICAL

UNIVERSITY DISCOVERIES A DRUG TO

BE USE TOTED TREAT

SCHIZOPHRENICS AND A CLINICAL

TRIAL IS ORGANIZED AT THAT

UNIVERSITY.

IS THAT PERMITTED UNDER CURRENT

REGULATION, MAYBE I SHOULD ASK

THAT QUESTION BEFORE I CONTINUE.

AND IF SO, IF THAT CLINICAL

TRIAL OCCURS AT THAT UNIVERSITY,

THE KNOWLEDGE THAT THE DRUG HAS

BEEN DEVELOPED OR DISCOVERED AT

THAT UNIVERSITY DOESN'T THAT

CREATE A CONFLICT AS WELL.

>> SO I CAN ONLY SPEAK TO WHAT

WE DO HERE AND THERE ARE

CERTAINLY PEOPLE WHO DISCOVER AN

ANTIBODY AND WANT TO USE THAT

ANTIBODY HERE AND WE DO REQUIRE

THAT THEY PUT THAT IN THE

CONSENT, THAT THEY HAVE A PATENT

AND THEY MIGHT FINANCIALLY BE

REHEWNERATED BUT THE PATENT

BELONGS TO THE GOVERNMENT BUT

ANYWAY, THOSE RULE VS GOTTEN

STRICTER AND I THINK THEY WERE

RECENTLY POSTED AND I HAVE

HAVEN'T LOOKED AT WHAT IS BEING

IMPOSED BUT THEY DO HAVE TO

DISCLOSE IN THE INFORMED

CONSENT.

THAT THEY ARE PART OF THE TRIAL

AND THEY THEY OWE STOCK IN X

COMPANY.

SO WE HAVE TRIED TO ADDRESS THAT

MORE AGGRESSIVELY RECENTLY.

>> DOESN'T THAT ALSO COMPLICATE

MATTERS WITH IRBs THAT ARE

COMPOSED IN PART OF

INVESTIGATORS OR ADMINISTRATORS

AT SAID UNIVERSITIES?

>> YEAH, SO THIS IS WHERE

CHRISTINE'S SUGGESTION WHERE

IRBs MIGHT SAY THE

INVESTIGATOR CANNOT BE THE

PERSON WHO MADE THE DRUG.

IT„i MUST BE A CLINICIAN WHOSE

SEPARATE FROM THE DRUG MAKES THE

DECISIONS ON CLINICAL TREATMENT.

SO IRBs DO OFTEN DO THAT.

>> WOB OF OUR SESSIONS NEXT WEEK

IS ALL ABOUT CONFLICTS OF

INTEREST.

YOU CAN HEAR ABOUT THAT NEXT

WREAK.

>> I HAVE A QUESTION REGUARDING

YOUR STATEMENTS ABOUT

ALLOCATIONS OF FUNDS FOR

PATIENTS SPECIFICALLY IN REGUARD

TO NATURAL HISTORY PROTOCOLS OR

STUDIES, AS HEALTHCARE ACCESS

BECOMES MORE AND MORE OF A

PROBLEM IN THIS COUNTRY, AND

FINDING THAT PATIENTS WHEN THEY

COME IN, YOU KNOW OFTEN WANT

EVALUATIONS FOR THINGS THAT MAY

NOT BE RELATED TO THEIR--YOU

KNOW ACTUAL PROBLEM THAT THEY'RE

ON THE PROTOCOL AND ALTHOUGH WE

MAY SUSPECT THAT THIS ACTUAL

COMPLAINT MAY HAVE NOTHING TO DO

WITH OUR UNDERLYING PROBLEM, WE

CAN'T ALWAYS PROVE THAT AND WE

DON'T ALWAYS KNOW FOR SURE AND

SO, YOU KNOW WE TEND TO BE

EMPATHET AND I CAN UNDERSTAND

THAT AND SORT OF WORK THINGS UP

AS NECESSARY.

BUT, I THINK THAT ALWAYS BECOMES

A CONFLICT AND I WAS JUST

CURIOUS WHAT YOUR THOUGHTS WERE

ON HOW THAT MAY BE GOING OR YOU

KNOW UNTIL WE HAVE HEALTHCARE

FOR EVERYBODY WHICH I THINK IS

SORT OF A FAR AWAY PLAN.

HOW WE DEAL WITH THAT.

>> THIS IS THE CRUX OF THE

ISSUE.

I CAN SAY THAT I HAVE OBSERVED

CHANGES IN OUR ATTITUDE TOWARDS

THESE ISSUES, OVER THE LAST

DECADE.

OR 2.

BUT THE ACTUAL, THE

CHARACTERISTICS OF THE PEOPLE

THAT ARE NOW IN

ENROLLING--ENROLLING IN OUR

PROJECT VS CHANGED AND AND THEY

AFFECT NONENGLISH SPEAKERS AND

LOWER ECONOMIC STATUS SO THESE

ARE PEOPLE WHO ARE FALLING

THROUGH THE CRACKS.

SO WE ARE CONFRONTING THIS ISSUE

EVERY DAY.

AND BECAUSE OF OUR COMMITMENT TO

BEING FISCALLY RESPONSIBLE

WITHIN THE CONTEXT OF THIS

HOSPITAL AND GOOD STEWARDS OF

TAXPAYERS DOLLARS, WE HAVE

ACTUALLY HAD TO DIP INTO AND

BECOME VERY WELL AQUANTED WITH

RESOURCES THAT ARE PROVIDED BY

THE DIFFERENT LOCAL GOVERNMENTS

AROUND THE NIH.

AND AS SUCH HAVE ACTUALLY EVEN

STARTED A CLINIC OUTSIDE TO TRY

TO ADDRESS SOME OF THESE ISSUES.

WE'VE STARTED--WE WORK WITH

MOBILE MED WHICH IS PART OF

A--NOT REALLY FREE BUT IT'S A

CLINIC TO ADDRESS THE NEEDS OF

UNINSURED PEOPLE IN MONTGOMERY

COUNTY AND IN THAT WAY, WE HAVE

ANOTHER PLACE THAT'S COMPLETELY

INDEPENDENT OF TAPPING INTO OUR

RESOURCES HERE AT NIH SO WE HAD

TO BE CREATIVE ABOUT HOW TO DEAL

WITH THESE THINGS.

SO IT'S A PROBLEM.

SNRK IT SEEMS BUILDING OFF THIS

MISSION COMMENT TSEEMS THAT

OFTEN ETHICAL DECISION MAKING

PROCESSES ARE BUILT WITH THE

ASSUMPTION THAT MAYBE THE

PATIENT POOL IS UNLIMITED OR

THAT THE RESOURCES ARE SOMEWHAT

LIMITED BUT ARE THERE

CONSIDERATIONS THAT THE TRIAL

THAT YOU MAY BE APPROVING IS

PERHAPS REMOVING A SET THAT ARE

BETTER SUITED FOR A DIFFERENT

TRIAL ASK IS THERE AN ETHICAL

CONSIDERATION FOR INCLUDING A

SET OF PATIENTS IN A TRIAL TO

APPROVE A DRUG THAT YOU KNOW IS

JUST SLIGHTLY DIFFERENT AND

MAYBE SLIGHTLY BETTER THAN AN

EXISTING DRUG INSTEAD OF LETTING

THOSE PATIENTS BE AVAILABLE IN

THE POOL FOR A NEW KIND OF DRUG

FOR THAT INDICATION?

THAT'S AN ISSUE THAT DRUG

COMPANIES HAVE TO ADDRESS AND

FACE AS OPPOSE TO RARE DISEASE

FOLKS.

USUALLY THE RARE DISEASE

INVESTIGATORS DON'T HAVE ANY

DRUG TO GIVE AND THEY LARGELY--I

SURE WOULDN'T WASTE MY TIME FOR

A MODEST INCREASE OVER WHAT'S

AVAILABLE ALREADY, TRYING TO DID

HE TELL AN UNTREATABLE DISEASE,

BUT DRUG COMPANIES DO THAT EVERY

TIME AND I THINK THAT THEY'RE

SORT OF ETHICAL CONSIDERATIONS

THAT ARE PROBABLY SUBSERVEIENT,

I WOULD SAY, THEY'RE GETTING IRB

TO APPROVE THAT.

A LOT OF THE TRIAL GUESS THROUGH

THAT.

SO AT THE LEVEL OF THE IRB

THAT,'S AN ETHICAL ISSUE, IS

REALLY WHAT YOU'RE SAYING.

YEAH THE QUESTION IS WHETHER

IRBs ADDRESS THAT.

IN OTHER WORDS BUT THE

CONSIDERATION IS SIMILAR TO THE

CONSIDERATION OF WHAT HAPPEN

FIST YOU DON'T DO THIS STUDY.

WHAT HAPPENS IF YOU DON'T DO THE

OTHER STUDY THAT MIGHT

BE--CREATE A SEAT CHANGE IN THE

TREATMENT OF AN INDIVIDUAL AND

ACTUALLY, I DON'T SEE THAT BEING

CONSIDERED BY IRBs.

EVER, I'VE ACTUALLY NEVER SEEN

THAT.

BUT I'M SURE THERE ARE MORE

EXPERIENCED PEOPLE HERE.

>> I THINK YOU'RE RIGHT, IRBs

DON'T DO THE COMPARATIVE, IS

THAT TRIAL BETTER THAN THAT

TRIAL TO APPROVE, THEY DEAL WITH

THE TRIALS AS THEY COME IN AND I

WOULD LIKE TO TAKE THAT

OPPORTUNITY TO INVITE STEVE TO

COME TO THE PANEL, STEVE HOLLAND

IS OUR FOURTH PANELIST WHO IS AN

INVESTIGATOR AS TO CHIEF OF

LABORATORY CLINICAL INFECT YOWS

DISEASES IN NATIONAL INSITUTES

OF ALLERG SCHEINFECT YOWS

DISEASES BUT ALSO REEBTLY BEEN

NAMED AS THE DEPUTY DIRECTOR FOR

INTRAMURAL RESEARCH.

SO, STEVE DO YOU WANT TO SAY A

WORD OR 2?

OR DO WE HAVE ANOTHER QUESTION,

TOO?

>> WELL I WONDER IF I COULD COME

BACK TO THE QUESTION ABOUT

ACTIVITIES ON NATURAL HISTORY

PROTOCOL.

SO THIS IS A CENTRAL 1 AND I

FEEL PRETTY STRONGLY THAT IF

YOU'RE DOING A NATURAL HISTORY

PROTOCOL, THAT'S THE NATURAL

HISTORY OF DISEASE IS UNDEFINED

AND IF IT'S UNDEFINED THAT

MEANS, YOU DON'T KNOW.

AND IF YOU DON'T KNOW, THE

TENDENCY IS TO SAY, LYOU'RE HERE

FOR YOUR INFECTION, BUT NOT FOR

YOUR COLONOSCOPY OR MAMMOGRAM OR

YOU KNOW YOUR CHOLESTEROL CHECK.

AND I THINK THE RISK IS, THAT WE

PIGEON HOLE PEOPLE UPFRONT AND

WE MISS FUNDAMENTAL CRITICAL

OBSERVATIONS AND YOU KNOW AS

THEY SAY GOOD JUDGMENTS COMES

FROM BAD JUDGMENT AND I'VE HAD

PLENTY AND I HAVE MADE PLENTY OF

WRONG CALLS, BUT WHOLE THAT'S

NOT PART OF YOUR PROBLEM.

DON'T TALK TO ME ABOUT THAT.

GO TO YOUR HOME DOCTOR.

WHETHER YOU HAVE 1 OR NOT,

THAT'S A SEPARATE ISSUE AND I

THINK THE CLINIC ISSUE--THOUGH

ARE IMPORTANT--THOSE ARE

IMPORTANT QUESTIONS BUT IF YOU

DON'T THE NATURAL HISTORY, HOW

DO YOU KNOW WHAT THEY'VE GOT AND

I COULD SPEND OF THE REST OF

YOUR DAY TELLING BUT THINGS THAT

WE THOUGHT WEREN'T RELATED, AND

YET TURNED OUT TO BE SOME OF THE

MOST FASCINATING OBSERVATIONS

WE'VE COME UP WITH.

SO YOU'RE EITHER SERIOUS ABOUT

YOUR IGNORANCE OR YOU'RE NOT.

IF YOU'RE SERIOUS ABOUT YOIR

IGNORANCE THEN IT'S COMPLICATED

ABOUT KNOWING WHEN TO SAY NO.

APPROXIMATE FISCAL ISSUES ASIDE

AND SCIENCE DRIVES THE PROTOCOL

AND IF SCIENCE SAYS I NEED TO

KNOW WHAT THIS DISEASE IS LIKE

YOU HAVE TO THINK HARD ABOUT

FIGURING THAT OUT.

>> I THINK YOU JUST ANSWERED MY

QUESTION BECAUSE IT WAS RELATIVE

TO THE MENTAL HEALTH DEPARTMENT

AND I WAS THINK BEING THE STUDY

OF ADHS FOR THE CHILDRENS AND AS

WE ULTIMATELY KNOW THAT IN HUMAN

DEVELOPMENT OUR BRAIN IS

DEVELOPING AND IT HAS DIFFERENT

STAGES OF DEVELOPING AND I HAVE

SOME STUDIES FOR THE YOUNG

CHILDREN DO BE ON MEDICATION SO

I WAS THINKING OR„i WORRYING
ABOUT

IF THEY DO THIS STUDY TO SEE

THIS, IS THE NORMAL DEVELOPMENT

FOR THIS STAGE OF THE CHILDREN

BEFORE THEY PUT THEM IN THE

MEDICATION, OR IF THEY GO WITH

THEIR STUDIES TO FIND OUT IF

WHEN THE FAMILY HAD THESE

CHILDREN, THEY HAVE PREVIOUS

HISTORY OF MEBT MENTAL BEFORE

THEY PUT THEM IN THE MEDICATION

AND SECOND PART OF THE QUESTION

IS ARE WE MONITORING TO MAKE

SURE WE'RE NOT GOING TO AFFECT

THEIR INTER--MENTAL INLECTUAL IQ

WHEN THEY'RE ON THOSE

MEDICATIONS.

BEFORE I HAVE SOME EXAMPLES OF

THE CHILDREN IN AFRICA WHO IF IT

WAS HERE THEY COULD BE ON THE

MEDICATION.

BUT AFTER THEY TURN 18, THEY

BECAME VERY BRAVE PEOPLE AND

SOME OF THEM NOW, THEY'RE

DOCTORS OR LAWYERS SO I DON'T

KNOW IF WE DO THOSE POLYPS TO

MAKE SURE WE'RE NOT AFFECTING

THESE KID WHEN IS THEY GET

SUPPOSE MEDICATIONS.

>> SO SOME OF THOSE STUDIES THAT

YOU MENTION INDIVIDUAL BEEN DONE

SO BEFORE IRBs GOT AS STRICT

AS THEY ARE NOW, THEY ACTUALLY

GAVE IT TO CHILDREN HEALTHY

CHILDREN IN THE PAST AND SHOWED

THAT BOTH HEALTHY CHILDREN AND

CHILDREN WITH ADHD DO BETTER ON

TESTING AND ARE ABLE TO SIT

STILL BETTER AND EVERYBODY HAS

BETTER FOCUS OF THE INTENTION

AND THE DOCTOR DID THIS HERE IN

THE 70S AND SO, AND THEN,

ACTUALLY WE TRIED TO REPEAT THE

STUDY ABOUT 10 YEARS AGO WITH

GIVING 1 DOSE OF METHYL FENNA

DATE AND DOING AN MRI TO SEE

WHAT THE CONNECTIONS WERE AND

WHERE THE BRAIN IS ACTIVATED TRY

TO UNDERSTAND BETTER THE

MECHANISM AND THAT WAS A VERY

CONTROVERSIAL CASE AND IN FACT,

IT WENT TO PUBLIC HEARING.

IT WAS THE FIRST JOINT HEARING

OF THE PEDIATRIC FDA ADVISORY

COMMITTEE AS WELL AS NI H'S

PEDIATRIC COMMITTEE AND THERE

WAS AN OPEN HEARING, AND THE

QUESTION IS, YOU KNOW, IS IT

MORE THAN MINIMAL RISK RESEARCH,

IS GIVING A DRUG ALWAYS MORE

THAN MINIMAL RISK.

IS GIVING A DRUG THAT YOU THINK

HAS AS MUCH CAFFEINE AS YOU KNOW

RED BULL, WHICH CHILDREN DO

DRINK, OR MOUNTAIN DUE, IS THAT

MORE THAN THEY WOULD ENCOUNTER

IN THEIR ORDINARY LIFE OR IS IT

TURNS OUT INTEREST HIGH SCHOOL

STUDENT CAN BUY PROBABLY 10 MILL

GRAPS OF RIDLYNN FROM THEIR

FRIENDS SO IS THAT MORE OF A

RISK THAN THEY WOULD ENCOULD YOU

WANTENER THEIR DAILY LIFE AND

THERE WAS A LARGE DISCUSSION

ABOUT THAT.

IN THE EPPED THEY DECIDED IT WAS

NOT THAT GREAT OF RAKE AND THEY

ALLOWED THE STUDY, APPROVED THE

STUDY AND RIGHT AFTER THAT,

THERE ARE SEVERAL CASES OF

SUDDEN DEATH FROM RIDLIN, SO WE

NEVER DID THE STUDY BECAUSE WE

DECIDE THAT WAS TOO GREAT A RISK

TO TAKE AT THE TIME.

AND AND SOME OF IT IS SUGGESTED

I BY--INTERESTING FACTOR THAT IT

DOES MATTER AND WHAT THE PUBLIC

WANTS SO THE PUBLIC WAS

DEMANDING IN THE TIME THAT YOU

INITIALLY STARTED, AREN'T THERE

BETTER TREATMENTS FOR THIS

HYPER-ACTIVITY, YOU CAN'T BE

AGGRESSIVE, YOU ARE NOT GOING

FAST ENOUGH, PEDIATRIC DRUGS AND

THEY'RE PUSHING VERY HARD FOR

THESE MEDICATIONS.

AND WE THEN WE HAVE THE BACKLASH

OF WE SHOULDN'T BE GIVING OUR

CHILDREN THESE MEDICATION FEIGN

THEY HAVE HYPERTENSION ACTIVITY

AND THERE ARE LONG STUDIES AND

THEY'RE DONE OUT OF BOSTON AND

THEY HAVE LOTS OF INFORMATION

ABOUTd– THE COGNITIVE FOLLOW UP

AND GENERALLY THOSE KIDS ARE

DOING BETTER, NOT EVERYBODY--SO

AS IS OFTEN THE CASE IN

MEDICINE, ONE-THIRD, YOU KNOW

SPONTANEOUSLY GET BETTER, 130 DO

FINE OR DON'T EXPHAINCH

ONE-THIRD GET A LOT BETTER ON

THE MEDICATION.

SO THE QUESTION IS WE ARE IN THE

SCIENCE THAT TELLS US WHICH IS

GOING TO DO WHAT.

SO IT IS HARD TO DO THESE TRIALS

IN DEVELOPMENT BECAUSE THEY DO

HAVE LONG STANDING CONSEQUENCES

AND I DON'T THINK ANIMAL MODELS

WILL FULLY TELL US WHAT WE NEED

TO KNOW BUT WE DO TRY TO USE

THOSE AS MUCH AS WE CAN FIRST

BUT AT SOME LEVEL WE DO NATURAL

HISTORY TRIALS THAT OCCUR FROM

CHILDREN THAT ARE TREATED.

I DON'T KNOW IF THAT ANSWERS

YOUR QUESTION.

>> YES MA'AM, THANK YOU.

>> I HAVE A QUESTION, WE EARLIER

TODAY WE HAD A SESSION ON IRBs

AND THEN A DISCUSSION ON RISK.

AND THERE WERE A COUPLE OF

QUESTIONS THAT IF YOU HAVE

OPINIONS ABOUT, WE WOULD LOVE TO

HEAR THEM, FIRST AS YOU KNOW

IRBECKS B HAS TED AUTHORITY TO

DISAPPROVE A STUDY, IT DOESN'T

HAPPEN VERY OFTEN BUT IT DOES

HAPPEN.U

OCCASIONALLY, AND ALSO IRBs

HAVE THE AUTHORITY TO TABLE A

STUDY AND ASK FOR MAJOR

REVISIONS.

SO 1 OF THE QUESTIONS THAT WAS

RAISED WAS, IN PASSING BUT IT'S

ALSO PROPOSED IN THE PROPOSED

REVISIONS TO THE COMMON RULE.

SHOULD THERE BE AN APPEAL

PROCESS, SHOULD THERE BE A

PROCESS WHEREBY AN INVESTIGATOR

WHOSE STUDY HAS BEEN DISAPPROVED

OR ASKED FOR SUBSTANTIAL

RENOVATION, SHOULD THERE BE AN

APPEAL PROCESS, THAT'S 1

QUESTION.

THE OTHER QUESTION WAS, THERE

SEEMS TO BE A GENERAL AGREEMENT

THAT THERE IS SOME LEVEL OF RISK

THAT'S UNACCEPTABLE.

BUT WHAT THAT LEVEL IS, NO 1'S

PUT THEIR FINGER ON, AND IT'S

PROBABLY TRUE THAT REASONABLE

IRBs DISAGREE ABOUT THAT BUT

IN YOUR VIEW DO YOU THINK THERE

SHOULD BE A THRESH HOLD OF RISK

THAT DEFINED SO THAT PEOPLE CAN

SAY ALL STUDIES HAVE TO NOT

EXCEED THAT LEVEL AS DAVE TALKED

ABOUT THIS MORNING NETRISK IN

OTHER WORDS IF YOU TAKE AWAY

WHAT RISK IS COMPENSATED FOR BY

THE RISK BENEFITS RISK ABOVE

THAT.

I DON'T THINK OF YOU HAVE THESE

ON EITHER OF THESE SUBJECTS.

IN 5 MINUTES.

>> NO, I'LL SAY THE APPEAL

PROCESS, IT'S TRUE, I MEAN IF

YOU HAVE A DISAPPROVED PROTOCOL,

IT CAN BE DISAPPROVED FOR MANY

REASONS.

INCLUDE TAG THERE ISN'T ENOUGH

SUBSTANTIVE SUPPORTING

PRECLINICAL EVIDENCE TO MOVE SAY

A DRUG FORWARD OR THERE'S SOME

CONTROVERSY AND I THINK THERE

COULD BE NEW INFORMATION THAT

WOULD THEN CAST THE ENTIRE

PROJECT IN A DIFFERENT LIGHT SO

I WOULD SAY THAT AN PEEL PROCESS

WOULD BE REASONABLE.

LEVEL OF RISK IS VERY DIFFICULT.

IT LET DR. GAUL.

[LAUGHTER]

>> ET BRUTE, OH, SORRY.

SO THANK YOU.

I DON'T THINK THERE IS AN

UNACCEPTABLE LEVEL OF RISK

THAT'S ABSOLUTE.

I THINK THERE ARE PEOPLE WHO

HAVE DISORDERS THAT ARE INVOLVED

WITH CERTAIN DEATH.

AND SOMETIMES CERTAIN DEATH

WITHIN LET'S SAY A WEEK,

SOMETIMES WITHIN A YEAR,

SOMETIMES WITHIN 2 YEARS OR 5 OR

WHATEVER, BUT CERTAIN DEATH AND

I THINK ONLY A VARIANT IF YOU

WERE ABLE TO PROVE THAT IT

WASN'T A VARIANT, THEN YOU CAN

COUNT ON THAT BEING CERTAIN

DEATH.

IN THAT CASE, IF YOU HAD A

POSSIBLE THERAPY THAT WAS

ASSOCIATED WITH 90% DEATH, IT'S

BETTER THAN CERTAIN DEATH.

SO, I THINK THAT THERE'S NOTHING

ABSOLUTE, BUT THAT THESE THING

VS TO BE BALANCED WITH THE

BENEFIT THAT IS POSSIBLE TO

ACCRUE FOR SOMETHING LIKE THIS.

NOW YOU WOULDN'T WANT TO ASSUME

A 50% RISK OF DEATH IF THE

BENEFIT DIDN'T INVOLVE A CHANCE

OF LIFE.

IN OTHER WORDS THERE'S ALSO THE

MAGNITUDE OF THE BENEFIT THAT'S

PRETTY IMPORTANT, SO, I THINK

ALL THESE THINGS NEED TO BE

WEIGHED AND THAT'S WHY WE HAVE

O’'j Bs AND SORT OF

CON--IRBs AND CONTEMPLATIVE

PEOPLE.

>> I THINK IT WAS BILL WHO

MENTIONED STUDYING II DON'T

FINISH THE IRB DISAPPROVED IT

BUT ASKED FOR MORE ANIMAL DATA

SO IN THAT CASE, DO YOU THINK

THAT'S APPROPRIATE IF THEY HAD

MORE ANIMAL DATA TO SHOW THIS

WAS A PROMISING THERAPY THEN THE

LEVEL IS RISK IS LESS IMPORTANT.

ISHAT A FAIR RESTATEMENT OF

WHAT YOU JUST SAID?

>> WELL, LET ME--I THINK MARILYN

WILL ANSWER THAT, YOU NOTICE HOW

THAT MOVES DOWN.

THE IRB APPROVED THAT WITHOUT

REQUIRES MORE ANIMAL STUDIES BUT

REQUIRED AN I&  D, AND THEN THE

FDA REQUIRED THE ANIMAL STUDIES

SO TO ME THAT WAS A DECISION

THAT WAS MADE ON ETHICAL

GROUNDS, IT WAS MADE ON

INSTITUTIONAL REGULATORY GROUNDS

WITHOUT THE CONSIDERATION OF THE

ETHICAL ISSUES.

>> SO I WAS GOING TO GIVE YOU,

WE HAD AN EXAMPLE OF AN

INVESTIGATOR WHO WANTED TO TRY

LITHIUM FROM DEMENTIA AND HE

WANTED TO TRY IT IN MODERATE TO

SEVERE DEMENTIA BECAUSE THERE

WERE PLASTICITY EFFECTS AND

ADNORONAL ASSISTANCE.OKb

SO BUT THE IRBs HAVE THE

TENDENCY TO WANT TO MINIMIZE

RISK SO THEY SAID NO, NO, HAVE

YOU TRY IT IN MILDLY DEMENTED

PEOPLE FIRST WHO CAN KIND OF

GIVE YOU PERMISSION TO BE IN THE

TRIAL BUT THAT NEGATIVE TRIAL

WOULD NOT NECESSARILY PROVE THAT

IT WOULD BE NEGATIVE IN MODERATE

TO SEVERE DEPRESSION.

SO THAT WAS NOT GOING TO ANSWER

THE QUESTION BUT THE IRB WOULD

NOT ALLOW THEM TO DO IT IN THE

MORE SEVERE BECAUSE THEY HAD THE

SENSE IT WAS TOO RISKY.

>> SO IN THAT CASE WOULD AN

APPEAL MATTER?

YOU DON'T KNOW?

>> I THINK AN APPEAL WOULD BE

APPROPRIATE WITH ADHOC MEMBERS

WHO COULD ADDRESS THE ISSUES.

>> SO WITH BOTH THOSE COMMENTS 1

OF THOSE POINTS OUT IS THE

CRITICAL IMPORTANCE OF HAVING

PEOPLE ON THE IRB THAT REALLY

UNDERSTAND THE DISEASE YOU'RE

TALKING ABOUT AND BOY WHEN YOU

START TALKING ABOUT THESE SORT

OF GENERIC NATIONAL IRBs I

DON'T KNOW HOW WESTERN IRB KNOWS

A LOT, YOU KNOW BUILDS DISEASES

THERE MIGHT BE 5 PEOPLE WHO KNOW

ABOUT THE DISEASES, BILL TREATS

AND 4 OF THEM ARE SITTING HERE.

IT'S COMPLICATED SO HOW ARE THEY

GOING TO ASSESS RISK IF BILL

SAYS HEY, THE RISK IS LIKE THIS.

IT'S GETS REALLY HARD.

SAME THING WITH DEMENTIA ISSUES,

IF YOU GET OFF, SOMEBODY SAYS

THESE ARE THE GENERIC ISSUES

ABOUT RISK.

CAN YOU MAKE RISK A GENERIC.

IT'S NOT GENERIC IT'S SPECIFIC

TO DISEASE, SPECIFIC TO PEOPLE,

SPECIFIC TO WHAT YOU'RE

INTERVENTION IS, AND YOU HAVE TO

TAILOR YOUR IRB ACCORDINGLY AND

I THINK THAT'S 1 OF THE THENTH

STRENGTHS HERE THAT WE'VE GOT

INSTITUTE SPECIFIC OR RELATIVELY

SPECIFIC IRBs THAT ARE FOLK

CULTURE CONFIRMEDDED ON WHAT WE

DO.

THEY KNOW, MY IRB KNOWS, BILL'S

IRB KNOWS, MARILYN'S IRB KNOWS,

THAT A DIFFERENCE IN WHAT THE

NATION IS MOVING TOWARDS IN

TERMS OF GENERIC ASSIGNMENTS.

CAN I JUST ADD 1 LITTLE POINT

THAT JEEZY GELSING ER WAS 1 WHO

DIED BECAUSE THE IRB CHANGED THE

CRITERIA FOR THAT BECAUSE OF THE

CONSIDERATIONS YOU WERE

MENTIONS.

THE ORIGINAL PROTOCOL WAS FOR

PEOPLE WHO HAD OTC DEFICIENCY OR

SOME DEFECT OR WHATEVER AND THAT

WAS CHANGED AND ACTUALY, MOB'S

EVER BEEN HELD TO ACCOUNT FOR

THAT.

>> YEAH, WE ACTUALLY TALKED

ABOUT THAT LAST WEEK.

>> SO THANK YOU VERY MUCH.

>> PLEASE JOIN ME IN THANKING

THIS PANEL.

[ APPLAUSE ]

>> DAVE MENTIONED EARLIER,

ANYBODY'S WHO INTERESTED IN HALF

AN HOUR, THE GRAND GROUNDS WILL

FOCUS ON DISCUSSION OF THE

PROPOSED CHANGES TO THE COMMON

RULE.

TODAY, IN THIS ROOM.