>> GOOD MORNING.

WHERE YOU OUT THERE?

LIGHTS ARE IN MY EYES.

THANK YOU FOR WITH THE SWITCH.

MY UNDERSTANDING IS BY NEXT

WEDNESDAY THEY CAN BE CORRECTED

AND WE CAN MEET BACK IN LIPSETT

NEXT WEEK.

SO THANK YOU FOR COMING OVER

HERE THIS MORNING.

ALSO AN ANNOUNCEMENT ABOUT

REGISTRATION.

EVERYBODY WHO WANTS

DOCUMENTATION THAT THEY HAVE

BEEN HERE NEEDS TO SIGN IN IN

THE MORNING AND NEEDS TO HAND IN

AN EVALUATION.

THOSE WHO ARE PARTICULARLY

INTERESTED IN CEUs OR THE

CERTIFICATE FOR THE CORE

CURRICULUM NEED TO BE PRECISE

ABOUT HOW MANY HOURS THEY WERE

HERE BECAUSE THEIR CERTIFICATE

WILL REFLECT THE NUMBER OF HOURS

SO SIGNING IN, FILLING OUT THE

EVALUATION AND REFLECTING THE

NUMBER HOURS IS IMPORTANT,

ESPECIALLY FOR THOSE OF YOU WHO

WANT PACIFIC -- SPECIFIC CEUs

OR EVIDENCE FOR THE CORE

CURRICULUM.

SO WITH THOSE ANNOUNCEMENTS WE

HAVE I THINK AN EXCITING DAY

TODAY.

WE'LL START WITH A DISCUSSION OF

CONFLICTS OF INTEREST, THEN

WE'RE GOING TO SPEND THE REST OF

THE MORNING LOOKING AT ISSUES

RELATED TO DIFFERENT DESIGNS IN

RESEARCH AND ETHICS OF DIFFERENT

DESIGN.

WE'RE PRIVILEGED TO HAVE

DR. STEVE JOFFE, ONCOLOGIST AT

THE DANA-FARBER CANCER INSTITUTE

AT HARVARD MEDICAL SCHOOL AND

DIRECTOR OF THE ETHICS PROGRAM

THERE AT THE HARVARD MEDICAL

SCHOOL.

HE'LL TALK TO US THIS MORNING

ABOUT CONFLICTS OF INTEREST.

>> THANK YOU, CHRISTINE, FOR

THAT INTRODUCTION.

THANK YOU, ALL OF YOU FOR BEING

HERE BRIGHT AND EARLY.

YOU WEREN'T KIDDING ABOUT THE

LIGHTS BEING THIS YOUR EYES IN

HERE.

WE'LL BE ALL RIGHT.

SO WE'RE GOING TO TALK ABOUT

CONFLICTS OF INTEREST FOR THE

NEXT 45 MINUTES AND FOCUS ON

FINANCIAL CONFLICTS OF INTEREST.

THOUGH I WON'T IMPLY THERE ARE

ISSUES RELATED TO NON-FINANCIAL

CONFLICTS OF INTEREST THIS IS

WHERE THE POLICY CONCERN AND

ACTION HAS BEEN SO THAT'S WHERE

WE'LL FOCUS OUR EFFORTS.

IN THE SPIRIT OF DISCLOSURE

WHICH IS ONE OF THE POLICY

SOLUTIONS, I DO HAVE ONE

DISCLOSURE.

I'M A MEMBER OF A SAFETY

MONITORING COMMITTEE FOR THEX#’

GENZYME CORPORATION, PART OF

SANOFI, NOT RELATED TO ANYTHING

I'LL BE TALKING ABOUT TODAY.

I HAVE THREE GOALS.

ONE, THE FIRST IS TO HELP

UNDERSTAND CONCERNS ABOUT BIAS

IN PARTICULAR RELATED TO

INVESTIGATORS FINANCIAL TIES

WITH INDUSTRY.

THIS PART OF THE TALK WILL BE

HEAVILY DATABASE BECAUSE I WANT

TO GO BEYOND STATEMENTS OF

PRINCIPLES TO SHOW YOU WHY THERE

ARE CONCERNS AND GIVE YOU SNAP

SHOTS OF THE DATA OUT THERE.

THERE ARE REAMES AND REAMES OF

DATA ABOUT FINANCIAL CONFLICTS

OF INTEREST AND WE CAN'T TOUCH

ALL BUT I'LL GIVE YOU

HIGHLIGHTS.

WE'LL SWITCH TO TALKING ABOUT

RECENT DATA REGARDING

ASSOCIATIONS BETWEEN

INVESTIGATORS FINANCIAL TIES AND

SCIENTIFIC CONTRIBUTIONS AND

PRODUCTIVITY.

ONE CONSIDERATION THAT HAS TO BE

IN THE MIX IN TALKING ABOUT

FINANCIAL CONFLICTS OF INTEREST

AND POLICIES FOR ADDRESSING THEM

ARE WHAT ARE THE IMPACT OF THOSE

POLICIES ON THE CONDUCT OF

SCIENCE ON TRANSLATION ON THE

PROGRESS OF SCIENCE.

SO WE DON'T HAVE AN ANSWER TO

THAT QUESTION AS YOU SEE BUT I

WANT TO GIVE YOUTANT RISING --

TANTALIZING HINTS.

THEN WE'LL TALK ABOUT POLICY

SOLUTIONS AND LIMITATIONS OF

THOSE SOLUTIONS.

SO LET ME TELL YOU A STORY TO

GET YOU IN[¨’ THE MOOD FOR THIS.

THE STORY IS AVANDIA,

ROSEAGLITIZOONE, IT WAS A DRUG

ADMINISTERED IN THE LATE '90s

TO IMPROVE BLOOD SUGAR CONTROL

IN PATIENTS WITH TYPE 2

DIABETES.

FROM THE BEGINNING THERE WAS

RECOGNITION THIS DRUG MIGHT BE

SOME ISSUES WITH THIS DRUG WHEN

USING WITH PATIENTS WITH HEART

FAILURE SO FROM THE BEGINNING

THERE WAS A LABEL PRECAUTION FOR

PATIENTS WITH HEART FAILURE.

5 OR 6 YEARS LATER GLAXO WHICH

MAKES ROSEGLITAZONE DID AN

INTERNAL COMPANY META ANALYSIS

SUGGESTING INCREASED RISK OF

CARDIOVASCULAR EVENTS AMONG

PATIENTS TAKING THE DRUG.

THEY BROUGHT THOIT THE ATTENTION

OF THE FDA WHICH STRENGTHENED

THE WARNING ON THE LABEL OF

AVANDIA RELATED TO

CARDIOVASCULAR EVENTS.

THE STORY GOT INTERESTED IN 2007

WHEN STEVEN (INDISCERNIBLE) AND

CATHY WOLSKE PUBLISHED A META

ANALYSIS SHOWING A 43% INCREASE

IN RISK OF MYOCARDIAL INFARCTION

AMONG PATIENTS TAKING THE DRUG.

WEAL SAY MORE ABOUT THIS IN A

MOMENT.

THE FDA ADVISORY COMMITTEE IN

LIGHT OF THIS META ANALYSIS IN

2007 AGREED THERE WAS INCREASED

CARDIOVASCULAR RISK BUT LEFT THE

DRUG ON THE MARKET AND THE FDA

ADDED A BOX WARNING WHICH IS

STRONGEST WARNING TO THE LABEL

REGARDING THIS MI RISK.

FOCUSING ON THE EVENTS IN 2007,

MAY 2007, THIS IS A LITTLE BIT

OUT OF A SPY NOVEL, ON

MAY 1st STEVE NISSON AND

CATHY SUBMITTED THEIR MANUSCRIPT

TO THE NEW ENGLAND JOURNAL AND A

DAY LATER THE JOURNAL RECOGNIZED

THE PUBLIC HEALTH IMPORTANCE OF

THIS SENT IT OUT FOR PEER

REVIEW.

ONE REVIEWER WAS STEVEN HAFNER

FROM UNIVERSITY OF TEXAS SAN

ANTONIO, WHO HAPPENED TO BE A

GLAXO COB SUL STANT.

INSTEAD OF -- CONSULTANT.

INSTEAD OF TREATING IT HE FAXED

IT TO HIS CONTACTS.

GLAXO ON THE RECEIVING END

CIRCULATED IT WIDELY WITHIN THE

COMPANY AND AN INTERNAL MEMO THE

HEAD OF RESEARCH BASICALLY

AFFIRMED THE CONCLUSIONS OF

NISSAN AND WALSKY.

THEY WANTED TO TALK WITH STEVE

SO THEY MADE AN APPOINTMENT TALK

WITH HIM ON MAY 10.

TEN DAYS LATER NOT SUPPOSED TO

HAVE ANY KNOWLEDGE THAT THE

MANUSCRIPT IS UNDER

CONSIDERATION AT THE NEW ENGLAND

JOURNAL.

THEY MAKE AN APPOINTMENT TO COME

TO MEET WITH STEVE KNOWING THAT

HAVING SOME INKLING OF WHAT

MIGHT BE GOING ON HE DECIDES TO

TAPE THE MEETING, SOMETHING

LEGAL IN OHIO AT THE TIME.

FOUR DAYS LATER GLAXO UNBLINDS A

TRIAL ON GOING IN EUROPE CALLED

THE RECORD TRIAL, A POST

MARKETING TRIAL IN CONCERT WITH

EUROPEAN REGULATORS TO TRY TO

COMPARE ROSEGLITIZONE, MAYBE

THIS WOULD PROVIDE EVIDENT THAT

THERE IS NOT AN INCREASED

CARDIOVASCULAR RISK.

SEVEN DAYS LATER NISSAN AND

WALSKY META NAILSIS IS PUBLISHED

ONLINE, TIME LINE MAY 1,

21st, THREE WEEKS TO

PUBLICATION IN THE NEW ENGLAND

JOURNAL IS GOOD.

THREE DAYS LATER GLAXO GOES TO

THE STEERING COMMITTEE FOR

PERMISSION TO UNBLIND THE RECORD

TRIAL.

SO MAY 14th THEY UNBLIND THE

TRIAL.

MAY 24th THEY ASKED NO,

MA'AM MALI INDEPENDENT STEERING

COMMITTEE TO UNBLIND THE TRIAL.

THIS STORY IS NOT ONE OF -- THAT

SORT OF REFLECTS WELL ON THE

CONDUCT OF AT LEAST THIS

PARTICULAR TRIAL.

THE -- WE KNOW THIS BECAUSE IN

2010 SENATOR GRASSLEY AT THE

TIME CHAIR OF THE SENATE'S

FINANCE COMMITTEE INVESTIGATED

THE EVENTS AROUND THE ROSE

GRKSLITAZONE STORY SO MANY

INTERNAL DOCUMENTS CAME THE

LIGHT BECAUSE OF THE SUBPOENA

POWER OF THIS COMMITTEE.

MANY OF YOU KNOW THE FDA

ADVISORY COMMITTEE MET IN JULY

OF 2010.

THE FDA INTERNAL REVIEWERS

CONCLUDES LOOKING AT THE RECORD

TRIAL WHICH WAS SUPPOSED TO

PROVIDE EVIDENCE OF THE I HAVE
SAFETY

OF ROSEGLITAZONE CONCLUDED THE

TRIAL WAS INADEQUATE TO ENSURE

THE SAFETY.

THE RESULTS SUGGEST IT INCREASES

THE RISK FOF MI THOUGH THE

CONFIDENCE INTERVALS ARE WIDE.

AND INCLUDE NO RISK WHILE BIASES

IN THE STUDY SUGGEST THE TRUE

RISK COULD BE HIGHER.

AND IN A DIVIDED VOTE THE

COMMITTEE, THE FDA ADVISORY

COMMITTEE RECOMMENDED STRICTER

CONTROLS ON PRESCRIPTION

ROSEGLITAZONE WHICH THE FDA DID

AND THE PRESCRIPTIONS HAVE PLUM

METED SINCE THESE EVENTS OF

2010.

I'LL COME BACK TO THIS FDA

REVIEWERS CONCLUSION THAT THE

TRIAL WAS INADEQUATELY DESIGNED

AND SHOW YOU REASONS THEY CAME

TO THE CONCLUSION.

WITH THAT AS A STORY TO AGAIN

GET YOU IN THE MOOD, I WANT TO

JUST DEFINE FOR A MOMENT THE --

WHAT A CONFLICT OF INTEREST IS,

WE ALL INTUITIVELY UNDERSTAND

WHAT THIS IS BUT THE BEST

WRITTEN DEFINITION I HAVE SEEN

COMES FROM A RESENT INSTITUTE OF

MEDICINE REPORT WHICH SAYS A

CONFLICT OF INTEREST IS A SET OF

CIRCUMSTANCES THAT CREATE
AS>+RISK THAT PR
OFESSIONAL JUDGMENT

OR ACTIONS REGARDING PRIMARY

INTEREST WILL BE UNDULY

INFLUENCED BY A SECONDARY

INTEREST.

I WANT TO FOCUS THE WORD

CIRCUMSTANCES, I PUT THAT IN

ITALICS AND I WANT TO FOCUS ON

THAT WORD BECAUSE IT'S ABOUT THE

CIRCUMSTANCES OF THE

RELATIONSHIPS AND NOT ABOUT THE

BEHAVIORS OF THE INDIVIDUALS WHO

HAPPEN TO BE IN THOSE

RELATIONSHIPS THAT CONSTITUTE

THE CONFLICT OF INTEREST SO NOT

THAT ANYBODY HAS TO BEHAVE IN A

PARTICULAR WAY JUST THAT CERTAIN

CIRCUMSTANCES EXIST.

THIS IS A KEY FEATURE OF

CONFLICT OF INTEREST

DEFINITIONS.

SO WHY DO WE CARE ABOUT CONFLICT

OF INTEREST IN I WANT TO POSIT A

FEW REASONS THEN FOCUS ON SOME.

THE FIRST IS OBVIOUSLY THE

POTENTIAL TO INFLUENCE

INVESTIGATORS' JUDGMENTS.

THIS CAN CAN LEAD TO A FEW

THINGS POTENTIALLY.

ONE IS BIAS IN SCIENCE AND THIS

IS WHERE WE'LL FOCUS MOST

ATTENTION.

THE SECOND AND THERE ARE WORRIES

ABOUT THIS, THE POSSIBILITY OF

INCREASE RISK TO SUBJECTS.

AND I PUT A QUESTION MARK NEXT

BECAUSE WE HAVE NO SYSTEMATIC

DATA TO SUGGEST RISKS ARE OR ARE

NOT INCREASED WHEN THERE ARE

FINANCIAL RELATIONSHIPS OR

CONFLICTS OF INTEREST.

SO IT'S A CONCERN BUT NOT BASED

ON EMPIRICAL EVIDENCE.

ANOTHER CONCERN LESS NOTED IS

THE POTENTIAL TO IMPEDE

SCIENTIFIC OPENNESS, EXCHANGE OF

IDEAS, METHODS, TECHNOLOGIES.

WE WILL COME BACK TO THAT AND

FINALLY MOST BROADLY TO

UNDERMINE PUBLIC TRUST IN THE

RESEARCH ENTERPRISE.

SO IT HELPS TO UNDERSTAND WHERE

MONEY IS COMING FROM, THIS SLIDE

SHOWS OVER A FIVE YEAR PERIOD OF

TIME WHAT HAS HAPPENED TO

VARIOUS SOURCES FOR FUNDING

BIOMEDICAL RESEARCH.

BOTTOM LINE IS IF YOU LOOK AT

LOWER STRIPTS OF THE GRAPH,S IF

THS THE FEDERAL STATE AND OTHER

GOVERNMENTAL AND NON-INDUSTRY

SOURCES OF FINANCIAL SUPPORT.

YOU SEE THEY HAVE BEEN

RELATIVELY FLAT FROM 2003 TO

2007.

SO IF YOU PUT ALL THESE GRAY AN

BLACK BARS TOGETHER THEY HAVE

BEEN RELATIVELY FLAT.

BUT IF YOU LOOK AT THE BLUE

BARS, LIKE MEDIUM AND DARKER

BLUE, THEY HAVE BEEN GROWN OVER

THAT PERIOD OF TIME SO

INCREASINGLY OVER TIME THE BULK

OF FUNDING HAS SHIFTED FROM

FEDERAL NON-PROFIT TYPE SOURCES

GOVERNMENTAL SOURCES TO INDUSTRY

SOURCES.

SO WHERE MONEY IS GOES INFLUENCE

SO THE CONCERN IS WITH THE

INDUSTRY MONEY COMING TO

RESEARCH DOES THAT TRANSLATE

INTO INFLUENCE AND IN PARTICULAR

INAPPROPRIATE INFLUENCE.

THIS IS MY MOST IMPORTANT SLIDE

SO I WANT TO FOCUS FOR A MOMENT.

THIS IS A META ANALYSIS

PUBLISHED IN BRITISH MEDICAL

JOURNAL IN 2003, THERE'S A

SIMILAR ONE IN JAMA AT THE SAME

TIME WHICH ASKS THE QUESTION IS

THERE A RELATIONSHIP BETWEEN THE

SOURCE OF SUPPORT FOR RESEARCH

AND STUDY OUTCOME, WHO IS

FUNDING THE RESEARCH AND IS WILL

RELATIONSHIP BETWEEN THE FUNDER

AND OUTCOME OF THE STUDY.

SO EACH DOT FOR THOSE NOT

FAMILIAR WITH READING META

ANALYSIS PLOTS, EACH LINES ON

THE GRAPH REPRESENTS ONE STUDY.

EACH STUDY TAKES A GROUP OF

PRIMARY STUDIES IN A PARTICULAR

AREA AND DIVIDES THEM UP INTO

ONE FUNDED FROM THE INDUSTRY ON

THE ONE HAHN AND THOSE NOT

FUNDED AND ASKS IF CONCLUSIONS

ARE SYSTEMATICALLY DIFFERENT AND

IN PARTICULAR TO THE INDUSTRY

FUNNED STUDY SYSTEMATICALLY

FAVOR THE NEW DRUG OR THE NEW

INTERVENTION.

THEY'RE SHIFTED TO THE RIGHT

SIDE OF THE LINE WHICH SUGGESTS

A SYSTEMATIC TENDENCY FOR

INDUSTRY FUNDED STUDIES.

TO FAVOR NEW EXPERIMENTAL AGENT

BEING STUDIED.

THE ODDS RATIO IS FOUR AND THE

CONFIDENCE INTERVALS ARE NARROW

ENOUGH TO BE CONFIDENT THAT

INDUSTRY FUNDED STUDIES DO IN

FACT FAVOR EXPERIMENTAL DRUGS

COMPARED WITH NON-INDUSTRY

FUNDED STUDIES.

SO WHAT WE NEED TO DO IS TO

EXPLAIN THIS AND ASK THE

QUESTION IS THIS SOMETHING WE

NEED TO BE CONCERNED ABOUT.

IS THIS REFLECTIVE OF SOOM BIAS

THAT WE NEED TO BE WORRIED

ABOUT.

SO WE'RE GOING TO TRY TO WORK

THROUGH THAT AND THINK ABOUT

SOME OF THE POSSIBLE MECHANISMS

BY WHICH WE MIGHT GET TO THE

FINDINGS THAT I JUST SHOWED YOU

ON THIS LAST SLIDE.

SO IF YOU THINK ABOUT HOW A

STUDY MIGHT BE BIASED OR ALTERED

OR AFFECTED IN A WAY THAT MIGHT

LEAD TO A BIAS CONCLUSION,

THERE'S A LOT OF STEPS, THERE'S

POTENTIAL PLACES WHERE BIAS

COULD IN THEORY CREEP IN.

THE FIRST THING WE GOT TO DO IN

PLANNING THE STUDY IS OBVIOUSLY

HEALTH NEEDS THAT WE'RE

CONCERNED ABOUT.

BUT THEN HAVING IDENTIFIED WE

OBVIOUSLY NEED TO DEFINE A

RESEARCH QUESTION.

HAVING DONE THAT WE NEED TO

DESIGN A PARTICULAR STUDY TO

ANSWER THAT RESEARCH QUESTION.

AS MOST OF YOU KNOW, THERE ARE

MANY DECISIONS THAT NEED TO BE

MADE IN TERMS OF DESIGNING THE

STUDY.

WE THEN HAVE TO CONDUCT THE

STUDY AND THERE'S LITTLE STEPS

INVOLVED IN CONDUCTING THAT

STUDY THAT WE HOPE TO GET

RIGHTCH WE HAVE TO ANALYZE THE

DATA FROM THAT STUDY AND AGAIN,

THERE ARE MANY CHOICES THAT CAN

BE MADE IN TERMS OF HOW A STUDY

IS ANALYZED.

WE HAVE TO INTERPRET THE

RESULTS.

ONE THING TO HAVE A STATISTICAL

ANALYSIS IN HAND, ANOTHER TO ASK

THE QUESTION WHAT DO THESE DATA

MEAN AND WHAT STORY DO THEY

TELL.

DIFFERENT PEOPLE TELL DIFFERENT

STORIES FROM THE SAME SET OF

DATA.

WE HAVE TO REPORT THAT STUDY.

IN OTHER WORDS WE HAVE TO HAVE A

REPORT THAT IS NUMBER ONE,

FAITHFUL TO THE DATA ANT TO A

REASONABLE INTERPRETATION AN

NUMBER TWO, GET INTO THE PUBLIC

RECORD.

IT'S NOT ENOUGH TO HAVE A SINGLE

STUDY WE HAVE TO COLLATE FREFD

BULK STUDIES TO SAY WHAT DOES

PARTICULAR EVIDENCE SAY ABOUT

SOMETHING, THROUGH SYSTEMATIC

REVIEW, META ANALYSIS,

GUIDELINES PANELS,

NON-STRUCTURED REVIEW ARTICLE,

THERE'S A NUMBER OF WAYS TO

COLLATE EVIDENCE.

AND ULTIMATELY HOPEFULLY WE HOPE

THIS LEADS TO IMPROVEMENTS IN

CLINICAL PRACTICE, IMPROVEMENTS

IN HEALTH AND CARE.

SOME HYPOTHESIS AS WE LOOK AT

THESE DATA, ONE POSSIBILITY

MIGHT BE THE CHOICE OF CONTROL

GROUPS THAT INVESTIGATORS MAKE.

AND WE'LL TALK ABOUT THAT.

OBVIOUSLY THERE'S LOTS OF

POTENTIAL FOR BIAS IN CONDUCTING

THE STUDIES.

ONE EXAMPLE IS AS CERTAINING THE

EVENTS, DECIDING WHAT

CONSTITUTES AN EVENT, EFFICACY

OR SAFETY EVENT.

WE CAN IMAGINE DIFFERENT WAYS

BIAS CREEPS TO NAILSIS.

WE CAN IMAGINE WAYS IN WHICH

BIAS MIGHT CREEP INTO

INTERPRETATION OF RESULTS, WHAT

YOU MIGHT CALL SPIN AND MANY OF

YOU ARE FAMILIAR WITH THE PRB OF

PUBLICATION BIASCH THIS IS NOT

AN EXCLUSIVE OR EXHAUSTIVE LIST

OF HYPOTHESES, THERE'S MANY MORE

YOU COULD ADD TO THIS LIST.

SO WHAT ABOUT THIS ISSUE OF

CHOICE OF CONTROL GROUP.

THIS DID NOT TRANSLATE WELL.

FROM MAC TO PC.

SO LET ME TRY TO HELP YOU

IMAGINE A PICTURE HERE.

HERE WE HAVE A STUDY PUBLISHED

IN 2000 IN THE LANSETT FOR

RANDOMIZED TRIAL FOR MULTIPLE

MYELOMA.

THE AUTHORS DIVIDED THE STUDIES

TO TO THOSE PUBLISHED BY

INDUSTRY AND THOSE PUBLISHED BY

-- SORRY THOSE FUNDED BY

INDUSTRY AND THOSE FUNDED BY

PUBLIC OR NOT FOR PROFIT

SOURCES.

THEY ASKED WHAT CONTROL GROUPS

DID INDUSTRY FUNDED STUDIES USE

AND WHAT CONTROL GROUPS DID THE

NON-INDUSTRY FUNDED STUDIES USE.

THE VAST MAJORITY OF THE

INDUSTRY FUNDED STUDIES, NOT THE

VAST MAJORITY BUT THE MAJORITY

CHOSE AN INACTIVE, A CONTROL

GROUP FOR OBSERVATION OR

PLACEBO, NOT AN ACTIVE AGENT

AGAINST MULTIPLE MYELOMA.

IN A PUBLICLY FUNDED STUDY IT IS

MAJORITY OF STUDIES USED AN

ACTIVE CONTROL.

AND NOT SURPRISINGLY BECAUSE

INACTIVE CONTROL STUDIES WERE

MORE LIKELY TO DEMONSTRATE THAT

THE EXPERIMENTAL ARM,

EXPERIMENTAL AGENT WAS

PREFERABLE, AGAIN, CONTROL GROUP

BEING INACTIVE IN THOSE CASES,

THE MIX OF STUDIES FAVORING

EXPERIMENTAL AGENTS WASf
 VERY

DIFFERENT ON THE PUBLIC SIDE

COMPARED TO INDUSTRY SIDE.

ON THE PUBLIC SIDE IT WAS ABOUT

50/50.

THERE WAS A REASONABLE

DISTRIBUTION OF STUDIES ON THE

ONE HAND THAT FAVORED THE

EXPERIMENTAL AGENT ON THE OTHER

HAND THAT DID NOT FAVOR THE

EXPERIMENTAL AGENT.

ON THE INDUSTRY FUNDED STUDY

SIDE THE VAST MAJORITY OF

STUDIES FAVORED THE EXPERIMENTAL

AGENT.

AND THIS SEEMED TO BE

ATTRIBUTABLE IN LARGE PART TO

THE FACT THAT THE CONTROL GROUPS

CHOSEN BY INDUSTRY WERE VERY

DIFFERENT FROM THOSE CHOSEN BY

PUBLICLY FUNDED INVESTIGATORS.

SO I HOPE THAT MAKES SENSE, I

APOLOGIZE FOR THE MISSING

PICTURES.

THE SECOND HYPOTHESIS THAT WE

FLOATED IS THERE MIGHT BE

DIFFERENCES IN THE WAYS -- THERE

MIGHT BE EFFECTS ON WAYS WE

CONDUCTED WHEN THERE'S INDUSTRY

FUND UNDERSTANDING IN THE MIX.

HERE I WANT TO COME BACK TO THE

GLAXO AND AVANDIA STORY AND TELL

YOU WHY FDA REVIEWERS WERE

CONCERNED ABOUT POSSIBILITY OF

BIAS CREEPING INTO RESEARCH.

SO IN THEIR REVIEW OF THIS

RECORD TRIAL, THIS WAS A

EUROPEAN TRIAL NOT DONE IN

CONJUNCTION WITH THE FDA OR WITH

ANY PRIOR FDA INVOLVEMENT BUT

THE FDA NOW HAD ACCESS TO THE

DATA FROM THIS TRIAL.

, THE REVIEWERS TOOK A SAMPLE OF

CASE REPORT FORMS FOR PATIENTS

RANDOMIZED TO THE CONTROL ARM OF

THE STUDY AND FOR PATIENTS WHO

HAD BEEN RANDOMIZED TO THE

ROSEGLITAZONE OR ACTIVE ARM OF

THE STUDY.

SO THEY TOOK ABOUT A 12, 13

SAMPLE OF CASE REPORT FORMS FROM

EACH ARM AND SAID CAN WE REVIEW

THOSE CASE REPORT FORMS IN

DETAIL AND FIND ANY PROBLEMS

WITH THOSE CASE REPORT FORMS.

FIRST FOCUS ON THE CONTROL SIDE.

OUT OF 271 CASE REPORT FORMS

THEY IDENTIFIED 25 PROBLEMS,

ABOUT 10% OF ALL CASE REPORT

FORMS THAT THEY LOOKED AT.

AND THEN THEY LOOKED -- SO WHAT

WAS THE DRUG FAVORED OR NOT

FAVORED BY THE PROBLEM THEY

IDENTIFIED?

AND WHAT THEY FOUND WAS THE

PROBLEMS WERE RELATIVELY

RANDOMLY DISTRIBUTED ACROSS IN

THE DIRECTION IN WHICH THEY

FAVOR SUGGESTING SOME ERROR HERE

BUT NOT A SYSTEMATIC BIAS IN

WHAT WAS FAVORED.

ON THE OTHER HAND ON THE

ROSEGLITAZONE SIDE, THOSE

PATIENTS RANDOMIZED, THEY FOUND

TWICE AS MANY PROBLEMS.

SECOND OF ALL, I THINK MOST

STRIKINGLY, THAT ALL THE

PROBLEMS, ALL OF THE PROBLEMS

EXCEPT ONE, 44 PROBLEMS FAVORED

THE ROSEGLITAZONE ARM.

THESE WERE DATA SUGGESTING THERE

MIGHT BE A SAFETY CONCERN, A

CARDIOVASCULAR EVENT CODED IN

SUCH A WAY TO MAKE IT NOT SHOW

UP TO BE ACTUALLY A

CARDIOVASCULAR EVENT.

THE DIFFERENCE BETWEEN THE

NATURE OF THE PROBLEMS THAT WERE

IDENTIFIED IN THESE TWO ARMS

SUGGEST THAT BIAS MAY HAVE CREPT

IN IN TERMS OF AS CERTAINMENT OF

SAFETY EVENTS IN THESE STUDIES.

THIS IS ONE STUDY, ANECDOTECH IT

DOESN'T IMPUGN THE CONDUCT OF

ALL INDUSTRY FUNDED RESEARCH BUT

IT IS A STRIKING EXAMPLE.

ANOTHER HYPOTHESIS WE TALKED

ABOUT IS STUDY ANALYSIS.

SO HERE I WANT TO TELL YOU A

STORY OF GABAPENTIN, AN

ANTI-SEIZURE DRUG BUT TURNS OUT

MOST IS USED, IF YOU LOOK AT

WHAT THINGS IT'S PRESCRIBED FOR

IS OFF-LABEL USE.

NEUROPATHIC PAIN, THAT SORT OF

THING.

SO A BUNCH OF DOCUMENTS FROM

INTERNAL COMPANY STUDIES BECAME

AVAILABLE AS A RESULT OF

LAWSUITS.

MANY THINGS THAT WE KNOW ABOUT

THE CONDUCT OF STUDIES BECAUSE

MOST DOCUMENTS TEND TO BE

CONFIDENTIAL DOCUMENTS COME OUT

OF THE TIME OF DISCOVERY DURING

LAWSUITS.

SO THESE AUTHORS IN THE NEW

ENGLAND JOURNAL LOOKED AT 20

TRIALS OF GABAPENTIN PUBLISHED

FOR OFF-LABEL INDICATIONSCH THIS

IS ARE NOT THE ON-LABEL

ANTI-SEIZURE INDICATIONS.

THEY COMPARED THE OUTCOME OF

WHAT WAS PUBLISHED TO THOSE IN

THE INTERNAL COMPANY DOCUMENTS.

HOW FAITHFUL IS THE PUBLISHED

RECORD THE THE INTERNAL

DOCUMENTS FROM THE COMPANY.

SO TURNED OUT THERE WERE 20

TRIALS.

12 WERE PUBLISHED.

AND WE IRE MISSING A SLIDE

THERE.

SO THE THE UPSHOT OF THIS

ANALYSIS, AGAIN, I APOLOGIZE FOR

THE MISSING PICKTURE THERE WERE

A COUPLE OF CONCLUSIONS TO BE

DRAWN FROM THIS.

THE FIRST CONCLUSION IS IF YOU

LOOK AT ALL OF THE INTERNAL

COMPANY DATA, NOT THE PUBLISHED

DATA BUT THE ENTIRE RECORD AND

YOU LOOK AT THE DISTRIBUTION OF

POSITIVE STUDIES, THERE WAS --

THERE WERE MANY STUDIES NEGATIVE

THAT TENDED NOT TO BE PUBLISHED.

SO THIS RAISES THE ISSUE OF THE

QUESTION OF PUBLICATION BIAS.

AND THAT'S SOMETHING THAT WE'LL

SPEAK ABOUT IN A MOMENT.

SECONDARILY, THEY LOOKED AT THE

PUBLISHED STUDIES AND LOOKED

WHETHER THE PUBLISHED END

POINTS, WHAT WAS CALLED THE

PRIMARY END POINT IN THE

PUBLICATION WAS ACTUALLY THE

SAME IN THE STUDY PROTOCOL AND

ANALYSIS PLAN.

THEY FOUND VERY OFTEN THAT THERE

WAS A DISCREPANCY BETWEEN WHAT

WAS CALLED THE PRIMARY END POINT

ANDr„ PUBLICATION AND WHAT WAS

INITIALLY DEFINED AS PUBLIC

PRIMARY END POINT IN THE STUDY

PROTOCOL OR STATISTICAL PLAN.

MOST THOUGH NOT ALL CASES, THE

SWITCH OF PRIMARY END POINTS WAS

ONE THAT TENDED TO FAVOR THE

EFFICACY OF GABAPENTIN SO NOT

ONLY DISCREPANCY IN WHAT WAS

PUBLISHED BUT THE PUBLISHED

RECORD DIDN'T REFLECT WHAT WAS

PLANNED IN TERMS OF STUDY

PROTOCOLS AND STATISTICAL

ANALYSIS PLANNED OR STATISTICAL

ANALYSIS REPORTS INTERNAL TO THE

COMPANY.

SO A DISCREPANCY BETWEEN THE

PUBLIC RECORD AND WHAT WAS GOING

ON WITHIN THE COMPANY'S WALLS.

WE ALSO TALKED ABOUT

INTERPRETATION OR WHAT I'M

CALLING SPIN.

THIS IS ACTUALLY I THINK A VERY

INTERESTING STUDY PUBLISHED BACK

IN J MA IN 2003.

(INDISCERNIBLE) NEILSEN LOOKED

AT THAT TIME RELATIONSHIP

BETWEEN THE FUNDING SOURCE AND

THE CONCLUSION IN 370 DRUG

TRIALS THAT HAVE BEEN INCLUDED

IN COCHRAN META ANALYSES.

AND ASKED WHAT ARE THE

PREDICTORS OF A POSITIVE

CONCLUSION?

AND BY POSITIVE CONCLUSION, A

POSITIVE STATEMENT ABOUT

EFFICACY OF THE DRUG IN THE

CONCLUDING PARAGRAPH OF THE

STUDY ABSTRACT.

THE FIRST THING -- SO THERE WERE

A NUMBER OF FACTORS THAT TURNED

OUT SIGNIFICANTLY A ASSOCIATED

WITH A POSITIVE OUTCOME.

THE FIRST, I'LL DISPENSE FOR A

MOMENT IS THAT DOUBLE BLINDED

STUDIES TENDED TO BE MORE

POSITIVE THAN DOUBLE BLINDED,

INTERESTING BUT NOT TO THE POINT

OF OUR CONVERSATION.

SECOND IS TREATMENT AFFECT, THE

STATISTICAL RESULT, THE AFFECT

SIZE, THE P VALUE OF THE STUDY,

NOT SURPRISINGLY WAS ASSOCIATED

WITH IS THE DIS WITH POSITIVE

STATISTICAL RESULTS THEY'RE MORE

LIKELY CALLED POSITIVE THAT'S

THE WAY IT SHOULD BE.

BUT WHEN YOU CONTROL IN

MULTI-VARIANT ANALYSIS FOR THOSE

FACTORS, FUNDING SOURCE PLAYED A

ROLE.

SO FOCUS ON THIS SLIDE, THOSE

STUDIED FUNNED BY FOR PROFIT

ASSOCIATIONS WERE 5.3 TIMES MORE

LIKELY TO DECLARE THAT THE DRUG

WAS EFFECTIVE OR THE AGENT WAS

EFFECTIVE, EVEN AFTER THIS IS

THE REMARKABLE PART, AFTER

CONTROLLING FOR THE STATISTICAL

RESULT OF THE ANALYSIS.

EVEN AL CROFFING THE

QUANTITATIVE -- CONTROLLING THE

QUANTITATIVE DATA.

THIS SUGGESTS THE

INTERPRETATIONS ARE MORE

FAVORABLE WHEN THERE IS INDUSTRY

FUNDING IN THE MIX.

AGAIN EVEN AFTER CONTROLLING FOR

WHAT THE DATA ACTUALLY SHOW.

FINALLY TO TALK ABOUT

PUBLICATION BIAS, I HAVE HINTED

AT THIS WITH THE GABAPENTIN

STORY, MONICA (INDISCERNIBLE)

AND COLLEAGUES LOOKED AT 510

LARGE RANDOMIZED TRIALS, MORE

THAN 200 SUBJECTS AT AN ONCOLOGY

MEETING OVER A TEN YEAR PERIOD

OF TIME.

AND THE FIRST THING TO SHOW YOU

IS THE TIME TO PUBLICATION

THAT'S WHAT THIS SURVIVAL CURVE

SHOWS YOU, THE TIME TO

PUBLICATION AND YOU CAN SEE BY

FIVE YEARS ABOUT 75% OR SO OF

THE STUDIES WERE PUBLISHEDCH

THIS IS AFTER PRESENTATION AT

THE MEETING.

FURTHERMORE, IF YOU LOOK AT THE

PHARMACEUTICAL STUDIES, THE

DARKEST BLACK LINE THEY WERE

PUBLISHED ON AVERAGE A LITTLE

MORE RAPIDLY THAN STUDIES FUNDED

BY OTHER SOURCES.

SO, SO FAR SO GOOD.

THE ISSUE COMES UP WHEN YOU LOOK

AT TIME TO PUBLICATION BY BOTH

SPONSOR AND NATURE OF THE

RESULTS.

SO FOCUS FOR A MOMENT ON TWO

LIGHTER GRAY BARS.

WHAT YOU CAN SEE IS THAT FOR THE

NON-INDUSTRY FUNDED, THE

PUBLICLY FUNDED STUDIES, THERE

IS DISCREPANCY IN TIME TO

PUBLICATION.

FUNDED STUDIES ARE PUBLISHED

MORE RAPIDLY THAN NEGATIVE

STUDIES BUT THE DIFFERENCE IS

NOT THAT GREAT AND ULTIMATELY

THE TWO CURVES COME TOGETHER.

ON THE OTHER HAND, IF YOU LOOK

AT THE INDUSTRY-FUNDED STUDIES

IN THE DARKER BLACK BARS, THERE

IS A WIDER GAP IN TIME TO

PUBLICATION BETWEEN POSITIVE AND

NEGATIVE STUDIES AND THE GAP

REMAINS, THIS IS ABOUT A 15

POINT DIFFERENCE, TWO CURVES DO

NOT COME TOGETHER.

THIS SUGGESTS THERE MAYBE MORE

OF A PUBLICATION BIAS IN

INDUSTRY-FUNDED STUDIES THAN

NON-INDUSTRY FUNDED STUDIES.

SO TO PUT IT TOGETHER, THIS IS

AN INTERESTING ARTICLE BY A

GROUP OF SIGH CHAI GISTS THAT --

PSYCHIATRISTS THAT ASK IF WE

TAKE SECOND GENERATION

ANTIPSYCHOTICS HEAD TO HEAD,

SOMETIMES ARC BEATS B BUT

SOMETIMES B BEATS A, SOMETIMES C

BEATS B.

WHAT DO DIFFERENT STUDIES COME

TO DISCREPANT RESULTS.

VERY OFTEN THE DRUG FOUND TO BE

DERT IS THE -- BETTER IS THE

SPONSOR OF THE PARTICULAR STUDY.

ASKING WHY THIS WAS, JUST A

QUOTE FROM THEIR ABSTRACT.

OF THE 42 REPORTS IDENTIFIED BY

THE OFFICE, HEAD TO HEAD

COMPARISONS OF SECOND GENERATION

ANTIPSYCHOTIC, 33 WERE SPONSORED

BY A PHARMACEUTICAL COMPANY.

IN 90% OF THE STUDIES THAT

REPORTED OVERALL OUTCOME WAS IN

FAVOR OF THE SPONSOR'S DRUG.

THIS PATTERN RESULTED IN

CONTRADICTORY CONCLUSIONS ACROSS

THE STUDIES.

WHEN FINDINGS OF STUDIES WITH

SAME DRUGS BUT DIFFERENT

SPONSORS WERE COMPARED.

POTENTIAL SOURCES OF BIAS

OCCURRED IN DOES AND DOSE

ESCALATION.

STUDY ENTRY CRITERIA AND

POPULATIONS, STATISTICS AN

METHODS AND REPORTING OF RESULTS

AND WORDING OF FINDINGS.

LOTS OF DIFFERENT REASONS WHY

THE SAME HEAD TO HEAD

COMPARISONS MIGHT COME TO

DIFFERENT CONCLUSIONS DEPENDING

UPON WHO WAS SPONSORING THAT

STUDY.

SO FAR I HAVE TALKED EXCLUSIVELY

ABOUT PERSONAL -- INDUSTRY

FUNDING AND NOT ABOUT PEOPLE'S

PERSONAL FINANCIAL TIES WITH

WITH INDUSTRY.

SO SAY A LITTLE BIT ABOUT THIS.

FIRST OF ALL HOW COMMON ARE

THESE.

THIS IS A RECENTLY PUBLISHED

STUDY THAT SURVEYED RANDOM

SAMPLE OF LIFE SCIENCES FACULTY.

THIS INCLUDES CLINICAL FACULTY

AND BASIC SCIENCE FACULTY.

AT 50 U.S. UNIVERSITIES WITH THE

MOST NIH SUPPORTS.

YOU CAN SEE ABOUT 50% OF

RESPONDENTS TO THE SURVEY

REPORTED HAVING A RELATIONSHIP.

IF YOU LOOK AT ANY RELATIONSHIP,

THEY WERE COMMON AMONG CLINICAL

FACULTY THAN NON-CLINICAL

FACULTY BUT THE DIFFERENCE WAS

NOT GREAT.

IN THE LOWER BARS YOU CAN SEE

WHAT THE RATES OF RELATIONSHIPS

WERE ON TERMS OF SCIENTIFIC

ADVISORY BOARD SERVING AS

CONSULTANT TO THE COMPANY AND

OTHER TYPES OF RELATIONSHIPS.

NOT SURPRISINGLY THOSE WHO WERE

MORE SENIOR WERE A LITTLE BIT

MORE LIKELY TO HAVE THESE

RELATIONSHIPS WITH INDUSTRY

THOUGH AGAIN, FOR MANY OF THESE

AREAS THE DIFFERENCES BY

SENIORITY WERE NOT ALL THAT

GREAT.

CERTAINLY CONSULTANTS, SENIOR

FACULTY ARE MORE LIKELY TO HAVE

CONSULTING RELATIONSHIPS AN MORE

ON ADVISORY BOARDS THAN COMPARED

WITH JUNIOR FACULTY.

DO THESE PERSONAL FINANCIAL

RELATIONSHIPS ACTUALLY AFFECT

TRIAL OUTCOMES OR ARE THEY

ASSOCIATED WITH TRIAL OUTCOMES?

THE REMARKABLE THING IS DESPITE

THE FACT THIS IS AREA OF GREAT

CONCERN THIS IS AN AREA WE HAVE

THE FEWEST DATA.

THE ANSWER TO THE QUESTION ABOUT

HOW PERSONAL TIES ARE ASSOCIATED

WITH OUTCOMES BUT A COUPLE OF

HINTS.

SO A STUDY PUBLISHED THREE YEARS

AGO BY VICTOR THEY LOOKED AT

REPORTS IN THE NEW ENGLAND

JOURNAL OR JAMA J 2001 AND FOUND

ABOUT FOR I THINK JAMA WAS 16%

FOR NEW ENGLAND JOURNAL 22% OF

ARTICLES HAD AT LEAST ONE AUTHOR

WHO REPORTED A FINANCIAL TIE TO

INDUSTRY.

AND THEN THEY LOOKED AT STUDY

OUTCOMEDY VIEDED UP BY WHETHER

PEOPLE DID OR DID NOT HAVE A

PERSONAL OR FINANCIAL TIE.

AMONG THOSE WITH NO PERSONAL

FINANCIAL TIES, THERE WAS MORE

POSITIVE STUDIES THAN NEGATIVE

BUT YOU CAN SEE THAT THERE'S A

REASONABLE DISTRIBUTION BETWEEN

POSITIVE AND NEGATIVE STUDIES.

ON THE OTHER HAND AMONG THOSE

WHERE AT LEAST ONE AUTHOR DID

HAVE A PERSONAL FINANCIAL TIE

THE MAJORITY OF STUDIES WERE

POSITIVE, ALMOST NO NEGATIVE

STUDIES.

THE PROBLEM WITH THIS ANALYSIS

IS IT DOESN'T CONTROL SOURCE OF

FUNDING.

I HAVE SHOWN YOU SURS OF FUNDING

IS ASSOCIATED WITH FUNDING

OUTCOME SO TO DIG DEEPER YOU

HAVE TO LOOK WHETHER THIS IS A

SOURCE OF CONTROL FOR FUNDING.

I SUSPECT THAT IS THE CASE BASED

ON HINTS IN THE LITERATURE BUT

NO GREAT SYSTEMATIC DATA TO

PROVE THAT POINT.

COMING BACK FOR THE LAST POINT

TO THE AVANDIA STUDY, SOME OF

THESE WERE ORIGINAL DATA OR

LETTERS OR REVIEWS OR

EDITORIALS.

ARTICLES THAT COMMENTED ON

ROSEGLITAZONE AND THE RISK OF

MYOCARDIAL INFARCTION AND WANTED

TO KNOW ARE THE AUTHORS PERSONAL

FINANCIAL TIES RELATED TO THE

POSITIONS THEY TOOK IN THEIR

ARTICLES.

WILL LITTLE OVER HALF HAD A

CONFLICT OF INTEREST STATEMENT

SO ONLY HALF THE ARTICLES COULD

SHE ACTUALLY IDENTIFY WHICH

AUTHORS DID OR DID NOT HAVE

RELATIONSHIPS.

OF THOSE 180 ARTICLES 90 AUTHORS

REPORTED A FINANCIAL

RELATIONSHIP.

SO HERE ARE THE DATA THAT SHE

FOUND FOCUSING FOR THE MOMENT ON

THE TOP BAR YOU CAN SEE AMONG

THOSE WITH ANY TIE TO A

PHARMACEUTICAL MANUFACTURER,

JUST UNDER 40% TOOK A FAVORABLE

POSITION ON WHETHER

ROSEGLITAZONE HAD RISK, ANOTHER

40% TOOK A NEUTRAL POSITION AND

20% TOOK AN UNFAVORABLE POSITION

SUGGESTING THAT ROSEGLITAZONE

DID HAVE SIGNIFICANT

CARDIOVASCULAR RISK.

THIS PATTERN IS SIMILAR WHEN YOU

LIMIT TO TIES TO GLAXO WHICH YOU

RECALL WAS THE MAKER OF AVANDIA.

COMPARE THAT ON THE OTHER HAND

TO THESE BARS WHICH REFLECT THE

AUTHORS WITH NO TIES TO ANY

PHARMACEUTICAL MANUFACTURER.

YOU CAN SEE THE PROPORTION WHO

TAKE A FAVORABLE POSITION ON THE

SAFETY OF ROSEGLITAZONE IS TINY,

AND A HIGHER PROPORTION ARE

UNFAVORABLE OR NEUTRAL ABOUT THE

SAICHTY OF ROSEGLITAZONE SO THIS

SUGGESTS SOME RELATIONSHIP

BETWEEN WHETHER OR NOT PEOPLE

HAVE FINANCIAL TIES AND THE

POSITION THEY'RE WILLING THE

TAKE ON THIS VERY IMPORTANT

PUBLIC HEALTH AND PHARMACEUTICAL

CONCERN.

SO WE TALKED ABOUT WHY THERE ARE

CONCERNS ABOUT BIAS RELATED TO

INVESTIGATORS FINANCIAL TIES

WITH INDUSTRY.

NOW I WANT TO TALK ABOUT THE

IMPLICATIONS OF RECENT DATA

REGARDING ASSOCIATIONS THAT

INVESTIGATORS HAVE REGARDING

ASSOCIATIONS BETWEEN THEIR

FINANCIAL TIES AND THEIR

SCIENTIFIC CONTRIBUTIONS.

SO THE FIRST QUESTION IS WHICH

AUTHORS OR WHICH SCIENTISTS HAVE

FINANCIAL TIES.

SO IN AN ARTICLE PUBLISH LAST

YEAR WE LOOKED AT REPORTS OF

CLINICAL TRIALS PUBLISHED IN

CLINICAL ONCOLOGY IN AN 18 MONTH

PERIOD OF TIME IN 2006 OR 2007.

THERE WERE 235 ARTICLES THAT MET

ELIGIBILITY CRITERIA.

THEN WEso! -- BECAUSE JCO IS
GOOD

ABOUT PUBLISHING DETAILED

AUTHORSHIP CONTRIBUTION

INFORMATION, WHAT PEOPLE SAID

THEY DID ON THE ARTICLE AND ALSO

FINANCIAL DISCLOSURES WE

ABSTRACTED THE INFORMATION FROM

ALL THOSE TABLES FOR JUST UNDER

3,000 AUTHORS AND WE WANTED TO

KNOW WHETHER THOSE AUTHORS WHO

REPORTED IN THE ARTICLE THEY HAD

PERFORMED A KEY SCIENTIFIC ROLE,

WHICH WE DEFINED CONCEPTION AN

DESIGN OF STUDY, ANALYSIS AND

INTERPRETATION OF THE STUDY OR

DRAFTING OF THE STUDY

MANUSCRIPT.

WHETHER THESE AUTHORS WERE MORE

LIKELY THAN OTHERS TO REPORT

FINANCIAL TIES.

THOSE AT THE CENTER OF THE

SCIENTIFIC ACTION IN INDUSTRY.

AND THE ANSWER WAS A RESOUNDING

YES.

IF YOU LOOK AT THE TOP BAR

THOSE, ABOUT 35% OF THOSE WHO

REPORTED THEY PERFORMED ONE OF

THESE THREE KEY ROLES HAD A

FINANCIAL RELATIONSHIP WITH

INDUSTRY COMPARED WITH LESS THAN

20% OF THOSE WHO DID NOT PERFORM

A KEY ROLE.

THE -- IF YOU LOOK AT JUST THOSE

STUDIES REPORTED BY INDUSTRY

WHICH WAS -- THAT WERE FUNDED BY

INDUSTRY WHICH IS A LITTLE MORE

THAN HALF OF THE TOTAL, YOU WILL

SEE THAT OVERALL THERE ARE MORE

FINANCIAL RELATIONSHIPS REPORTED

AND THE DIFFERENCES ARE ACTUALLY

BIGGER WITH 55% OF THOSE PERFORM

AD KEY REPORT REPORTING THEY HAD

FINANCIAL RELATIONSHIPSCH

INTERESTINGLY THOUGH THE NUMBERS

OF RELATIONSHIPS WAS SMALLER ON

THE NON-INDUSTRY FUNDED SIDE YOU

SEE THE SAME PATTERN EXISTS.

THOSE AUTHORS WHO PERFORMED KEY

ROLES ARE MORE LIKELY TO HAVE

INDUSTRY RELATIONSHIPS THAN

THOSE WHO DID NOT.

WE DON'T KNOW THE MECHANISM

BEHIND THIS RELATIONSHIP AND

THERE'S A NUMBER OF HYPOTHESES

ONE CAN SPECULATE INCLUDING THE

MOST LIKELY, THOSE AUTHORS WHO

ARE THE MOST ACADEMICALLY ACTIVE

WHO RECOLLECTS ARE MOST SENIOR,

RECOGNIZED AS EXPERTS IN THE

FIELD ARE MOST LIKELY TO PLAY

KEY ROLES IN RESEARCH AND LIKELY

TO DEVELOP RELATIONSHIPS WITH

INDUSTRY.

AS BOTH AS REFLECTIONS OF THEIR

SENIORITY AND RECOGNIZED

EXPERTISE, NOT NECESSARILY A

NEFARIOUS EXPLANATION BUT

NONETHELESS, THE ASSOCIATION AT

LEAST IN THE ONCOLOGY WORLD IS

CLEARLY THERE.

TO ASK A BROADER QUESTION HOW

ARE FINANCIAL TIES RELATED TO

PRODUCTIVITY, I WANT TO TAKE YOU

BACK TO THE STUDY TWO YEARS AGO

IN HEALTH AFFAIRS, WHERE THEY

LOOKED AT STRATIFIED RANDOM

SAMPLE OF LIFE SCIENCES FACULTY

AT THE 50 UNIVERSITIES WITH THE

MOST NIH SUPPORT.

AND THEY FOUND INTERESTING

DIFFERENCES BETWEEN AUTHOR WHOSE

DID VERSUS DID NOT HAVE

FINANCIAL TIES TO INDUSTRY.

CONSISTENTLY THOSE WHO HAD

FINANCIAL TIES THE INDUSTRY IN

THE DARK BLUE BARS WERE MORE

LIKELY TO SUPPORT -- REPORTED

GREATER MARKERS OF ACADEMIC

PRODUCTIVITY COMPARED TO THOSE

WITHOUT TIES SO THEY PUBLISHED

MORE PUBLICATIONS IN THE PAST

THREE YEARS, AN AVERAGE OF 13,

COMPARED WITH ABOUT EIGHT.

THEIR PUBLICATION RATE WAS

ACCELERATING RAPIDLY, AMONG

THOSE WITH FINANCIAL TIES

COMPARED TO THOSE WHO DID NOT.

THE IMPACT OF THE JURY ROOMS

THEY PUBLISHED IN WAS HIGHER.

UNRELATED TO DIRECT PRODUCTIVITY

MEASURES THOSE WITH FINANCIAL

TIES WERE MORE ENGAGED IN

SERVICE ACTIVITIES AT THEIR

LOCAL INSTITUTIONS OR NATIONAL

ORGANIZATIONS SO VARIOUS WAYS

MAKING CONTRIBUTIONS TO THE

SCIENCE COMMUNITY OF SCIENCE.

ALL THESE WERE ADJUSTING FOR ALL

THE THINGS THAT YOU MIGHT THINK

ARE CONFOUNDERS LIKE RANK, YEARS

IN IN PROFESSION, SEX, TOTAL

AMOUNT OF RESEARCH FUNDING IN

ONE'S PORTFOLIO AND THE

DEPARTMENT THAT ONE CAME FROM.

THIS WAS NOT A MONOTONIC

RELATIONSHIP.

THE PEOPLE MOST PRODUCTIVE HAD

ABOUT BETWEEN 1 TO 33% OF

RESEARCH PORTFOLIO COMING FROM

INDUSTRY.

SO THOSE VIRTUALLY EXCLUSIVELY

INDUSTRY-FUNDED WERE LESS

PRODUCTIVE THAN THOSE WHETHER

HAD A BALANCED PORTFOLIO WITH

SOME INDUSTRY FUNDING BUT SOME

FUNDING FROM OTHER SOURCES.

SOME OF THE IMPLICATIONS OF

THESE DATA, TO SUMMARIZE THES

DATA BEFORE MOVING TO THE NEXT

SECTION, THERE'S EVIDENCE

ACADEMIC AUTHORS WITH FINANCIAL

TIES ARE MAKING GREATER

SCIENTIFIC CONTRIBUTIONS THAN

PEERS WITHOUT TIES.

I'M NOT IMPLYING CAUSAL

RELATIONSHIP THERE, IT DOESN'T

NECESSARILY MEAN THESE

RELATIONSHIPS FOR LEADING THEM

TO BE MORE PRODUCTIVE BUT

THERE'S AN ASSOCIATION.

INDUSTRY SUPPORT AT LEAST WITHIN

A BALANCED RESEARCH PORTFOLIO

CORRELATES WITH GREATER

SCIENTIFIC PRODUCTIVITY.

WE KNOW NOTHING ABOUT THE

MECHANISMS BEHIND THESE

RELATIONSHIPS AND I SUGGEST THIS

IS A FRUITFUL AREA FOR FURTHER

STUDY.

BUT ONE THING THAT LEADS ME TO

WONDER IS WHAT -- AS WE

INCREASINGLY RESTRICT ACADEMIC

INDUSTRY COLLABORATIONS, WE'LL

OBVIOUSLY THINK WHAT ARE THE

POSITIVE OUTCOMES OF THOSE

RESTRICTIONS BUT WE AT LEAST

HAVE TO BE OPEN TO THE

POSSIBILITY THAT THERE ARE GOING

TO BE SOME ADVERSE EFFECTS OF

SCIENCE AND THE PROGRESS OF

SCIENCE AND THE PROCESS OF

TRANSLATION.

SO FINALLY HAVING TALKED ABOUT

WHY THERE ARE CONCERNS ABOUT

BIAS HAVING THOUGHT ABOUT THESE

RECENT DATA CONCERNING THEy

RELATIONSHIP BETWEEN

PRODUCTIVITY OPT ONE HAND AND

THEIR FINANCIAL TIES ON THE

OTHER, LET'S TALK BRIEFLY ABOUT

POLICY SOLUTIONS AND ABOUT THEIR

LIMITATIONS.

THERE IS A LOT OF ACTION ON THIS

FRONT AS I'M SURE YOU ALL KNOW.

CONGRESS HAS BEEN PAYING

ATTENTION TO THIS.

LEGISLATURES HAVE BEEN PAYING

ATTENTION TO THIS, I LISTED

THERE SOME OF THE STATES THAT

HAVE ENACTED LAWS SOMEHOW

RESTRICTING OR REQUIRING

DISCLOSURE OF CERTAIN KINDS OF

RELATIONSHIPS.

FEDERAL FUNDERS OBVIOUSLY THE

NIH IS CONCERNED ABOUT THIS AND

HAS NEW POLICIES.

UNIVERSITIES AND ACADEMIC

MEDICAL CENTERS AND THE

ORGANIZATIONS THAT REPRESENT

THEM HAVE WEIGHED IN.

THE INSTITUTE OF MEDICINE

RECENTLY ISSUED AN IMPORTANT

REPORT.

COMPANIES AND THEIR TRADE

ASSOCIATIONS, ARE CONCERNED

UNDER DEVELOPING POLICIES.

AND JOURNALS ARE DEVELOPING

POLICY.

SO LET'S TOUCH ON EACH OF THESE.

SO HOW DO WE ADDRESS FINANCIAL

CONFLICTS OF INTEREST?

ONE OBVIOUS POTENTIAL SOLUTION

OR PARTIAL SOLUTION IS

DISCLOSURE.

A SECOND IS MANAGEMENT.

I'LL SAY MORE ABOUT WHAT I MEAN

BY THAT.

OBVIOUSLY DISCLOSURE AND

MANAGEMENT ARE NOT IN ANY WAY

MUTUALLY EXCLUSIVE.

FINALLY THE QUESTION COMES UP

SHOULD WE BE PROHIBITING

FINANCIAL RELATIONSHIPS WITH

INDUSTRY?

IN SOME CIRCUMSTANCE OS ALL

CIRCUMSTANCES.

IF WE'RE TALKING DISCLOSURE,

THERE ARE LOTS OF QUESTIONS TO

BE ASKED AND ANSWERED, TO WHOM

DO WE DISCLOSE THIS INFORMATION.

TO THE SPONSORS, FOR EXAMPLE IF

I HAVE AN INDUSTRY RELATIONSHIP

AND I APPLY TO THE NIH FOR

EXTRAMURAL GRANT SHOULD I BE

DISCLOSING IS THAT TO THE NIH OR

TO THE POTENTIAL SPONSOR OF MY

WORK.

DO WE DISCLOSE TO IRBs WHEN WE

SUBMIT HUMAN SUBJECTS PROJECTS

FOR REVIEW AND APPROVAL?

DISCLOSE TO OUR INSTITUTIONS,

FOR EXAMPLE TO CONFLICTS OF

INTEREST COMMITTEES OR OFFICERS

RESPONSIBLE FOR OVERSIGHT IN

THIS AREA.

DO WE DISCLOSE TO THE CONSUMERS

OF OUR SCIENCE?

JOURNALS, THE READERS OF OUR

JOURNAL ARTICLE, PEOPLE WHO

ATTEND OUR TALKS AT MEETINGS.

AND THEN THE VERY IMPORTANT

QUESTION, WHAT ABOUT THE

RESEARCH SUBJECTS WHO MIGHT

CONSIDER JOINING OUR STUDIES.

SO WHAT DO RECIPIENTS THINK

ABOUT DISCLOSURE?

I PLAYED A ROLE IN A RECENT META

NAILSIS FROM A GROUP AT YALE.

WHERE THEY LOOKED AT RECIPIENT

VIEWS ON DISCLOSURE, THAT WAS

DEFINED PATIENTS IN THE CLINICAL

CONTEXT, RESEARCH SUBJECTS IN

THE RESEARCH CONTEXT AND ALSO

INVESTIGATORS OR CLINICIANS AS

THEY RECEIVE DISCLOSURES FOR

EXAMPLE IN CONJUNCTION WITH

JOURNAL ARTICLES.

OUR KEY CONCLUSION IN THIS

PARTICULAR CONTEXT THAT ASSESS

IMPORTANCE OF DISCLOSURE AS SEEN

FROM A POINT OF VIEW OF PATIENTS

AND/OR RESEARCH SUBJECTS.

MOST PATIENTS AND PARTICIPANTS

BELIEVE FINANCIAL TIES SHOULD BE

DISCLOSED SO STRONG STATEMENT IN

FAVOR OF DISCLOSURE.

THE APPROXIMATELY QUARTER

BELIEVED IT SHOULD BE DISCLOSED.

ASSESSING WILLINGNESS TO

PARTICIPATE IN RESEARCH.

ALMOST ALL OF THESE THEY WERE

HYPOTHETICAL STUDIES, NOT

ACTUALLY ASKING PEOPLE ABOUT

DISCLOSURES IN THE CONTEXT OF A

REAL STUDY THE PERSON WAS

CONSIDERING.

APPROXIMATELY A QUARTER OF

PARTICIPANTS REPORTED LESS

WILLINGNESS AFTER DISCLOSURE

FINANCIAL TIES.

SO WHAT DO WE DRAW FROM THIS?

YOU MIGHT LOOK AND SAY A

MINORITY OF POTENTIAL SUBJECTS

IN OUR RESEARCH ACTUALLY MIGHT

CHANGE THEIR MINDS OR MIGHT BE

LESS WILLING TO PARTICIPATE IN

THE RESEARCH SO DISCLOSURE IS

NOT DOING A LOT OF WORK SO

THEREFORE IT'S NOT IMPORTANT OR

YOU MIGHT LOOK AND SAY WELL, ALL

WELL AND GOOD THAT IT DOESN'T

MATTER THREE QUARTERS OF THE

PEOPLE BUT DOES MATTER TO A

QUARTER SO WE SHOULD GIVE HEM

THE INFORMATION IF THEY CONSIDER

IT MATERIAL TO THEIR DECISION

ABOUT BEING IN THE RESEARCH.

THINK I THINK THESE FINDINGS ARE

INTERPRETED DIFFERENT WAYS BY

DIFFERENT PEOPLE.

THE HEALTHCARE REFORM ACT HAD

SOMETHING TO SAY ABOUT

DISCLOSURE.

SO MANY OF YOU KNOW CHARLES

GRASSLEY HAD A BILL PRIOR TO

AFFORDABLE CARE ACT CALLED THE

PHYSICIAN PAYMENT SUNSHINE ACT

SO MANY PROVISIONS OF THAT ACT

WERE FOLDED INTO THE HEALTHCARE

REFORM ACT.

SO WHAT THIS SAYS IS U.S.

MANUFACTURERS OF DRUGS, DEVICES,

BIOLOGICALS AND MEDICAL SUPPLIES

COVERED UNDER FE RAL HEALTHCARE

PAYMENT PROGRAMS MUST REPORT ANY

PAYMENT THEY MAKE TO PHYSICIANS

OR TEACHING HOSPITALS TO THE

DEPARTMENT OF HEALTH AND HUMAN

SERVICES ARE ON AN ANNUAL BASIS.

THIS COVERS PHYSICIAN

INVESTIGATORS, NON-PHYSICIAN

INVESTIGATORS WOULDN'T BE

COVERED.

IT COVERS ALL TYPES OF PAYMENTS

WORTH $10 OR MORE INCLUDING

RESEARCH FUNDING.

IMPLEMENTATION, IN OTHER WORDS,

THE PERIOD DURING WHICH

COMPANIES MUST BEGIN TO REPORT

THIS INFORMATION BEGINS ON

JANUARY 1st OF NEXT YEAR.

SO COMPANIES ARE BUSY GATHERING

THESE DATA SO BY THE END OF 2012

THEY'LL HAVE THE DATA TO REPORT

TO HEALTH AND HUMAN SERVICES.

THE COMPANIES ARE AT RISK OF

SUBSTANTIAL FINES IF FOUND TO BE

NON-COMPLIANT, ESPECIALLY IF

THERE'S REASON TO BELIEVE THEIR

NON-COMPLIANCE WAS KNOWING

NON-COMPLIANCE.

I INVOKE THE CONCEPT OF

MANAGEMENT A FEW MINUTES AGO.

THERE'S ACTUALLY NOT AS MUCH AS

ONE MIGHT THINK WRITTEN ABOUT

WHAT MANAGEMENT IS AND MORE

IMPORTANT, WHAT WORKS AND WHAT

DOESN'T WORK IN TERMS OF

MANAGING FINANCIAL

RELATIONSHIPSCH ONE BETTER

POLICY I HAVE SEEN CAME FROM THE

UNIVERSITY OF WASHINGTON WHICH

HAS A POLICY CALLED THE

SIGNIFICANT FINANCIAL INTEREST

DISCLOSURE POLICY.

THEY OUTLINE POSSIBLE STEPS THAT

THE INSTITUTION CAN TAKE WHEN AN

INVESTIGATOR HAS FINANCIAL

RELATIONSHIPS THEY BELIEVE NEEDS

MANAGEMENT.

SO THESE MIGHT MEAN MONITORING

OF THE SEARCH BY INDEPENDENT

CO-RESEARCHERS OR REVIEWERS,

INDIVIDUALS NAMED BY INSTITUTION

TO OVERSEE THE INVESTIGATOR'S

DISINTERESTED COMMITTEE.

IT MIGHT MEAN THE INVESTIGATOR

PLACES COPIES OF HIS OR HER

RESEARCH DATA WITH A MUTUAL

PARTY AND IT CERTAINLY WILL MEAN

THERE HAS TO BE ANNUAL REPORTS

BY THE INVESTIGATOR TO THE

UNIVERSITY IN TERMS OF THE

OUTCOME OF THE RESEARCH AND THE

PROGRESS OF THE FINANCIAL

RELATIONSHIPS.

SO ESSENTIALLY A LEVEL OF

MONITORING, ONE THING THAT'S

IMPLIED HERE THAT I THINK PEOPLE

DON'T LIKE IS A CERTAIN AM OF

MISTRUST.

THE INVESTIGATOR, IF I HAVE A

FINANCIAL RELATIONSHIP NEED THIS

LEVEL OF INDEPENDENT MONITORING

AN YEAR SIGHTCH THIS IS ONE

THING THAT I THINK INVESTIGATORS

DON'T LIKE WHEN THEY'RE ASKED TO

DO THIS.

THE NIH AS MANY OF YOU KNOW HAS

NEW RULES FOR EXTRAMURAL

GRANTEES THAT CHANGE SOME OF THE

IMPORTANT OLD PROVISIONS AND TO

GIVE YOU SOME OF THE HIGHLIGHTS,

ONE OF THE DEFINITION OF

SIGNIFICANT FINANCIAL INTEREST

HAS CHANGED.

USED TO BE THE NIH WAS ONLY

CONCERNED ABOUT RELATIONSHIPS

OVER $10,000.

NOW THEY'RE COCERTAINED ABOUT

RETION SH -- CONCERNED ABOUT

RELATIONSHIPS OVER $5,000.

FUNDAMENTALLY, THE WAY

INVESTIGATORS AND INSTITUTIONS

HANDLE THEIR SIGNIFICANT

FINANCIAL INTEREST HAS CHANGED.

USED TO BE THE INVESTIGATOR

WOULD LOOK AT HIS OR HER

FINANCIAL RELATIONSHIPS, DECIDE

WHICH POSE A CONFLICT WITH

RESPECT TO THE RESEARCH THEY

WERE DOING AND TELL THE

INSTITUTION ONLY ABOUT THOSE

THAT THE INVESTIGATOR THOUGHT

POSED A CONFLICT.

THAT PURCHASE CHANGED.

NOW THE INVESTIGATOR HAS TO

REPORT TO THE INSTITUTION ALL OF

THEIR FINANCIAL RELATIONSHIPS

AND IT'S NOW THE INSTITUTION'S

JOB TO DECIDE WHICH OF THOSE

FINANCIAL RELATIONSHIPS

CONSTITUTES THAT CONFLICT.

WHENEVER THE INSTITUTION

IDENTIFIES SOMETHING AS A

CONFLICT IT HAS TO DEVELOP A

MANAGEMENT PLAN FOR THAT

CONFLICT.

THE RULES DO NOT GIVE GUIDANCE

ON WHAT CONSTITUTES AN

APPROPRIATE MANAGEMENT PLAN.

AND THEN THE INSTITUTION HAS TO

DISCLOSE THE NATURE OF THE

CONFLICT AND THE KEY ELEMENTS OF

THE MANAGEMENT PLAN TO THE PHS

FUNDER

A. USED TO BE SIMPLY

INSTITUTIONS TELL THE

INSTITUTIONS YES WE HAVE THE

CONFLICT AND WE'RE MANAGING IT

AND NOW THEY HAVE TO PROVIDE

MORE DETAIL.

INSTITUTION VERSUS TO MAKE THEIR

CONFLICT OF INTEREST INFORMATION

VAIL TO BELIEVE THE PUBLIC ON A

PUBLIC WEBSITE WHICH IS FREELY

ACCESSIBLE AND NOT PASSWORD

PROTECTED, OR IF THEY DON'T WANT

TO DO THAT THEY DON'T HAVE TO

RESPOND TO ANY WRITTEN REQUEST.

SO THERE'S INCREASED LEVEL OF

TRANSPARENCY COMPARED TO WHAT

WAS TRUE A FEW YEARS AGO.

FINALLY THE FINAL POLICY

SOLUTION TO CONFLICT OF INTEREST

IS TO PROHIBIT THEM IN SOME OR

ALL CIRCUMSTANCES.

THE INSTITUTE OF MEDICINE

ACTUALLY HAS SOMETHING THAT

COMES CLOSE TO ADVOCATING THIS.

JUST TO READ FROM THEIR REPORT,

ACADEMIC MEDICAL CENTERS AND

OTHER RESEARCH INSTITUTIONS

SHOULD ESTABLISH A POLICY THAT

INDIVIDUALS GENERALLY MAY NOT

CONDUCT RESEARCH WITH HUMAN

PARTICIPANTS IN EXISTING OR

POTENTIAL PRODUCT OR COMPANY

THAT COULD BE AFFECTED BY THE

OUTCOME AFFECTED BY THE OUTCOME

OF THE RESEARCH.

EXCEPTIONS SHOULD BE MADE ONLY

IF CONFLICT OF INTEREST

COMMITTEE DETERMINES AN

INDIVIDUAL -- A, DETERMINES AN

INDIVIDUAL'S PARTICIPATION IS

ESSENTIAL FOR THE CONDUCT OF THE

RESEARCH AND B, ESTABLISHES AN

EFFECTIVE MECHANISM FOR MANAGING

THE CONFLICT AND PROTECTING THE

INTEGRITY OF THE RESEARCH.

SO THE PRESUMPTION HERE IS NO

INVOLVEMENT OF FINANCIAL

INTEREST INVESTIGATORS ABOVE A

CERTAIN DE MINIMIS IN HUMAN

SUBJECTS RESEARCH BUT THAT

PRESUMPTION IS REBUTTABLE IN

LIMITED CIRCUMSTANCES.

SO THE QUESTION WE'RE LEFT WITH,

I DON'T HAVE THE ANSWERS TO

THESE QUESTIONS, IS HOW WELL DO

THESE RULES ACCOMPLISH THE GOAL

SET OUT.

THE MAIN GOALS ARE MINIMIZING

THE RISK TO HUMAN SUBJECTS.

I TOLD YOU AT THE BEGINNING WE

DON'T HAVE DATA THAT RISKS TO

HUM SUBJECTS WERE INCREASED WHEN

THERE ARE FINANCIAL INTERESTS.

HOW WELL DO THEY REDUCE RISK IN

BIAS AND SCIENCE.

THAT'S AN OPEN QUESTION.

THEY CERTAINLY DO HAVE THE

POTENTIAL TO REDUCE FACULTY AND

ACADEMIC INSTITUTIONS AN

NON-COMMERCIAL FUNDERS IN BIASED

SCIENCE.

HOW WELL DO THEY PROTECT

REPUTATION OF ACADEMIC FACULTY

AND INSTITUTIONS OR PROTECT

ACADEMIC VALUES THOUGH MANY OF

YOU RECOGNIZE THAT THERE'S

CONTROVERSY AROUND WHAT THOSE

ACADEMIC VALUES ARE AND HOW WELL

DO THEY PRESERVE THE PUBLIC

TRUST.

ARE THEY EFFECTIVE ACCOMPLISHING

THAT IMPORTANT GOAL.

SO JUST THE SUMMARIZE KEY POINTS

I TRY TO MAKE, THERE IS A STRONG

EVIDENCE BASE I BELIEVE FOR BIAS

IN INDUSTRY FUNDED RESEARCH.

THERE'S A WEAKER BUT GROWING

EVIDENCE BASE THAT PERSONAL

FINANCIAL TIES AS OPPOSED TO

INDUSTRY FUNDING OF THE RESEARCH

ITSELF POSE ADDITIONAL RISK.

THERE'S NEW EVIDENCE CONTRARY

POINT FINANCIAL TIES CORRELATE

WITH SCIENTIFIC CONTRIBUTIONS

AND PRODUCTIVITY THOUGH I STRESS

THIS DOES NOT MEAN THOSE

FINANCIAL TIES CAUSE INCREASE IN

PRODUCTIVITY.

THERE'S PL SI ACTIVITY GOING ON

IN THIS AREA BUT I THINK

QUESTIONS REMAIN HOW WELL THE

POLICY ACCOMPLISH THEIR KEY

GOALS.

WITH THAT I'LL STOP AND THANK

YOU FOR YOUR ATTENTION AND I'LL

WELCOME ANY QUESTIONS YOU MIGHT

HAVE.

THANK YOU.

[APPLAUSE]

>> THANK YOU FOR THAT WONDERFUL

SUMMARY.

I HAVE A POINT AND A QUESTION.

ONE IS THAT YOU HAD TALKED ABOUT

THIS DISTINCTION BETWEEN

NON-INDUSTRY AND INDUSTRY

STUDIES.

AS DISTINGUISHING BETWEEN

OUTCOMES OR BIASES.

BUT I WANTED TO KNOW YOUR

DEFINITION NOW OF NON-INDUSTRY

BECAUSE SITUATIONS FOR EXAMPLE

LIKE THE RECENT TENURE OF

DR. SUSAN DESMOND HELLMAN AT

UCSF WHO WAS WELL PLACED IN

INDUSTRY, NOW IS THE CHANCELLOR

OF A NON-PROFIT PUBLIC

INSTITUTION, UCSF, WHICH

PERFORMS CLINICAL RESEARCH

RELATED TO PHARMACEUTICAL

DEVELOPMENT AND DRUGS.

DOESN'T THAT BLUR DISTINCTION

SINCE DR. HELLMAN HAS GONE ON

RECORD AS SAYING THAT SHE WANTS

TO BRING MORE INDUSTRY TIES AND

COLLABORATION?

THAT'S THE FIRST QUESTION.

SECOND IS, YOU REALLY DIDN'T

TOUCH UPON THE FDA OR ANY OF THE

REGULATORY ISSUES THAT LIE

DOWNSTREAM OF CLINICAL STUDIES

AND WHETHER THEY ARE BIASED OR

NOT.

FOR EXAMPLE, MANY OF THOSE

ADVISORY PANELS SEEM TO HAVE AT

TIMES RATHER UNUSUAL

RELATIONSHIPS, NOT ALWAYS

FINANCIAL TO THOSE INDUSTRIES,

FRIENDSHIPS, PERSONAL TIES AND

PERHAPS MAYBE MOST INSIDIOUS, IS

THE EXPECTATION FOR FUTURE

REMIEWN RATION OR RELATIONS FROM

THOSE INDUSTRIES IF FAVORABLE

OUTCOMES COME.

I WAS WONDERING IF YOU COULD

COMMENT ON THOSE.

>> THOSE ARE BOTH GREAT POINTS

AND GREAT QUESTIONS.

THE THINGS YOU BRING UP ARE IN

THE FULL DAY COURSE ON CONFLICT

OF INTEREST.

THERE'S ONLY SO MUCH INTEREST WE

CAN COVER IN 45 MINUTES, THE

FIRST CASE I THINK IT IS

GENERALLY POSSIBLE TO MAKE A

DISTINCTION BETWEEN WHAT IS

VERSUS NOT INDUSTRY FUNDED.

IN ORDER WHO IS WRITING THE

CHECKS, RECOGNIZING THERE IS A

REMARKABLY LARGE SET OF STUDIES

THAT INVOLVE PARTNERSHIPS

BETWEEN INDUSTRY AN NON-INDUSTRY

FOUNDATION INDUSTRY PARTNERSHIP

OR PUBLIC PRIVATE PARTNERSHIP SO

THERE'S A THIRD CATEGORY WHERE

FUNDING SOURCES ARE MIXED.

THE CASE YOU RAISED OF

DR. HELLMAN AND PROBABLY READ

THE SAME FROM FILE A COUPLE OF

DAYS AGO IN THE NEW YORK TIMES

THAT I DID, I THINK IT'S

IMPORTANT TO RAISE THE ISSUE OF

INSTITUTIONAL CONFLICT OF

INTEREST WHICH IS ANOTHER TOPIC

I DIDN'T TOUCH ON.

SO WHEN EITHER INSTITUTIONS HAVE

INSTITUTIONAL MONEY OR LARGE

INSTITUTIONAL FINANCIAL

RELATIONSHIPS WITH INDUSTRY OR

IN THIS CASE INSTITUTIONAL

LEADERS HAVE PERSONAL FINANCIAL

RELATIONSHIPS, AND BY VIRTUE

LEADERSHIP AND INFLUENCE OVER

THE ORGANIZATION, THEIR PERSONAL

RELATIONSHIPS BECOME

INSTITUTIONAL.

AND I THINK HER CASE IS BEST

THOUGHT OF IN THAT WAY.

I LOOKED AT THAT AND I ENCOURAGE

ALL OF YOU TO READ THIS PROFILE

OF HER IN THE NEW YORK TIMES.

I ALSO WONDERED WHAT THE

IMPLICATION UCSF IS MY MEDICAL

ALMA MATER AND I WONDER WHAT THE

IMPLICATIONS OF THIS WERE FOR

THE INSTITUTION AND HOW SHE

PROPOSED TO ON THE ONE HAND

BUILD PARTNERSHIPS FOR

TRANSLATION AND BUILD

PARTNERSHIPS TO DO BETTER

SCIENCE AND MAKE PUBLIC HEALTH

CONTRIBUTIONS, ON THE OTHER HAND

TO MANAGE THESE RELATIONSHIPS.

SO IT'S AN OPEN QUESTION.

THE FDA STORY IS AN IMPORTANT

AND COMPLICATED STORY FOR A

NUMBER OF REASONS.

ONE, THERE ARE ACTUALLY USER

FEES SO SOME OF THE FDA FUNDING

ACTUALLY COMES FROM THE

INDUSTRIES THAT THEY'RE INTENDED

TO REGULATE.

TWO, AS YOU POINT OUT MANY OF

THE PEOPLE ON THEIR ADVISORY

PANELS HAVE FINANCIAL

RELATIONSHIPS WITH INDUSTRY AND

THIS CALLS INTO QUESTION THEIR

OBJECTIVITY WHEN THEY SERVE AS

MEMBERS OF THOSE ADVISORY

PANELS.

VERY INTERESTING STUDY I HAD ON

A PRIOR VERSION OF THIS TALK

THAT I TOOK OUT JUST FOR TIME

REASONS.

BUT DONE BY SID WOLF AND PETER

LURERY AT PUBLIC CITIZEN, TWO

PEOPLE PREDISPOSED TO FIND BIAS

IN COMMITTEE DECISIONS AS A

RESULT OF OR IN RELATIONSHIP TO

THE FINANCIAL RELATIONSHIPS OF

THE MEMBERS OF THOSE COMMITTEES.

TO THEIR CREDIT THEY PUBLISH IN

JAMA THE NEGATIVE STUDY.

WE LOOKED HARD FOR BIAS AND

COULDN'T FIND EVIDENCE THAT

DECISION THE COMMITTEES MADE OR

VOTES OF INDIVIDUAL MEMBERS WERE

AFFECTED BY THE PERSONAL

FINANCIAL RELATIONSHIPS THAT

THEY HAD.

THAT WAS AT LEAST ONE PIECE OF

AN ENCOURAGING STORY.

BUT THE FDA IS A HUGELY

IMPORTANT REGULATOR OF WHAT

HAPPENS WITH THE BIOMEDICAL DRUG

AND DEVICE INDUSTRY IN THIS

COUNTRY.

AS YOU POINT OUT THERE ARE BOTH

STRUCTURAL AND INSTITUTIONAL

RELATIONSHIPS BETWEEN THE FDA

AND THE COMPANIES AND

RELATIONSHIPS OR POTENTIAL FOR

RELATIONSHIP BETWEEN FDA STAFF

AND COMPANIES AND THE PEOPLE WHO

SERVE ON THE ADVISORY COMMITTEE.

PEGGY HAMBERG SAID SHE WANTS TO

INCREASE THE RELATIONSHIPS --

NOT THE FINANCIAL RELATIONSHIPS

-- LESSEN THE BARRIERS FOR

EXAMPLE TO PEOPLE SERVINGEN

ADVISORY COMMITTEES WHO MAY HAVE

INDUSTRY RELATIONSHIPS.

I KNOW THERE'S SOME CONCERN ON

THE CONFLICT OF INTEREST WORLD

ABOUT THAT.

THANK YOU FOR THE QUESTIONS.

SORRY FOR THE LONG ANSWERS.

YEAH.

>> THIS IS A PURPOSELY NAIVE

QUESTION BUT HAS ANYONE EVER

LOOKED AT TAKING A STEP BACK AND

LOOKED AT THE RESULTS OF SOME OF

THESE STUDIES JUST LONG-TERM

FINANCIAL EFFECTS ON THE

COMPANY?

IF YOU'RE PUBLISHING FALSE OR

MISLEADING DATA, EVENTUALLY -- I

GOT TO BELIEVE THAT EVENTUALLY

OVER TIME THE TRUTH IS GOING TO

COME OUT WHICH DRUGS ARE MOST

EFFECTIVE, WHICH DRUGS ARE GOING

TO CAUSE HARM.

AND I KNOW THAT BUSINESS TENDS

TO BE MORE SHORT-SIGHTED BUT HAS

ANYBODY LOOKED AT OVER TIME WHAT

THE FINANCIAL REPERCUSSIONS ARE

OF USING GOOD SCIENCE AND REALLY

GETTING THE TRUTH OUT FOR THE

COMPANIES THEMSELVES, THE

POTENTIAL FOR LAWSUITS, AND I

REALIZE THE FRONT END WHEN

THEY'RE STILL UNDER LICENSE,

THAT'S WHERE THEY MAKE THE MOST

MONEY AND IF THEY CAN GET PAST

THAT POINT THEN THEY HAVE MADE

THEIR PROCESS.

>> I HAVE NOT SEEN, I DON'T KNOW

IF ANYBODY ELSE IS AWARE OF SUCH

A STUDY.

I HAVE NOT SEEN A REAL ECONOMIC

ANALYSIS LOOKING AT WHETHER THE

COSTS WHEN THESE CONCERNS ABOUT

SAFETY COME TO LIGHT WHETHER THE

COSTS, LAWSUIT COSTS, OTHER

COSTS OUTWEIGH THE UP FRONT

PROFITS MADE FROM BEING ABLE TO

SELL THESE DRUGS.

I HAVE THE SENSE THAT EVEN IN

CLASS ACTION LAWSUITS THE AMOUNT

OF MONEY COMPANIES ARE FORCED TO

SHELL OUT IS CONSIDERABLY LESS,

AT LEAST FOR THE BLOCKBUSTER

DRUGS THAN THEY MADE EARLIER

BEFORE THESE FACTS CONTACT TO

LIGHT.

I HAVE THE SENSE THIS IS ALMOST

BUDGETED IN AS A COST OF DOING

BUSINESS, THAT THERE MAYBE

DOWNSTREAM COSTS FROM DEFENDING

LAWSUITS OR PAYING OUT

SETTLEMENTS.

BUT THAT THOSE ARE JUSTIFIED BY

THE PROFITS MADE UP FRONT.

I ALSO HAVE ENOUGH RESPECT FOR

INDUSTRY TO KNOW THEY ARE MAKING

DECISIONS, FINANCIAL DECISIONS

THAT AT THE END OF THE DAY ARE

ON AVERAGE NET WINNERS RATHER

THAN NET LOSERS SO I SUSPECT THE

FACT THAT THESE EVENTS ARE

HAPPENING SUGGEST THAT A

FINANCIAL CALCULATION HAS BEEN

MADE.

THAT'S A GREAT QUESTION.

IF ANYBODY HAS THE ABILITY TO DO

SUCH A STUDY, IT WOULD BE

FASCINATING THE SEE.

>> I HAVE A QUESTION FOR YOU.

YOU POINTED OUT NO SYSTEMATIC

DATA TO SHOW RISK FOR SUBJECTS

IN RESEARCH BASED ON THE KINDS

OF BIASES THAT MIGHT EXIST.

BUT ONE COULD SURMISE TO THE

EXTENT THERE IS BIAS IN TERMS OF

CHOICE OF CONTROL OR

INTERPRETATION OF THE ANALYSIS

OF THE DATA, INTERPRETATION, ANY

STEP ALONG THE WAY, THAT THAT

POSES RISK TO PARTICIPANTS IN

THE STUDY BUT ALSO TO THE

CONSUMERS OF THE STUDY OF THE

KNOWLEDGE.

SO MY QUESTION IS, YOU DID

ALLUDE TO THIS, BUT HOW MANY

DOES DISCLOSURE ADDRESS ANY OF

THAT?

YOU POINTED OUT SOME PEOPLE

WOULD NOT PARTICIPATE IF THEY

HAD CERTAIN FINANCIAL INTEREST

DISCLOSED.

BUT THE MAJORITY WOULD.

AND AS I UNDERSTAND THE

LITERATURE THE MAJORITY SAY THEY

DON'T CARE ABOUT IT, NUMBER ONE,

OR, A VERY SMALL NUMBER WOULD

SAY IT MIGHT BE MAKE THEM MORE

INCLINED TO PARTICIPATE.

HOW DO YOU THINK DISCLOSURE

ADDRESSES THE POTENTIAL RISK TO

BOTH PARTICIPANTS AND CONSUMERS?

>> I THINK IT PROBABLY DOES

LITTLE TO NOTHING TO ADDRESS

RISK EITHER TO THOSE WHO MIGHT

CONSIDER TAKING PART IN STUDIES

FOR CONSUMERS DOWN STREEM.

IN TERMS OF -- I THINK IT HAS

MUCH MORE TO DO WITH THE SENSE

OF TRUSTWORTHINESS THAT COMES

WITH THE SENSE THAT THIS IS A

TRANSPARENT ENTERPRISE.

SO I THINK DISCLOSURE IS

MAINTAINING TRUST IN INSTITUTION

INSTITUTIONS, MAINTAINING TRUST

MORE BROADLY.

IN TERMS OF MITIGATING RISK

FIRST, BECAUSE WE DONE HAVE DATA

TO SUGGEST PEOPLE ARE AT

INCREASED RISK IT'S NOT CLEAR

THERE IS AN EXCESS RISK TO BE

MITIGATED BY DISCLOSURE OR ANY

OTHER MECHANISM, MAY OR MAY NOT

BE, THERE'S JUST NO DATA ON THE

QUESTION.

SECONDLY, I DON'T THINK IF

DISCLOSURE TO RESEARCH SUBJECTS

WAS THE POINT WAS TO ALLOW

PEOPLE TO PROTECT THEMSELVESS

FROM RISK, I THINK ACTUALLY

THAT'S NOT IN MY VIEW, THIS IS

SOMETHING THAT MAY COME UP

ELSEWHERE IN THIS COURSE, THE

MAIN PURPOSE OF INFORMED CONSENT

IN MY VIEW IS NOT TO ALLOW

RESEARCH SUBJECTS TO PROTECT

THEMSELVES FROM RISK.

I THINK WE RELY ON IRBs AND

OVERSIGHT PROCESSES TO MITIGATE

RISK IN RESEARCH.

SO IF THAT GENERAL STATEMENT IS

TRUE T MORE SPECIFIC STATEMENT

THAT DISCLOSING FINANCIAL

INTEREST TO RESEARCH SUBJECTS

ALLOW THEM TO MITIGATE AND MON

TR THEIR OWN RISK, I THINK IT

DOESN'T WORK THAT WAY.

>> THANK YOU.

>> ALL RIGHT.

THANK YOU.

[APPLAUSE]

>> THANK YOU, STEVE.

OUR NEXT SPEAKER IS GOING TO

ADDRESS, THE ETHICS OF

RANDOMIZED CLINICAL CLINICAL
TRIALS AND

CLINICAL EQUIPOISE.

TO DO THAT WE HAVE BOB TRUE,

PROFESSOR OF ANESTHESIOLOGY AND

MEDICALAT

MEDICAL SCHOOL.

AND CHILDREN'S HOSPITAL IN

BOSTON.

AND BOB HAS BEEN DOING THIS

LECTURE FOR US SINCE THE FIRST

TIME WE TAUGHT THIS COURSE, I

THINK NOW 13 TIMES IN A ROW.

SO WE'RE LUCKY TO HAVE HIM BACK.

>> GREAT.

THANK YOU, CHRIS.

THANK YOU FOR BEING HERE THIS

MORNING.

SO AS YOU CAN SEE MY TOPIC IS

ETHICAL CONFLICTS THAT ARISE IN

RANDOMIZED CONTROL TRIALS.

AND I'LL SAY UP FRONT I'M NOT

GOING TO PROVIDE ANY SORT OF

SYSTEMATIC OR COMPREHENSIVE

REVIEW OF THIS ISSUE.

RATHER, WE'RE GOING TO FOCUS ON

A PARTICULAR CASE THAT I WAS

INVOLVED WITH AT A FEW YEARS

BACK WHEN I WAS A FELLOW.

AND IT FASCINATED ME AND I

THOUGHT A LOT ABOUT IT AND I

THOUGHT WE'RE GOING TO EXPLORE

TOPICS AN ISSUES THAT IT RAISED.

SO THIS IS THE CASE, IT DEALS

WITH THE TECHNOLOGY CALLED ECMO

THAT I'LL DESCRIBE TO YOU.

AND WE'LL LOOK AT WHAT I WOULD

SAY IS THE FUNDAMENTAL CONFLICT.

THAT IS, THE ROLE THAT WE HAVE

BETWEEN CLINICIAN AN

INVESTIGATOR.

AND THEN WE'LL LOOK AT SOME OF

THE WAYS THAT CONFLICT CANNING

MITIGATED.

TECHNIQUES LIKE ADAPTIVE

RANDOMIZATION WHICH BALANCE

CONFLICTING OBLIGATIONS OR AN

APPROACH CALLED ZALEN

RANDOMIZATION WHICH EASES THE

PSYCHOLOGICAL BURDENS ON

INVESTIGATORS.

FINALLY I'LL CLOSE WITH A

SOMEWHAT CRITICAL LOOK AT

RANDOMIZED CONTROL TRIALS IN

GENERAL.

AND THE EMPHASIS THAT WE PLACE

ON THESE SOMETIMES REGARDING

THEM IS REALLY THE ONLY WAY TO

LEARN.

SO THIS IS A PAPER THAT I'M

GOING TO REVIEW ABOUT ECMO.

IN OTHER WORDS TO EXPLAIN IT TO

YOU I NEED TO TELL YOU AB ECMO.

HERE IS A DIAGRAM OF WHAT THIS

TECHNOLOGY IS ABOUT.

SO ECMO IS A FORM OF CARDIO

PULMONARY BYPASS FOR PATIENTS

WITH LIFE THREATENING DEGREES OF

RESPIRATORY FOR CARDIAC FAILURE.

SO WE BYPASS THE HEART AND

LUNGS.

SO AN INCISION IS MADE IN THE

NECK AND CANNELLA ARE PLACED

DOWN NEAR THE RIGHT ATRIUM AND

AORTIC ARCH.

BLOOD IS DRAINED FROM THE RIGHT

ATRIUM TO A RESERVOIR WHERE A

PUMP OR ARTIFICIAL HEART PUTS IT

THROUGH A MEMBRANE OXYGEN ATOR,

A LARGE SILICON ENVELOPE ROLLED

UP INTO A CYLINDER AND THE BLOOD

IS PUMPED THROUGH THE INSIDE OF

THE ENVELOPE, GAS IS PUMPED ON

THE OUTSIDE, AND GAS EXCHANGE

OCCURS, BLOOD IS WARMED BACK UP

TO BODY TEMPERATURE AND HEAT

EXCHANGER AND PUT BACK INTO THE

BODY.

AND THESE PATIENTS ARE TOO SICK

TO GO TO THE OPERATING ROOM TO

HAVE THE CANNELLA PLACED.

WE BRING THE OPERATING ROOM TO

THE ICU, WE CREATE A STERILE

ENVIRONMENT.

HERE IS THE SURGEON PLACED IN

THE CANNELLA.

THEN THIS IS WHAT IT LOOKS LIKE

AT THE BEDSIDE ONCE THE BABY IS

ON ECMO.

HERE IS THE BABY OBVIOUSLY.

AND THIS IS THE RESERVOIR WHERE

THE BLOOD IS DRAINING TO.

HERE IS THE PUMP WHICH IS TAKING

OVER FOR THE HEART.

HERE IS THE MEMBRANE OXYGENATOR

AND THEN BLOOD BACK TO THE BABY.

TWO PEOPLE AT THE BEDSIDE ALL

THE TIME, WE HAVE ECMO

TECHNICIAN AN ICU NURSE.

THIS IS WHAT A PATIENT LOOKS

LIKE ON ECMO.

COUPLE OF THINGS TO NOTICE HERE.

FIRST NOTICE THAT THE PATIENT

ISN'T CONNECTED TO A VENTILATOR.

THE ENDOTRACHEAL TUBE IS

FLOATING THERE IN SPACE.

AND THAT MAKES THE POINT WHEN

YOU'RE ON ECMO YOU DONE HAVE TO

BREATHE WHICH IS DRAMATIC.

IF YOU USE YOUR IMAGINATION

CLOSELY, YOU MIGHT CONVINCE

YOURSELF THE BLOOD DOWN HERE IS

DARKER THAN THE BLOOD UP HERE.

SO THIS IS THE VENUS BLOOD BEING

DRAINED OUT AND HERE IS ARTERIOL

BLOOD PUT BACK IN.

SO A LITTLE BACKGROUND TO THE

TRIAL THAT I'M GOING TO TELL YOU

ABOUT.

SO THERE HAVE BEEN AN NIH FUNDED

RCT THAT HAVE BEEN DONE IN

1970s THAT HAVE SHOWN ECMO WAS

NOT EFFECTIVE IN ADULTS WITH THE

ACUTE RESPIRATORY DISTRESS

SYNDROME.

AND ONE OF THE SURGEONS WHO WAS

INVOLVED IN THIS TRIAL, NAME WAS

BOB BARTLETT.

HE HAD THE IDEA THAT THE REASON

ECMO DIDN'T WORK IN THIS STUDY

WAS BECAUSE THESE ADULTS ALREADY

HAD IRREVERSIBLE LUNG DISEASE.

AND KEEPING THEM GOING ANOTHER

TWO OR THREE WEEKS WITH ECMO

WOULDN'T MAKE A DIFFERENCE.

HE THOUGHT IF WE COULD FIND A

DISEASE THAT IS STILL

REVERSIBLE, THEN MAYBE ECMO

WOULD HAVE A ROLE.

SO TECHNOLOGY IN SEARCH OF

DISEASE, IF YOU WILL, AND HE

WHEN FROM MASS GENERAL TO

UNIVERSITY OF MICHIGAN.

AND HE FOUND DISEASE THAT FIT

THESE SPECIFICATIONS.

IT WAS CALLED PERSISTENT

PULMONARY HYPERTENSION OF THE

NEWBORN OR PPHN.

WHAT THISchx IS, IT'S WHERE
THERE'S

A SPASM OF THE PULMONARY

ARTERIES THAT CLAMP DOWN AFTER

BIRTH, THEY DO THIS IN RESPONSE

TO VARIOUS KINDS OF IRRITATION.

MOST COMMONLY, MUCONIUM

ASPIRATION, WHEN THEY ASPIRATE

DURING BIRTH, IT IRRITATES THE

LUNGS AN CAUSES THE ARTERIES TO

CLAMP DOWN.

AND OF COURSE IF YOU'RE NOT

GETTING BLOOD FLOW TO THE LUNG

YOU CAN'T LIVE.

BUT WHAT WE KNOW IS THAT IF WE

CAN KEEP PATIENTS ALIVE FOR

THREE, FOUR, FIVE DAYS THAT

SPASM STARTS TO RELAX, BLOOD

FLOW IS RESTORED AND THEY GO ON

AND DO FINE.

SO HE WAS TREATING BABIES WITH

THIS CONDITION AND IN HIS MIND

THE RESULTS WERE NOTHING LESS

THAN SPECTACULAR.

BABYING WERE COMING IN REALLY

LOOKED LIKE THEY WERE NOT GOING

TO SURVIVE.

HE WAS GETTING 80, 90% SURVIVAL.

THE PROBLEM WAS IS THAT NOBODY

ELSE WAS BELIEVING HIM.

EVERYBODY KEPT SAYING LOOK, DO

THE RANDOMIZED CONTROL TRIAL.

DEMONSTRATE FOR US THAT IT

WORKS.

AND SO THIS TO ME IS A CLASSIC

DILEMMA.

HERE HE IS, HE SAYS I HAVE GOT

THIS NEW THERAPY THAT I BELIEVE

IS REVOLUTIONARY LIFE SAVING.

I CAN GO ON AND SAVE BABIES HERE

AT THE UNIVERSITY OF MICHIGAN

FOR THE REST OF MY CAREER AND DO

GOOD WORK.

OR IF I'M GOING TO CONVINCE THE

REST OF THE WORLD THAT THIS IS A

GOOD THERAPY, I HAVE TO DO A

RANDOMIZED CONTROL TRIAL BUT

THAT'S GOING TO INVOLVE ME

HAVING TO PUT BACK IN THE

CONTROL GROUP, NOT USE

INEVITABLY OF COURSE SOME OF

THOSE BABIES ARE GOING TO DIE.

BABIES THAT I MIGHT HAVE BEEN

ABLE TO ALMOST CERTAINLY COULD

HAVE SAVED.

SO WHAT SHOULD HE DO?

HE DID A PROSPECTIVE RANDOMIZED

STUDY.

HE GOT THE RIGHT WORD IN IT.

PROSPECTIVE RANDOMIZED BUT IF

YOU LOOK AT WHAT HE DID IT'S

MORE COMPLICATED THAN THAT.

LET ME EXPLAIN TO YOU THE

APPROACH HE TOOK.

HE WENT TO HIS STATISTICIANS AND

THEY CAME UP WITH A PLAY THE

WINNER DESIGN.

LET ME TELL YOU HOW IT WORKS.

LISTEN CAREFULLY BECAUSE IT'S

COMPLICATED.

SO WHEN YOU START OFF YOUR TRIAL

YOU HAVE A BLUE ARM WITH TWO

MARBLES IN IT, THE YELLOW FOR

ECMO, BLACK FOR CONVENTIONAL

MEDICAL THERAPY, VENTILATOR

THERAPY.

THE FIRST PATIENT YOU REACH INTO

THE EARN AND PULL OUT ONE OF

THOSE MARBLES, HERE IS THE HARD

PART.

IF THAT PATIENT SURVIVES, FOR

THE NEXT DRAW YOU PUT IN ANOTHER

MASHABLE OF THE SAME COLOR.

IF THAT PATIENT DIES FOR THE

NEXT DRAW YOU PUT A MASHABLE OF

THE OPPOSITE COLOR IN THE YEARN.

SO I'LL SHOW YOU HOW IT WORKS

AND YOU'LL SEE.

THE FIRST BABY DREW A YELLOW

MARBLE, GOT ECMO AN SURVIVED.

SINCE THAT BABY SURVIVED, NEXT

DRAW ANOTHER MARBLE OF THE SAME

COLOR, YELLOW, WAS PUT BACK IN.

FOR THE SECOND PATIENT IN THE

STUDY, THAT BABY DREW A BLACK

MASHABLE, GOT CONVENTIONAL

MEDICAL THERAPY AND DIED.

SO SINCE THAT BABY DIED FOR THE

NEXT DRAW A MARBLE OF THE OTHER

COLOR, YELLOW, GOES SO YOU CAN

SEE HOW IT GOES.

AND WHEN THE STUDY WAS

COMPLETED, THERE HAD BEEN 11

PATIENTS ENROLLED, TEN RECEIVED

ECMO, ALL SURVIVED.

THE ONE WITH CONVENTIONAL

THERAPY IS ONE THAT DIED.

AT THAT POINT THE STATISTICIAN

SAID THIS IS STATISTICALLY

SIGNIFICANT STUDY WAS DONE AND

THEY PUBLISHED THE PAPER.

IF YOU'RE A NEONATAL GIST IN THE

UNITED STATES AND YOU HAVE BEEN

WATCHING WITH INTEREST BARTLETT

DEVELOPED A NEW THERAPY AND YOU

NOW READ THIS PAPER.

HOW MANY OF YOU SAY OKAY THAT'S

THE RANDOMIZED CONTROL TRIAL

THAT I WAS LOOKING FOR.

NOW I'M GOING TO START AN E CMO

PROGRAM IN MY HOSPITAL.

HOW MANY DO THAT BASED ON THIS

DATA?

ONE, SHE'S PRETTY IMPORTANT.

SO SHE'S IMPORTANT.

SO JUST ONE COMMENT, WOULD

SOMEBODY SAY WHY NOT?

TAKE MY WORD FOR IT, THIS IS P

LESS THAN .05.

YES.

SO YOU JUST DON'T EVEN BUY THAT

IT'S A RANDOMIZED CONTROL TRIAL.

OKAY.

ALL RIGHT.

SO THIS DID GET A LOT OF

SKEPTICISM AND THERE WAS AN

EDITORIAL PUBLISHED.

AT THE SAME TIME FROM TWO

HARVARD PHYSICIANS, JAMES WARE

WHO WHEN ON TO BECOME DEAN OF

THE SCHOOL OF PUBLIC HEALTH.

THEY SAID CLINICAL INDICATIONS

FOR THIS NEW COMPLEX TREATMENT

REMAIN UNDEFINED.

FURTHER RANDOMIZED CONTROL

TRIALS WILL BE DIFFICULT BUT

REMAIN NECESSARY.

THEY DID NOT BUY IT AND NOT

SURPRISINGLY THEY THEN WENT ON

TO DO ANOTHER STUDY THAT THEY

THOUGHT WOULD BE DEFINITIVE.

THAT'S THE ONE I SHOW YOU

PUBLISHED HERE.

LET ME TELL YOU ABOUT THE BACK

GROWB TO THIS TRIAL AND HOW THEY

DESIGNED IT.

THIS MAYBE MORE DETAILED THAN

YOU THINK YOU NEED.

BUT ALL THIS IS RELEVANT.

THE WAY THEY DESIGNED THE TRIAL

WAS THEY WERE GOING TO DELIVER

CONVENTIONAL THERAPY AND ECMO IN

TWO LOCATIONS.

IN THE NEONATAL ICU, ECMO IN THE

PEDIATRIC ICU.

PART OF THE REASON HERE HONESTLY

WAS THE PARENTS OF THE BABIES

RECEIVING THESE TWO THERAPIES

WOULD BE IN DIFFERENT PLACES.

NOT WATCHING EACH OTHER'S CHILD

IN THE SAME ICU.

THE NICU STAFFED BY

NEONATOLOGIST, THE PEDIATRIC ICU

STAFFED BY ANESTHESIOLOGISTS AND

SURGEONED.

WHERE I WAS WORKING ON THE FIFTH

FLOOR.

NEONATOLOGIST MORE MEDICALLY

ORIENTED.

ANESTHESIOLOGISTS AND SURGEONS

PROCEDURALLY ORIENTED, PROCURE

MENTALITY.

THIS IS AN INVASIVE NEW THERAPY.

OVER HERE NO PATIENTS HAD BEEN

OFFERED ECMO BEFORE.

THAT'S IMPORTANT BECAUSE UNLIKE

WHAT HAPPENED IN MICHIGAN IT'S

NOT LIKE WHEN THE STUDY STARTED

THAT PATIENTS WOULD BE COMING IN

WHO PREVIOUSLY WOULD HAVE HAD

ACCESS TO THE THERAPY BUT NOW

THAT THERE'S A RESEARCH TRIAL

GOING ON WOULDN'T HAVE ACCESS TO

IT.

THIS WAS REALLY A PROBLEM FOR

BARTLETT IN MICHIGAN, THAT ONE

BABY THAT DIED HAD A CHANCE

SPEAK WITH THEM A FEW YEARS AGO.

THE ONE BABY THAT DIED HE SAID

WAS WOMAN IN HER EARLY 40s WHO

HAD BEEN TRYING TO GET PREGNANT

FOR YEARS WITH FERTILITY

TREATMENTS, FINALLY THIS WAS HER

FIRST BABY, SHE HAD

COMPLICATIONS DURING PREGNANCY,

DURING DELIVERY, HAD TO HAVE A

HYSTERECTOMY AS PART OF THE

DELIVERY PROCESS, THIS WAS GOING

TO BE HER ONLY CHANCE AT A BABY.

THE NEONATOLOGIST CALLED

BARTLETT AND SAID FORGET ABOUT

THIS STUDY.

YOU HAVE TO GIVE THIS BABY ECMO.

HE SAID NO, I CAN WE'RE DOING A

TRIAL NOW.

I CAN'T DO IT.

AND HE SAID INITIALLY THEY

THOUGHT THE BABY WAS GOING TO

VIRO, GOT BETTER A DAY OR TWO

AND THEN WENT DOWNHILL AND DIED.

AND HE SAID IT JUST TORE HIS

HEART OUT TO HAVE TO DO THAT.

SO WE WEREN'T GOING TO HAVE THAT

PROBLEM AT HARVARD BECAUSE WE

HAD NEVER DONE ECMO FOR THIS

CONDITION.

WE WERE USING ECMO ON BABIES

WITH CONGENITAL DISEASE, WHERE

ONE SIDE OF THE DIE GRAF GRAM

DOES NOT FORM AND SIMILARLY

CAUSES LIFE-THREATENING

RESPIRATORY FAILURE.

THIS IS IMPORTANT BECAUSE

BECAUSE ECMO IS COMPLEX.

A STEEP LEARNING CURVE, THE

FIRST BABIES USUALLY DON'T DO

THAT WELL.

BUT WE HAD EXPERIENCE, I WAS

GOING TO SAY PRACTICE BUT WE HAD

EXPERIENCE NOW WITH ECMO SO WE

WERE BEYOND THE STEEP PART OF

THE LEARNING CURVE.

AND WE WERE GOOD AT DOING IT.

SO IT WAS GOING TO BE A FAIR

COMPARISON.

THE BABIES WERE GOING TO BE

GETTING ECMO FROM PEOPLE SKILLED

AT DOING IT.

YOU MIGHT SAY THERE WAS A

HEALTHY COMPETITION HERE.

THE NEONATOLOGIST BEING

ANTI-EMO, ANESTHESIOLOGISTS AN

SURGEONS BEING PRO-ECMO.

SO THE STUDY WAS DI SIGN SOD THE

NEWBORNS HAD PPHN AND PREDICTIVE

MORTALITY OF 85% BASED ON

RETROSPECTIVE DATA FROM OUR OWN

ICU.

REMEMBER THAT NUMBER IT WILL BE

BACK IN A SECOND.

THE STUDY WAS DESIGNED IN TWO

PHASES.

TONAL STATISTICIAN KNEW THIS UP

FRONT.

PHASE 1, 50/50 RANDOMIZATION OF

THE BABIES BETWEEN THE TWO

TREATMENTS UNTIL THERE WERE FOUR

DEATHS IN ONE ARM.

AND AT THAT POINT IT WOULD SHIFT

INTO PHASE TWO AND ALL PATIENTS

WERE GOING TO BE ASSIGNED TO

WHATEVER WAS MORE SUCCESSFUL

THERAPY.

UNTIL THE THERE WERE FOUR DEATHS

IN THAT ARM OR UNTIL STATISTICAL

SIGNIFICANCE WAS ACHIEVED.

AND THEN FINALLY THE STUDY WAS

DESIGNED SO THAT CONSENT WAS

SOUGHT ONLY FROM THOSE PARENTS

WITH THE STANDARD THERAPY ECMO.

THIS IS THE ZALEN RANDOMIZATION

I'LL TELL YOU ABOUT IN A MOMENT

PEOPLE ASK ME WE HAVE MORE

DISCUSSION IF IT'S A SMALLER

ROOM BUT IF WE HAD TIME PEOPLE

SAY WHERE IS NUMBER FOUR FROM?

THAT SEEMS AD HOC.

I AGREE IT DOES.

SO I DID GO BACK INTO JIM WARE'S

WRITINGS WHERE HE DESCRIBED THIS

STUDY, THE STATISTICIAN, TO SEE

IF I COULD FIND AN EXPLANATION

FOR THE FOUR.

HERE IS AN ACTUAL PAGE FROM THE

JOURNAL ARTICLE WHERE HE

DESCRIBES, NOTICE A FOUR HERE.

THERE'S A FOUR DOWN HERE.

THAT'S THE BEST EXPLANATION AS

TO WHERE THE FOUR CAME FROM.

I TEACH THIS WITH PROFESSOR WARE

AND HE GIVES BETTER EXPLANATION

THAN THAT.

SUFFICE IT THE SAY THE

STATISTICS HERE ARE COMPLICATED.

SO HOW DID THE STUDY TURN OUT?

DURING PHASE 1 THERE WERE NINE

BABIES RANDOMIZED TO ECMO, ALL

SURVIVED.

DURING PHASE 2, THERE WERE TEN

BABIES, SORRY, IN PHASE 1, TEN

BABIES WHO GOT CONVENTIONAL

THERAPY, SIX SURVIVED, FOUR

DIED.

WHEN THE FOURTH DEATH OCCURRED

THE STUDY WENT TO PHASE 2 WHERE

ALL THE BABIES WERE ASSIGNED TO

THE MORE SUCCESSFUL ARM, 20

PATIENTS ENROLLED, 19 SURVIVED,

ONE DIED AND AT THIS POINT THE

STUDY WAS TERMINATED AND ECMO

WAS DECLARED THE WINNER.

THE ENROLLMENT CRITERIA WHERE A

PREDICTED MORTALITY OF 85%, THE

NUMBERS ARE SMALL HERE.

BUT WHAT DID WE SEE FOR A

MORTALITY IN THIS STUDY?

40%.

IT MIGHT BE SMALL NUMBERS AND

RANDOM CHANCE BUT I THINK IT

DOES SHOW ONE OF THE PEARLS, IF

YOU WILL, OF RELYING ON

RETROSPECTIVE HIS RICKAL DATA.

IN A -- HISTORICAL DATA IN A

SITUATION LIKE THIS.

HERE IS HOW IT ENDEDCH I WANT TO

GO FROM HERE AND TALK ABOUT THE

ETHICAL ISSUES INVOLVED.

MAYBE TIME FOR ONE QUICK

QUESTION IF ANYBODY HAS ANY

QUESTION ABOUT THE STUDY ITSELF.

OKAY.

YEAH.

(OFF MIC)

>> SO YOU RAISE THE QUESTION FOR

THOSE THAT MIGHT NOT HAVE HEARD,

WHAT LOOKS LIKE RETROSPECTIVE

DATA SHOWING 85% MORTALITY,

ANYTHING THIS DRAMATICALLY GOOD,

WHY ARE WE TALKING ABOUT DOING

STUDIES.

I WOULD LIKE TO COME BACK TO

THAT.

BUT I WOULD ALSO LIKE TO POINT

OUT THAT WAS BOB BARTLETT'S VIEW

IN MICHIGAN.

BUT NOBODY CHANGED THEIR

PRACTICE.

HE WAS THE ONLY ONE THAT WAS

DOING IT.

AND SO WE'RE GOING -- THERE'S A

GREAT SEGUE, WITH WE'LL COME

BACK TO THIS, WHY DO WE INSIST

ON SEEING THESE RANDOMIZED

TRIALS IN SITUATIONS LIKE THIS.

MAYBE THE SINGLE MOST IMPORTANT

POINT I WOULD LIKE YOU THE TAKE

AWAY IS THE CONFLICT THAT WE

HAVE BETWEEN HEELER AN

INVESTIGATOR.

AND I WOULD SAY THIS CONFLICT

GOES TO THE BONE, IT GOES ALL

THE WAY DOWN AND THERE REALLY IS

NOT A WAY OF RECONCILING THE TWO

VIEWS.

FRANK MILLER HERE AT THE NIH AND

STEVE JOFFE WHO JUST FINISHED

SPEAKING HAVE WRITTEN QUITE A

BIT ABOUT THIS.

SOME OF THE BEST WORK ON THIS.

THEY TALK ABOUT TWO VIEWS OF

MEDICAL RESEARCH, ONE THE

DIFFERENCE POSITION, THE OTHER,

SIMILARITY POSITION.

THE DIFFERENCE POSITION MEANING

THAT SCIENCE AND CLINICAL CARE

ARE DIFFERENT.

THAT THE ETHICS OF RESEARCH IS

DETERMINED BY SCIENTIFIC

PERSPECTIVE, GOVERNED BY THE

REQUIREMENTS OF GOOD SCIENCE.

THE FLIP SIDE OF THE COIN IS THE

SIMILARITY POSITION OR THE

CLINICAL PERSPECTIVE.

WHICH THE CLINICAL TRIALS ARE

INTENDED AS BENEFICIAL THERAPY

AND THEY'RE GOVERNED BY ETHICS

OF THE PATIENT PHYSICIAN

RELATIONSHIP.

TWO VERY DIFFERENT WAYS OF LOOK

AT ETHICS OF RESEARCH.

IT GUESS THROUGH ALL THE ETHICS

WE TALK ABOUT.

I'M ONLY TALKING ABOUT HERE IN

THE CONTEXT OF RCTs.

BUT IT'S A VERY FUNDAMENTAL WAY

OF FRAMING THE PROBLEMS.

HERE IS ANOTHER WAY OF PUTTING

IT.

A DILEMMA CONFRONTS PHYSICIAN

INVESTIGATORS.

PHYSICIANS ARE DEDICATED THE

CARING FOR PATIENTSCH AS

INVESTIGATORS THEY ARE DEDICATED

TO CARING FOR RESEARCHCH THESE

TWO COMMITMENTS CONFLICT

WHENEVER AN INDIVIDUAL

PHYSICIAN/INVESTIGATOR COMES

FACE TO FACE WITH AN INDIVIDUAL

PATIENT/SUBJECT.

PUBLIC IS AWARE OF THIS, A

CARTOON FROM A NEW YORKER.

THE PATIENT IN THE PLACEBO GROUP

DIDN'T GET THE KIND OF CLINICAL

CARE THAT HE MIGHT HAVE GOTTEN

THAT WOULD HAVE KEPT HIM ALIVE

SO THERE'S DISTRUST IN THE

PUBLIC ABOUT THIS.

WHEN CE WE SAY THE DIFFERENCE

POSITION, WHAT DO WE MEAN?

HEALTH LAWYER REBECCA

(INDISCERNIBLE) PUTS IT LIKE

THIS.

RESEARCH MUST GIVE STARK BOLE

THAT RESEARCH IS DIFFERENCE FROM

CLINICAL CARE.

INSTEAD OF WHITE COATS

ASSOCIATED, INVESTIGATORS COULD

WEAR RED ONES.

CLEAR MESSAGE THAT THESE ARE

DIFFERENT ROLES THAT PERSON IS

PLAYING.

HOW ABOUT SAYING TO A PATIENT

THIS MORNING I WAS YOUR DOCTOR

AND YOU WERE MY PATIENT BUT THIS

AFTERNOON I'M GOING TO BE GIVING

YOU EXPERIMENTAL MEDICATION.

AND THEN I'M PO NO LONGER YOUR

DOCTOR BUT AN INVESTIGATOR.

AND YOU -- DURING THIS TIME

PLACE PURSUIT OF SCIENTIFIC

KNOWLEDGE ABOVE YOUR INTEREST

AND NO LONGER PROVIDE YOU WITH

INDIVIDUALIZED CARE.

YOUR CARE WILL BE DRIVEN BY

PROTOCOL.

THIS IS I THINK HALF OF THE

TRUTH.

THIS IS PART OF WHAT'S GOING ON

IN RESEARCH, PARTICULARLY

PLACEBO CONTROL TRIALS FOR

EXAMPLE.

MOST OF YOU ARE PROBABLY SITTING

THERE THINKING I'M NOT

COMFORTABLE WITH THIS.

SO ANOTHER POSITION HAS BEEN

DEVELOPED, THE OTHER SIDE OF THE

COIN, CALLED THE SIMILARITY

POSITION WHICH SAYS RESEARCH AND

CLINICAL CARE ARE NOT

FUNDAMENTALLY INCOMPATIBLE.

THE EARLIEST VERSION IS THE

PERSONAL EQUIPOISE REQUIREMENT.

IF YOU ENROLL PATIENTS IN

RCTs, YOU AS INVESTIGATOR MUST

BE PERSONALLY UNBIASED BETWEEN

THE TWO TREATMENT ARMS.

PERFECTLY BALANCED ON THE EDGE

OF THE SWORD, IF YOU WILL.

NICE IN THEORY BUT VERY

UNCOMMONLY TRUE, WHY?

BECAUSE RESEARCHERS USUALLY

BELIEVE IN THE TREATMENTSTHEY

ARE STUDYING.

THOSE YOUNG IN YOUR CAREERS AND

STARTING CLINICAL TRIALS THAT

OCCUPY DAY AND NIGHT THE NEXT

SEVERAL YEARS, YOU WON'T DO IT

IF YOU DON'T BELIEVE YOU HAVE

SOMETHING NEW AN PROMISING TO

OFFER.

SO YOU WOULD NOT BE IN A STATE

OF PERSONAL EQUIPOISE AN

WOULDN'T ENROLL A PATIENT AND

SAY GEE, YOU KNOW, FLIP OF A

COIN, I HAVE NO IDEA.

THE PROBLEM IS REQUIRING

PERSONAL EQUIPOISE LEAVING

INVESTIGATORS FEELING GUILTY

LIKE I SHOULDN'T BE ENROLLING

PATIENTS OR CYNICAL LIKE THIS

ETHICS IS A BUNCH OF CRAP.

SO FORTUNATELY A CANADIAN

BIOETHICIST CAME TO THE RESCUE

AND GAVE US ANOTHER STANDARD

CALLED CLINICAL EQUIPOISE.

HE SAID IT'S NOT NECESSARY YOU

AS INVESTIGATOR BE PERSONALLY

INEQUIPOISE BUT RATHER THAT WE

HAVE UNCERTAINTY WITHIN THE

MEDICAL COMMUNITY AS A WHOLE,

THAT'S WHAT WE NEED.

SO THE CONVERSATION NOW GOES

SOMETHING LIKE THIS.

I'M ENROLLING YOU IN THIS STUDY.

I BELIEVE TREATMENT A IS BETTER.

BUT IF YOUR APPOINTMENT HAD BEEN

WITH MY COLLEAGUE DOWN THE HALL

SHE WOULD HAVE RECOMMENDED

TREATMENT B.

SO IT'S BY CHANCE.

SO IF YOU WANT TO BE IN THIS

STUDY, WOULD YOU AGREE TO HAVE

YOUR TREATMENT DETERMINED BY A

COIN FLIP?

SO THAT RATHER THAN IT JUST

HAPPENING, WE CAN LEARN

SOMETHING FROM THIS EXPERIENCE.

SO THIS IS HOW BENJAMIN FRIEDMAN

CHARACTERIZES THIS IDEA OF

CLINICAL EQUIPOISE.

HE SAID THIS IS WHY DOING

RESEARCH IS NOT COMPLETELY

INCOMPATIBLE WITH DOING CLINICAL

CARE, WHEN THE STATE OF CLINICAL

EQUIPOISE EXISTS.

I WAS TAKEN A FEW YEARS AGO

READING WHAT MARSHA ANGEL, AT

THE TIME EDITOR OF NEW ENGLAND

JOURNAL OF MEDICINE HAD TO SAY

ABOUT THIS.

I THOUGHT IT WAS INTERESTING,

HERE WE ARE ONE OF THE PREMIER

RESEARCH JURY ROOMS OF THE WORLD

AND SHE WROTE PHYSICIANS ACT IN

THE BEST INTEREST OF PATIENTS

UNDER THEIR CARE AN PATIENTS

EXPECT THIS OF THEIR PHYSICIAN.

IF THIS COMMITMENT TO THE

PHYSICIAN IS ATTENUATED TO

BENEFITS OF FUTURE PATIENTS,

THAT IS RESEARCH, THE IMPLICIT

ASSUMPTIONS OF DOCTOR PATIENT

RELATIONSHIP ARE VIOLATED.

WE WOULD LOSE MORE THAN WE WOULD

GAIN BY ADOPTING SUCH AN

APPROACH.

I'M READING THIS AND SAYING WHAT

IS HE SAY SOMETHING SHE'S SAYING

THAT MAYBE WE CAN'T DO RCTs.

SHE SAYS WHAT CAN BE DONE WHEN

NON-RANDOMIZED DESIGNS ARE

CONSIDERED INADEQUATE BUT

RANDOMIZATION WOULD BE

DIFFICULT.

SHE SAYS NOT ALL PROBLEMS HAVE

SOLUTIONS.

AND I THINK THIS IS THE ONE

POINT I WANT TO LEAVE YOU WITH.

I DON'T THINK THIS HAS A

SOLUTION.

I THINK SHE WAS RIGHT ABOUT

THIS.

THE CONFLICT BETWEEN HEALER AND

INVESTIGATOR RUNS ALL THE WAY

DOWN, SOMETHING WE WILL STRUGGLE

WITH ALL OUR LIVES DOING

CLINICAL RESEARCH AND THOUGH WE

HAVE SOME APPROACHES AND I'LL

TELL YOU MORE IN A MINUTE TO TRY

TO MITIGATE SOME OF THAT

CONFLICT THERE'S NOTHING WE CAN

DO TO MAKE IT COMPLETELY GO

AWAY.

SO TO TELL YOU TWO STRATEGIES

USED IN THIS TRIAL THE DO JUST

THAT.

TO RELIEVE TENSION BETWEEN THIS

ROLE OF CLINICIAN AN ROLE OF

INVESTIGATOR.

THE FIRST TECHNIQUE USED WAS

ADAPTIVE RANDOMIZATION.

SO THE DEFINITION OF THAT IS

DEVIATING FROM BALANCE OR 50/50

RANDOMIZATION SO THAT MORE

PATIENTS ARE ASSIGNED THE

THERAPY THAT IS LEADING DURING

THE TRIAL.

WE COULD CALL THIS BETTING ON

THE HORSE WHO IS OUT IN FRONT

BEFORE WE KNOW HOW THE RACE IS

GOING TO END.

THERE'S ADVANTAGES TO THIS

APPROACH.

FIRST IT TENDS TO MITIGATE THE

CONFLICT OF HEALER VERSUS

INVESTIGATOR AND ATTEMPTS TO

ASSIGN -- IN THE BARTLETT TRIAL

50/50 RANDOMIZATION BUT

GUARANTEED ONLY FOR THE FIRST

PATIENT.

REMEMBER THAT WAS STRONGLY

CRITICIZED BY THE HARVARD TEAM

BUT THEY ENDED UP DOING THE SAME

THING ONLY THERE 50/50

RANDOMIZATION WAS GUARANTEED

UNTIL THE FOURTH DEATH OCCURRED

IN ONE ARM.

AT SOME LEVEL THEY WERE COMING

UP AGAINST THIS DISEASE THAT

WOULD HAVE GONE ALONG WITH DOING

A STANDARD RCT.

THE TRIAL WAS CRITICIZED FROM

BOTH DIRECTIONS.

FROM THE JOURNAL OF STATISTICS

ON THIS TRIAL, THERE WERE THOSE

WHO SAID NO PATIENTS SHOULD HAVE

BEEN ASSIGNED TO CONVENTIONAL

MEDICAL THERAPY, AS THIS

GENTLEMAN OVER HERE SAID.

WE HAD ENOUGH INFORMATION TO

SHOW ECMO WAS A NEW LIFE SAVING

TREATMENT.

OTHERS SAID NOT ENOUGH PATIENTS

WERE ASSIGNED TO CONVENTIONAL

MEDICAL THERAPY.

HERE IS INVESTIGATORS HAD THE

PERFECT CHANCE TO DO A GOOD

STANDARD RCT, PUT THE ISSUE TO

REST AND THEY BLUE IT.

THEY BLUE IT.

THEY COME UP WITH THIS

COKEAMAMIE SCHEME THAT DOESN'T

CONVINCE ANYBODY.

SO WE MIGHT SAY THIS APPROACH

WAS A GOOD BALANCE GIVEN THE

DIVERGENT VIEWS.

CERTAINLY IN A CLINICAL SENSE

THAT NUMBER 4 WAS MAGICAL.

I REMEMBER AT THE TIME AS BABIES

WERE PUT INTO THE NICU NOT

GETTING ECMO AS THEY WERE DYING

AND BABIES ON THE FIFTH FLOOR

WERE SURVIVING, THE NURSES IN

THE NICU WERE INCREASINGLY

BECOMING UNWILLING TO CONTINUE

TO PARTICIPATE IN THE STUDY AND

BY THE TIME THE FOURTH DEATH

OCCURRED UP THERE, THEY WERE

REACHING SOMEWHAT OF A MUTANTOUS

POINT SAYING WE'RE NOT GOING TO

DO THIS ANY MORE.

AT THIS POINT THE STUDY ENTERED

PHASE 2 AN PATIENTS GOT ECMO SO

THE NUMBER FOUR WAS SIGNIFICANT

AT MANY LEVELS.

THIS WIN WRITING ADAPTIVE

METHODS SHOULD BE USED AS A

MATTER OF COURSE.

IT NEVER PAYS TO PROTOCOL BEFORE

THE STUDY OR OBTAINED DURING ITS

COURSE IS IGNORED IN THE

TREATMENT OF A PATIENT.

AND INDEED, THIS WAS ONE OF THE

FIRST ARTICLES I FOUND IN 2006

ABOUT THE FDA BEGINNING TO

ACCEPT ADAPTIVE DESIGNS, NOW

OVER THE LAST 3, 4, 5 YEARS

WE'RE SEEING MANY, MANY MORE

STUDIES DONE WITH ADAPTIVE

DESIGN.

SO IT IS BECOMING QUITE A BIT

MORE POPULAR AND ACCEPTABLE.

THE LAST CONTROVERSIAL IS

RANDOMIZED CONSENT.

THIS WAS DONE PRIMARILY TO EASE

PSYCHOLOGICAL BURDENS ON BOTH

INVESTIGATORS AND THE PARENTS ON

CHILDREN ENROLLED IN THE TRIAL.

LET ME EXPLAIN TO YOU HOW THIS

WORKS.

FIRST WE DETERMINE THE PATIENT

IS ELIGIBLE AND WE RANDOMIZE

THEM TO GET TREATMENT AX OR B.

OF COURSE WE DO THIS BECAUSE

WHAT'S MISSING HERE IS THERE'S

NO INFORMED CONSENT.

SO HOW DOES IT LOOK WITH

INFORMED CONSENT?

WE DETERMINE A PATIENT IS

ELIGIBLE, WE SEEK THEIR INFORMED

CONSENT.

IF THEY AGREE THEY GET

RANDOMIZED THE A OR B.

IF THEY DON'T AGREE THEY'RE

DROPPED.

IT'S GETTING COMPLICATED HERE

BECAUSE WE HAVE GOT TO NOW TRY

TO BE SURE THAT THOSE DON'T

DIFFER IN SUBSTANTIAL WAYS WHO

SAY NO.

A NUMBER OF YEARS AGO MARVIN

ZALEN A STATISTICIAN AT THE

HARVARD SCHOOL OF PUBLIC HEALTH

PROPOSED ANOTHER METHOD OF

RANDOMIZATION KNOWN AS ZALEN

RANDOMIZATION.

LET ME SHOW YOU HOW THAT WORKS.

HERE WE DETERMINE A PATIENT IS

ELIGIBLE AND THEY ARE

RANDOMIZED.

IF THEY ARE RANDOMIZED TO

EXPERIMENTAL TREATMENT THE

PATIENT OF THE FAMILY IS

APPROACHED AND SAYS WILL YOU

ACCEPT B?

IF THEY SAY YES THEY GET B, IF

THEY SAY NO THEY GET THE CONTROL

TREATMENT.

IF THEY'RE RANDOMIZED TO THE

CONTROL TREATMENT AND DON'T SEEK

CONSENT WE GIVE THEM THE CONTROL

TREATMENT.

THIS WAS THE APPROACH THAT WAS

ADOPTED IN THE HARVARD TRIAL.

THE WAY IT WORKED, SINCE BABIES

WERE CARED FOR AT CHILDREN'S HOP

AND WE DON'T HAVE A DELIVERY

SERVICE THERE, ALL THE BABIES

WERE COMING IN FROM OUTSIDE

HOSPITALS, SO WHILE THEY WERE IN

THE AMBULANCE ON THEIR WAY IN,

THE ENVELOPE WOULD BE OPEN, WE

WOULD FINE OUT DO THEY GO TO THE

FIFTH OR 7TH FLOOR AN ONCE THEY

DOT THERE, IF ON THE 5TH FLOOR

THEY WERE APPROACHED ABOUT

WHETHER THEY WOULD AGREE TO

ECMO.

IF THEY DID, THEY GOT ECMO.

IF THEY WENT TO THE #th

FLOOR THEY GOT THE -- 7TH FLOOR

THEY GOT THE SAME TREATMENT

REGARDLESS IF THE TRIAL HAD BEEN

GOING ON.

ONE THING I FORGET TO MENTION TO

YOU, AT THIS TIME CHILDREN'S IN

BOSTON WAS THE ONLY ECMO CENTER

IN NEW ENGLAND SO THERE WEREN'T

OTHER OPTIONS FOR THEM TO GET

ECMO.

THE NEAREST OTHER CENTER WOULD

HAVE BEEN IN PHILADELPHIA,

BABIES WERE FAR TOO SICK TO BE

TRANSPORTED DOWN THERE.

REALLY THIS WAS THE ONLY OPTION

FOR ECMO AT THE TIME.

SO IF WE JUST PLUG IN THE

NUMBERS HERE, THIS WAS HOW THE

SCHEME LOOKED LIKE.

I'D ACTUALLY LIKE TO TAKE A

COUPLE OF MINUTES MAYBE AND ASK

YOU DO YOU THINK THIS IS AN

ECAL APPROACH -- ETHICAL

APPROACH OR NOT?

SO MAYBE START WITH A SHOW OF

HANDS HOW MANY OF YOU WOULD SAY

THIS IS AN ETHICAL APPROACH THE

RANDOMIZATION.

HOW MANY SAY NO?

NO TWO-THIRDS YES ONE-THIRD.

USUALLY THERE'S A LOT MORE

KNOWS.

HOW ABOUT NO THIS IS NOT AN

ACCEPTABLE APPROACH, WHAT IS THE

NUMBER ONE PROBLEM WITH IT?

SINCE YOU'RE NEXT THE THE

MICROPHONE WOULD YOU MIND

STANDING THEREUPON?

>> I THINK THE PEOPLE IN THE

CONTROL ARM ARE NOT EVEN

INFORMED, THEY'RE PART OF A

CLINICAL TRIAL.

THEY'RE PART OF A CLINICAL

STUDY.

AND YOU'RE NOT SEEKING CONSENT.

>> THAT'S THE MOST OBVIOUS

PROBLEM WITH IT.

HOWEVER, LET ME JUST TRY TO MAKE

THE CASE HERE.

THE CARE THEY WERE GETTING WAS

EXACTLY THE SAME CARE THAT THEY

WOULD HAVE GOTTEN IF NO STUDY

HAD BEEN STARTED.

ALL THESE BABIES ALL WHEN TO THE

NICU, ALL TREATED WITH

CONVENTIONAL MEDICAL THERAPY.

IF WE HAD NEVER THOUGHT ABOUT

DOING THIS TRIAL, THEIR CARE

WOULD HAVE BEEN ABSOLUTELY THE

SAME.

NOTHING WOULD HAVE BEEN

DIFFERENT.

FURTHERMORE ALL WE WERE DOING IS

COLLECTING INFORMATION ON THEM.

WE DO THAT ALL THE TIME WITHOUT

INFORMED CONSENT.

DID THAT CONVINCE YOU?

NO.

ONE BEHIND YOU, YEAH.

>> I WAS GOING TO SAY PEOPLE

RANDOMIZED TO THE CONTROL ARM

WERE NOT INFORMED THERE WAS AN

ALTERNATIVE THERAPY AVAILABLE.

>> OKAY.

BUT LET ME SAY THAT THERE WASN'T

AN ALTERNATIVE THERAPY AVAILABLE

WHEN THE ENVELOPE WAS OPEN AND

IT SAW THE CRIMINAL ARM ECMO WAS

NOT AVAILABLE TO THEM.

AND THERE WASN'T AN ALTERNATIVE

THERAPY AVAILABLE BECAUSE THEY

WERE TOO SICK TO GO TO

PHILADELPHIA.

>> I AGREE -- I'M NOT

DISAGREEING BUT I HAVE A

QUESTION.

WHAT IS THE JUSTIFICATION FOR

HAVING A LIFETIME NOT CONSENTED

TRADITIONAL STANDARD TREATMENT

GROUP VERSUS A RETROSPECTIVE?

WHY DOES THAT CHILD HAVE TO BE

LIVE TIME NOT RECEIVING THE

TREATMENT?

WHY CAN'T IT BE FROM FIVE MONTHS

AGO, TWO MONTHS AGO, A WEEK AGO?

>> GOOD POINT.

WITH REGARD TO EVEN FROM FIVE

MONTHS AGO IT WAS ODD WHEN WE

LOOK AT RETROSPECTIVE DATA WE

WERE GETTING AN 85% MORTALITY

FOR THESE BABIES AN AS SOON AS

WE START THE TRIAL IT DROPS TO

40.

SO IT DOES SEEM TO BE IMPORTANT

THAT IT BE CONTEMPORANEOUS, I'M

NOT GOING TO TRY TO TELL YOU WE

DIDN'T COLLECT DATA ON THE

CONVENTIONAL CONTROL BABIES

WHILE THEY WERE ALIVE BUT WE

WOULDN'T HAVE HAD TO.

WE COULD HAVE WAITED UNTIL THEY

WERE DISCHARGEED FROM THE

HOSPITAL AND THEN COLLECT THE

DATA.

AND THEN IT'S A STANDARD THING

WE COULD HAVE COULD HAVE DONE
WITH INFORME
D

CONSENT.

>> I THINK THE ARGUMENT THAT WAS

MADE BEFORE IS SPACIOUS ABOUT

WHETHER THERE WAS ALTERNATE

THERAPY SO IT WAS IN THE PUBLIC

DOMAIN, WHETHER STANDARD THERAPY

WAS ANOTHER QUESTION ENTIRELY.

BUT IT WASN'T AVAILABLE.

YOU WOULD AGREE WITH THAT, IT

WASN'T AVAILABLE.

THERE WAS NO WAY A BABY COULD

GET ECMO ONCE THE ENVELOPE WAS

OPENED.

WHAT'S THE POINT OF TELLING

SOMEBODY THERE'S A THERAPY

AVAILABLE IN MICHIGAN BUT

THERE'S NO WAY YOU CAN GET IT.

MAYBE THE SAME THING HERE.

WHAT'S THE POINT OF TELLING THE

PARENT THERE'S THERAPY AVAILABLE

ON THE FIFTH FLOOR BUT YOU CAN'T

HAVE IT.

>> I HOPE THE POINT IS -- WELL

--

(OFF MIC)

>> CAN YOU STAND UP AT THE END

THERE?

THEN WE'LL -- THEN I'M GOING TO

MOVE ON.

>> PHYSICIANS ALL TIME REFER

PATIENTS TO OTHER CENTERS WHERE

EVEN EXPERIMENTAL WORK IS BEING

DONE.

SO I THINK THE NOTION THAT NOT

HAVING THIS AVAILABLE IS SORT OF

DISENGENIUS BECAUSE CLINICIANS

COULD AND WOULD BE AWARE OF THAT

STUDY.

>> I CAN SEE THAT.

I'M PUSHING BACK HERE, I HOPE

YOU APPRECIATE, I'M NOT TRYING

TO PUSH BACK, SHARPEN OUR

ARGUMENT ALL OF OUR THINKING

ABOUT THIS.

I GUESS I AM STRUGGLING A LITTLE

BIT WITH THE VALUE OF SITTING

DOWN WITH THE FAMILY AND SAYING

WE ARE DOING THIS STUDY

EXPLORING A NEW THERAPY CALLED

ECMO, WE KNOW YOUR CHILD CAN'T

GET IT UNFORTUNATELY BUT WE FEEL

LIKE YOU HAVE A RIGHT TO KNOW

THAT.

WHAT IS THE VALUE TO THAT?

I WOULD ALSO POINT OUT HERE THAT

THIS RANDOMIZED CONSENT VERY

MUCH CHANGE IT IS NATURE OF THE

DISCUSSION DOWN HERE.

INSTEAD OF SAYING YOUR BABY IS

ELIGIBLE AND NOW WE'LL FLIP A

COIN TO SEE WHAT TREATMENT WE

GET, NOT ONLY ARE WE SAYING YOUR

BABY IS ELIGIBLE BUT ALSO

ALREADY DECIDED YOU CAN GET ECMO

IF YOU WANT IT.

ALL YOU HAVE TO DO IS SAY YES.

I THINK IT'S NO SURPRISE OF THE

29 CHILDREN THAT WERE RANDOMIZED

DOWN HERE NOT A SINGLE PARENT

SAID NO.

KIND OF LIKE THIS IS YOUR LUCKY

DAY, GREAT.

I HAVE GOT THE ACCESS TO THE NEW

HOT THERAPY.

HOW DID THIS GO?

I CAN REMEMBER THE DAY THE STUDY

WAS PUBLISHED I WAS EATING

BREAKFAST AND I OPENED THE

BOSTON GLOBE AND IN THE CORNER

WAS A STUDY BY RICHARD KNOX, A

BOSTON GLOBE REPORTER WHO NOW

REPORTS FOR NPR.

THIS IS GREAT, I WAS PART OF

THAT, FUN THE READ.

APPARENTLY SOMEBODY CLIPPED THAT

AND SENT IT TO THE NIH.

AND THE NIH SAID HUH.

WHAT'S GOING ON HERE?

SO THEY WROTE TO CHILDREN'S

HOSPITAL IRB AND SAID EXPLAIN

THIS CONSENT PROCESS.

AND SO HERE IS WHAT THE IRB

WROTE BACK TO THE NIH.

WE DID NOT FEEL WE IMMEDIATED TO

GET CONSENT TR THE CONTROL ARM

BECAUSE THE CONTROL PATIENTS

WERE NOT REALLY RESEARCH

SUBJECTS.

PARENTS OF THE CONTROL PATIENTS

WERE NOT BEING OFFERED A CHOICE.

SO WHY SUBJECT THEM TO STRESS?

AND THE PRESSURE TO CROSS OVER

FROM CONVENTIONAL THERAPY TO

ECMO WOULD HAVE BEEN UNBEARABLE.

AS THESE BABIES ARE DYING, BY

THAT TIME IT WOULD HAVE BEEN TOO

LATE, THEY ONE HAVE BENEFITED

FROM ECMO.

SO THIS WAS THE IRB REACTION.

HOW DID THAT FLY AT THE NIH?

WELL, THEY REPRIMANDED THE

HOSPITAL.

THE DIRECTOR OF OPRR AT THE TIME

SAID THE HOSPITAL IRB MADE

DECISIONS THAT RIGHTFULLY BELONG

TO PARENTS.

THEY BLUE IT AND -- THEY REALLY

BLEW IT AND GEORGE ANESS A

FAMOUS HEALTH LAWYER AT BOSTON

UNIVERSITY, OPPORTUNITY TO TAKE

A SHOT AT HARVARD T DOCTOR DID

WHAT THEY DID BEFORE HAVING

INFORMED CONCEPT, MAKING TE

SIGNATURES FOR PARENTS.

THAT'S HOW IT WENT.

SO WITH THAT I WANT TO CLOSE.

I'LL CIRCLE BACK A LITTLE BIT.

I WANT TO AT THE END HERE RAISE

THIS QUESTION OF ARE RCTs THE

ONLY WAY TO LEARN.

WE KNOW THAT'S NOT THE CASE.

WE KNOW THERE'S A LOT OF WAYS WE

LEARN STARTING FROM ANECDOTAL

CASE REPORTS WE CAN LEARN FROM

THEM ALL THE WAY UP THROUGH

RCTs AND BEYOND THAT TO META

ANALYSES.

THE ISSUE IS NOT WHETHER WE CAN

LEARN BUT THE ISSUE OF

CONFIDENCE WE HAVE IN THE

METHODOLOGY.

BUT IT'S FUNNY WE DON'T THINK

THIS WAY.

FOR A LONG TIME PEOPLE HAVE BEEN

COMMENTING ON THIS, THE

BRILLIANT SUCCESS OF THE RCT HAS

BECOME A FORM OF INTELLECTUAL

TYRANNY.

WE HAVE SHOULDN'T PROCEED ON THE

FALLACIOUS ASSUMPTION THAT WHERE

THERE'S NO RANDOMIZATION THERE

IS NO TRUTH.

THE DIFFERENCE BETWEEN THE RCT

AND OBSERVATION RETROSPECTIVE IS

NOT THE DIFFERENCE BETWEEN GOOD

AND BAD SCIENCE, TRUCE OR

FALSITY BUT THE DIFFERENCE

BETWEEN VARYING DEGREES OF

CONFIDENCE.

RECENTLY WE'RE LEARNING THAT

THIS DISTINCTION MEANS EVEN

LESS.

HERE IS AN ARTICLE FROM NEW

ENGLAND JOURNAL 2000, WE FOUND

LITTLE EVIDENCE THAT ESTIMATES

OF TREATMENT EFFECTS AND

OBSERVATIONAL STUDIES REPORTED

AFTER 1984 ARE CONSISTENTLY

LARGER THAN OR CALL TAI ACTIVELY

DIFFERENT FROM THOSE OBTAINED IN

RANDOMIZED CONTROL TRIALS.

MORE RECENTLY LAST YEAR ONE OF

THE LEADING FIGURES IN CRITICAL

CARE MEDICINE WROTE I WILL ARGUE

IN MANY SITUATIONS WITH THE ICU

CONTEXT THE RCT AS WE KNOW IT

SHOULD BE ABAN DOONED, AT LEAST

TEMPORARILY AND MUCH GREATER

EMPHASIS BE PLACED ON GATHERING

INFORMATION FROM WELL DESIGNED

OBSERVATIONAL STUDIES.

SO I WOULD LIKE TO JUST

STIMULATE YOUR IMAGINATION A

LITTLE BIT.

WHEN SHOULD WE THINK ABOUT

ALTERNATIVES TO ACT?

IT IS A POWERFUL METHODOLOGY.

MAYBE WHEN WE EVALUATE

POTENTIALLY LIFE SAVING

THERAPIES LIKE ECMO, NOT SO MUCH

SUBJECTS CHOOSING TO ENROLL BUT

ARE CHOSEN BY THEIR DISEASE, THE

RELATIONSHIP IS FIDUCIARY, BASED

ON TRUST.

NOT CONTRACT CHRL.

WE SEE PHYSICIAN AMBIVALENCE.

ONE STUDY SHOWED 35% OF

PHYSICIAN INVESTIGATORS SAY THEY

ARE WILLING TO STRICTLY ADHERE

TO THE PROTOCOL IN THESE

SITUATIONS.

IF THE PATIENT DETERIORATES THEY

SEEK TO ALTER THE PROTOCOL OR

GET COMPASSIONATE USE OF THE

EXPERIMENTAL TREATMENT SO THIS

PUTS A LOT OF PSYCHOLOGICAL

STRAIN EVEN BEYOND THE BREAKING

POINT AS WE CAN SEE, FOR THOSE

WHO ARE INVOLVED.

ANOTHER TIME TO CONSIDER AN

ALTERNATIVE IS EVALUATING

RAPIDLY DEVELOPING TECHNOLOGIES.

RCTs GENERALLY TAKE, 3, 4

YEARS TO DO.

THAT'S JUST THE NORMAL TIME

FRAME.

IMPROVEMENTS IN BOTH THE

EXPERIMENTAL AND THE CONTROLa

TREATMENTS MAY MAKE THE RESULTS

OF THE RCT OBSOLETE.

BY THE TIME IT IS PUBLISHED.

THIS WAS CERTAINLY TRUE WITH THE

ECMO TRIAL.

BY THE TIME THAT WAS PUBLISHED

THERE HAD BEEN MAJOR CHANGES IN

NEONATAL CARE.

THE ONSET OF SURFACTANT, HIGH

FREQUENCY VENTILATION.

THE RESULTS OF THE TRIAL WERE

OBSOLETE.

THIRD, WHEN RCTs ARE NOT THE

MOST EFFICIENT WAY TO ACQUIRE

KNOWLEDGE, ONE FAMOUS CRITICAL

CARE TRIAL WAS THE STUDY OF

TITLE VOLUMES, $15 MILLION,

CONFIRMED SECULAR TREND THAT WAS

ALREADY OCCURRING BASED ON OTHER

DATA THAT CLINICIANS HAD ACCESS

TO.

AND ONLY ONE OF MULTIPLE

PERMUTATIONS IS VENTILATOR

MANAGEMENT.

IF WE STUDY EVERY WAY WE CAN

TWEAK THE NODS ON A VENTILATOR,

IT'S PROHIBITIVELY EXPENSIVE.

FINALLY WE SHOULD CONSIDER

ALTERNATIVES WHEN THE

NON-RANDOMIZED DATA ARE

COMPELLING.

RETURN TO YOUR POINT FROM THE

BEGINNING, AT THE TIME THESE

TRIALS WERE BEING DEVELOPED

THERE WAS A DATABASE AVAILABLE

ON BABIES WHO RECEIVED ECMO.

750 NEW -- 715 NEWBORNS.

IT WAS JUST A DATABASE.

THERE WERE NO CONTROL PATIENTS.

IN THE DATABASE THERE WAS AN 81%

SURVIVAL, WHICH THEY CALCULATED

WITH STATISTICALLY SUPERIOR TO

ANY OTHER TREATMENT WITH A

SURVIVAL RATE LESS THAN 78%.

SO THIS WAS OUT THERE AT THE

TIME THAT THESE RCTs WERE

BEING DEVELOPED.

SO THE QUESTION IS GIVEN THESE

DATA WAS THE BAR LET TRIAL

NECESSARY?

-- BARTLETT TRIAL NECESSARY?

WAS IT ETHICAL?

WAS THE HARVARD TRIAL NECESSARY?

WAS IT ETHICAL?

SHOULD WE HAVE BEEN LOOKING AT

THE NON-RANDOMIZED DATA AND

CHANGING OUR PRACTICE INSTEAD OF

PUTTING BABYINGS INTO A CONTROL

GROUP -- BABIES INTO A CONTROL

GROUP ALBEIT WITH A DESIGN

TRYING TO CONTROL THE NUMBER BUT

STILL BABIES IN THE CONTROL

GROUP THAT DIED.

SO WITH THAT AND ALL THAT YOU

HAVE SEEN ARE YOU NOW CONVINCED

THAT ECMO IS SUPERIOR TO

CONVENTIONAL THERAPY?

WITH ALL THE INFORMATION THAT I

HAVE GIVEN YOU IS THERE ANYBODY

IN THE ROOM, IF YOU WERE A

NEONATOLOGIST WHOLE NOT CHANGE

YOUR PRACTICE AT THIS POINT AND

START AN ECMO PROGRAM?

NO ONE IS BRAVE ENOUGH TO RAISE

THEIR HAND ANYWAY.

SOMEONE OVER HERE?

YES.

(OFF MIC)

>> I -- THERE'S A PROBLEM.

AND I SAW THERE'S A PROBLEM

BECAUSE THERE ISN'T CONVINCING

EVIDENCE.

I MEAN, THERE IS SOME SORT OF --

THERE IS EVIDENCE THAT COB

CONSIDERED CONVINCING BUT AT THE

SAME TIME YOU WANT TO TEST IT

WITH ANOTHER -- IT'S LIKE SHAM

SURGERY IN A WAY, THIS IS

TOTALLY DIFFERENT.

YOU WANT TO COMPARE THE RESULTS

YOU HAVE FOR ECMO WITH ANOTHER

-- WITH ANOTHER PROCEDURE.

I MEAN GRANTED HI HAD 8 -- HE

HAD 85%, ABOUT 85% RESULTS THAT

WERE POSITIVE BUT YOU WANT TO

HAVE EVIDENCE THAT IS BEYOND A

SHADOW OF A DOUBT, YOU KNOW.

AND I KIND OF SEE IT IN A WAY AS

MAYBE APPLYING PLACEBO OR PEOPLE

ARE GOING TO ARGUE WHY DO YOU

USE PLACEBO BUT IN CERTAIN CASES

IT WOULD BE NECESSARY.

>> OKAY.

I'M TAKING TWO THINGS FROM WHAT

YOU SAY.

ONE UP IT BEYOND A SHADOW OF A

DOUBT.

TWO YOU SAY WHAT LOOKS LIKE

TREATMENT VERSUS PLACEBO.

A LITTLE BIT OF THAT IS BECAUSE

I DIDN'T EXPLAIN IT VERY WELL.

REMEMBER, THESE PATIENTS ARE

BEING AGGRESSIVELY TREATED WITH

EVERYTHING ELSE THAT NEONATOLOGY

HAS TO OFFER IN TERMS OF ADVANCE

VENTILATOR TECHNIQUES,

MEDICATIONS, THE WHOLE THING.

SO IT REALLY WASN'T PLACEBO

CONTROLLED IN THAT SENSE.

BUT I THINK YOU JUST HAVE A

GNAWING DOUBT ABOUT THE STUDY

DESIGNS THAT YOU HAVE SEEN, THEY

DONE -- THEY'RE NOT AS

CONVINCING TO YOU.

SO LET ME GO ON AND SAY THAT YOU

WESTERN THE ONLY ONE WHO FELT

THAT WAY BECAUSE IN THE EARLY

1990s THE UNITED KINGDOM WAS

DECIDING WHETHER THEY WERE GOING

TO ADD ECMO INTO THEIR CARE OF

NEONATES.

THEIR FINANCING ARE MORE

CONSTRAINED THAN OURS, THEY

WANTED TO MAKE A RESPONSIBLE

DECISION SO THEY LOOKED AT ALL

THE INFORMATION YOU LOOKED AT

THIS MORNING AND SAID NO, NOT

CONVINCING.

SO THEY PUBLISHED THIS STUDY BUT

HERE IS HOW THEY JUSTIFIED IT.

THE EXISTING NEONATAL ECMO

SUGGESTED REDUCTIONS8

MORTALITY BUT WERE NOT

CONCLUSIVE.

BOTH USED ADAPTIVE DESIGN, THEY

WERE LOOKING AT THE BOSTON AND

HARVARD TRIAL, BOTH USE ADAPTIVE

DESIGN WHICH MAY HAVE INTRODUCED

BIAS.

SO THEY FELT THEY WERE GOING TO

GO AHEAD AND DO THEIR OWN RCT

THOUGH THEY WERE GOING TO DO IT

RIGHT.

BETWEEN VERSUS CONVENTIONAL

THERAPY.

THE TRIAL WAS STOPPED EARLY BY

THE DATA SAFETY MONITORING BOARD

WITH AN ECMO SURVIVAL OF 65%,

CONVENTIONAL THERAPY OF 41%.

ONE OF THE REASONS THIS IS

PROBABLY LOW, RELATIVELY LOW IS

BECAUSE THESE WERE NEW ECMO

CENTERS, SO THEY WERE ON THE

STEEP LEARNING CURVE.

THEY WEREN'T GOOD AT IT BUT THEY

HAD A DRAMATIC DIFFERENCE.

MY COLLEAGUE IN BIOETHICS JOHN

LANTOS WROTE A LETTER AND SAID

THIS WAS AN UNETHICAL TRIAL, 22

BABIES WHO WE WOULD HAVE

EXPECTED TO SURVIVE WERE

UNNECESSARILY SACRIFICED IN

ORDER TO PLACATE THE RCT GOD,

YOU MIGHT SAY.

SO THE QUESTION IS, THIS WAS

DONE, I THINK THE BRITISH

PHYSICIANS WROTE A WRONG LER

BACK SAYING NO, THE STUFF WAS

NOT CONVINCING.

WE HAVE NOW PROVEN IT AND WE'RE

GOING TO GO AHEAD WITH ECMO.

THAT'S HOW THAT ENDED.

WE'LL HAVE MORE TIME TO TALK

ABOUT THAT IN A MOMENT SO LET'S

WRAP UP.

THE CONFLICT BETWEEN

INVESTIGATORS AN PHYSICIANS CAN

CAN NEVER BE ENTIRELY

ELIMINATED.

ADAPTIVE RANDOMIZATION IS A WAY

TO BALANCE THE COMPETING

OBLIGATIONS, THIS IS

INCREASINGLY BEING USED.

ZALEN RANDOMIZATION REARE DEUCES

THE PSYCHOLOGICAL BURDENS ON

INVESTIGATORS AND POSSIBLY

FAMILIES.

IT'S PROBABLYETH CLIS

UNACCEPTABLE.

MY OWN VIEW, I TELL YOU I THINK

YOU CAN ETHICALLY DEFEND IT BUT

WITH A WAY THAT THE NIH

RESPONDED I WOULDN'T RECOMMEND

TO ANY OF YOU THAT YOU WRITE

THIS INTO YOUR GRANT ANY TIME

SOON.

RCTs ARE THE BEST APPROACH FOR

EVALUATING NEW THERAPIES.

I WORRY SOME WILL TAKE AWAY FROM

MY TALK THAT I'M ANTI-RCT OR

SOMETHING LIKE THAT.

I'M NOT.

IT'S OVERWHELMINGLY A POWERFUL

METHODOLOGY AND USEFUL FOR A LOT

OF THINGS BUT I THINK

ALTERNATIVES SHOULD BE

CONSIDERED WHEN THERAPIES ARE

POTENTIALLY LIFE SAVING WHEN THE

TECHNOLOGIES ARE DEVELOPING

RAPIDLY, WHEN RCTs ARE NOT

SUFFICIENT METHOD AND WHEN

NON-RANDOMIZED DATA ARE

COMPELLING.

FOR THIS TO CHANGE

INVESTIGATORS, JOURNAL EDITORS

AN GRANTING AGENCIES HAVE TO

RECONSIDER THEIR BLIND

INSISTENCE UPON RCTs.

IS I'LL QUOTE WITH A -- SO I'LL

QUOTE WITH A QUOTE FROM BENJAMIN

FRIEDMAN, THE BIOETHICIST WHO

GAVE US THE CON SECHT OF

CLINICAL HE CAN -- CONCEPT OF

EQUIPOISE.

IT HAS HIGH PRIESTS,

STATISTICIAN, SUPPLY CAN'T, THE

JOURNAL EDITORS AN RESEARCHERS,

AND IT'S ORTHODOX.

THE POS OF.05 IS QUOTE UNQUOTE

SIGNIFICANT.

IF HE WERE ALIVE TODAY HE WOULD

TELL US TO RESIST THIS ORTHODOXY

AND ALSO THE ORTHODOXY AROUND

RCTs AND ALL THE OTHER PARTS

OF STATISTICS TELLING US TO

NEVER, EVER THINK OUTSIDE OF THE

BOX.

THANK YOU FOR YOUR ATTENTION.

WITH THEY'LL CLOSE AND I HOPE WE

HAVE MORE CONVERSATION.

[APPLAUSE]

>> THANK YOU.

I ENJOYED THAT TALK VERY MUCH.

I DO HAVE A QUESTION THOUGH IT'S

PROBABLY NOT SPECIFICALLY

GERMANE TO ALL THE TOPICS YOU

HAVE COVERED.

THAT IS, THE ROLE OF HEALTH

INSURANCE CARRIERS IN

DETERMINING WHAT WILL BE

CONFERRED STANDARD TREATMENT

GIVEN DIFFERENT ORTHODOX IES AND

NATURE OF CLINICAL STUDIES OF

THIS SORT.

OBVIOUSLY YOU CAN SEE THEY MAY

SET A HIGHER BAR USING

RANDOMIZED CLINICAL TRIALS AND

WOULDN'T ACCEPT FOR EXAMPLE, A

S

>> GOOD QUESTION.

THERE'S A FEW THINGS THAT ARE

WRAPPED UP IN THAT.

I THINK THAT EVERYONE IS SO

BOUGHT INTO THE RCT ORTHODOXY

THAT IT IS HARD THE GET PEOPLE

TO LOOK AT OTHER WAYS OF

DEMONSTRATING THE TRUTH OF

SOMETHING.

SO THAT'S NUMBER ONE.

NUMBER TWO WHERE THE CONCEPT OF

CLINICAL HE CAN POI POISE --

EQUIPOISE PLAYS A ROLE GOING

FORWARD.

STEVE JOFFE AN FRANK MILLER HAD

AN ARTICLE RECENTLY ABOUT A

HYPOTHETICAL INSURANCE COMPANY

WHO SAYS TO PEOPLE WE WILL GIVE

YOU A BREAK ON YOUR PREMIUMS IF

YOU WOULD BE WILLING TO BE

RANDOMIZED IN SITUATIONS WHERE

WE ARE IN CLINICAL EQUIPOISE.

WE HAVE TWO ANTI-HYPERTENSIVES

LET'S SAY, AND WE'D LIKE TO GET

RID OF ONE OF THEM FROM THE

FORMULARY, SO WE'RE GOING TO

JUST GIVE YOU ONE OR THE OTHER.

IF YOU'RE WILLING TO BE

RANDOMIZED WE'LL GIVE YOU A CUT

ON YOUR PREMIUMS.

THEY POSE IT AS A HYPOTHETICAL

BUT IT COULD BE A VERY GOOD WAY

FOR US TO ACTUALLY ENLIST PEOPLE

IN THAT PROCESS OF LEARNING.

ANY OTHER COMMENTS ABOUT THE

HARVARD TRIALS?

COME UP TO MICROPHONE IF YOU

WOULD LIKE.

>> FROM MY UNDERSTANDING OF

EQUIPOISE, THERE'S CLINICAL

EQUIPOISE AND THEORETICAL

EQUIPOISE AND YOU MENTIONED

PERSONAL EQUIPOISE.

BASED ON THE DIFFERENT

CATEGORIES OF EQUIPOISE THAT YOU

GAVE NOW, DON'T YOU THINK THAT

THE STUDY WAS ACTUALLY OR

ETHICALLY ACCEPTABLE BECAUSE

THERE WAS A SORT OF CONSENSUS

AMONG THE EXPERT COMMUNITY ON

THE FACT THAT ECMO WAS

SUBJECTIVE?

THERE WASN'T A 100% CERTAINTY OF

ABOUT THE BENEFITS OF ECMO.

SO IN THAT SENSE WOULD ECMO BE

JUSTIFIED AS THERAPY?

EQUIPOISE SEQUENTIALLY MEANS

GENUINE UNCERTAINTY.

>> GREAT QUESTION.

I REALLY DON'T THINK THERE WAS

EQUIPOISE, CLINICAL EQUIPOISE AT

THE TIME THESE TRIALS WERE DONE,

IT WAS TRUE IN OUR NEONATAL UNIT

THEY WERE NOT IN FAVOR OF ECMO,

AND TRUE THERE WERE FEW ECMO

CENTERS IN THE COUNTRY.

AS I LOOK BACK ON IT, IF WE WERE

TRULY IN EQUIPOISE WE WOULD BE

MORE WILLING TO DO A REGULAR

RANDOMIZED CONTROL TRIAL.

THE FACT THEY WERE USING THESE

ADAPTIVE METHODS BELIED THE FACT

THAT EVERYONE SUSPECTED ECMO

WOULD BE VERY EFFECTIVE AND

PEOPLE WERE UNCOMFORTABLE WITH

THE IDEA IN A STANDARD RCT IT

WOULD BE WITHHELD FROM A NUMBER

OF PATIENTS WHO WERE DONE.

>> SO THEY COULD HAVE STOPPED

IT.

>> YOU KNOW, I THINK YOU HAVE TO

LOOK AT THIS ALMOST FROM A

SOCIOLOGICAL POINT OF VIEW WHAT

DOES IT TAKE TO GET PEOPLE TO

CHANGE PRACTICES AND HOW DO YOU

GET THEM THERE WITH THE LEAST

LOSS OF LIFE.

VERY GOOD WAY OF LOOKING AT

TRYING TO DEVELOP IT ALL BUT IT

GOES TO HOW BRAIN WORKS OF

PHYSICIANS AND WHAT GETS THEM TO

CHANGE THEIR PRACTICE.

>> THANK YOU.

>> SOMEBODY BACK HERE?

>> I HAD QUESTION QUICK

QUESTION, MORE A COMMENT.

THE UK STUDY HOW THEY DID

INFORMED CONSENT.

FROM THE PARENTS' PERSPECTIVE,

I'M SURPRISED THEY AGREED BASED

ON THE HISTORICAL DATA AND WHEN

THEY WENT OVER RISKS, BENEFITS.

>> I THINK YOU'RE RIGHT TO BE

SKEPTICAL.

I WAS NEVER PART OF THE

ACCORDANCES BUT YOU'RE A

PHYSICIAN WHO DOES IT AND YOU'RE

SITTING DOWN WITH THE FAMILY

ALREADY RANDOMIZED TO ECMO.

NOW THEY HAVE BEEN RANDOMIZED

YOU WANT TO MAKE SURE THEY DO

GET IT.

IF MANY SAY NO, THE DATA IS

ANALYZED ON INTENTION TO TREAT

BASIS SO IT STARTS TO MESS UP

YOUR STATISTICS.

SO YOU'RE MOTIVATED TO WANT TO

PRESENT ECMO IN A POSITIVE

LIGHT.

IN THE ZALEN RANDOMIZATION THERE

ARE A LOT OF THINGS GOING

AGAINST A ROBUST AND GOOD

INFORMED CONSENT.

AND THERE'S A LOT OF THINGS THAT

ARE PUSHING IN THE DIRECTION OF

TALKING THE FAMILY INTO IT.

I THINK THAT'S ANOTHER PROBLEM

WITH THAT TECHNIQUE THAT'S NOT

OFTEN DISCUSSED BUT IT DOES

EXPLAIN WHY 29 OUT OF 29 SAID

YES.

>> THANK YOU FOR THE TALK,

STIMULATE A LOT5
 THOUGHTS YOU

MAKE CIRCUMSTANCES AND MANY

ASPECTS WHERE RCTs MAY NOT BE

THE WAY TO GO FOR CLINICAL

RESEARCH AND THERE'S NOTHING

THAT GETS TO THE HEART MORE AND

IS MORE COMPELLING THAN TALKING

BABIES AN SOMEONE AT THE

BEGINNING OF LIFE AND ALL THAT

POTENTIAL THERE.

AND THIS CASE AND THESE FEW

CASES WITH ECMO THAT YOU

DESCRIBED ARE VERY COMPELLING.

I'M WONDERING IF THEY HAVE BEEN

USED SPECIFICALLY TO TRY TO

ADVANCE THE PHYSICIANS THINKING

OR THE FOLKS WHO WRITE COCHRAN

REVIEWS OR PEOPLE WHO ARE OUT

THERE SETTING THE GUIDELINES FOR

THE REST OF US WHO DONE HAVE THE

OPPORTUNITIES TO PARTICIPATE IN

HUGE STUDIES OR MAYBE EVEN A

SINGLE STUDY TO TRY TO ANSWER

THE QUESTIONS FOR OURSELVES.

WHAT IS MOVING FORWARD?

>> TELL ME MORE WITH WHAT

SPECIFICALLY WHERE YOU'RE GOING.

>> I THINK THERE IS A NICE

THEORETICAL ARGUMENT THAT YOU

HAVE MADE HERE THAT RCTs ARE

NOT THE ONLY WAY TO ANSWER

QUESTIONS.

>> RIGHT.

>> AND I THINK THAT WHEN YOU ASK

THE QUESTION ABOUT WAS THE ZALEN

RANDOMIZATION ETHICAL I WAS IN

THE TWO-THIRDS THAT SAID IT WAS,

I DIDN'T THINK THE STUDY WAS

ETHICAL BUT GET PAST THE STUDY

ETHICAL, HOW DO WE GO FORWARD

WHEN THERE'S QUESTIONS OUT TR

ABOUT STUDIES SHOULD BE DONE OR

SCIENCE THAT SHOULD BE DRAWN

FROM RETROSPECTIVE STUDY?

>> I GOT IT NOW.

I GUESS I WOULD SAY WHAT I WOULD

HOPE FOR WOULD BE ONE, TO BE

MORE SENSITIVE TO ETHICAL ISSUES

OF RCTs AND ASKING YOURSELF

WHETHER THE RCT CAN ETHICALLY BE

DONE.

I DON'T THINK THE ANSWER IS

ALWAYS YES.

YOU MIGHT LOOK TO OTHER

TECHNIQUES PARTICULARLY

RANDOMIZATION AS A WAY OF MAKING

THE RCT MORE ACCEPTABLE.

I THINK AS TO -- AND HERE IS

WHERE I'M NOT SURE THAT I'M

BEING VERY SUCCESSFUL BUT I

WOULD HOPE WE WOULD HAVE AN OPEN

MINE FOR WHAT COUNTS AS MORE

OPEN MIND WHAT COUNTS AS

EVIDENCE AND BE WILLING TO LEARN

FROM A VARIETY OF DIFFERENT

RESEARCH APPROACHES RATHER THAN

THIS SINGLE-MINDED FOCUS WE HAVE

ON RCTs.

I HAD ONE MORE I WAS GOING TO

SIGH AND IT'S SLIPPING MY MINE

RIGHT NOW BUT MOSTLY TO INCREASE

THE SENSITIVITY AROUND IT.

AND HAVE YOU THINK MORE DEEPLY

AN LESS REFLEXIVELY.

THANK YOU.

ONE MORE, KRISTIN.

>> MAYBE MORPH A POINT BUT SEEM

-- MORE OF A POINT BUT SEEMS

INTERESTING HOW WE WERE HAVING

DISCUSSION HOW RCTs ARE

HALLOWED GROUND AND ABSOLUTELY

NECESSARY BUT WHEN YOU LACK AT

CLINICAL PRACTICE THE DECISIONS

THAT ARE MADE THERE ARE OFTEN

COMPLETELY SEPARATE FROM WHAT

THE RANDOMIZED TRIALS HAVE SHOWN

WHEN YOU LOOK AT CASES OF HOW

THE NCC AND ADVISERS USE OF

(INDISCERNIBLE) CONTRARY TO WHAT

THE FDA HAS SEN.

>> THANK YOU.

THAT'S A FABULOUS POINT.

WE LOOK TO RCTs YET THE

BIGGEST HURDLE BY FAR IS GETTING

PEOPLE TO CHANGE THEIR PRACTICE

IN THE PHASE OF OVERWHELMING

EVIDENCE THAT THEY SHOULD BE

DOING SOMETHING DIFFERENT.

ONE OF THE RESPONSES WE HAVE

WHEN WE SEE THE PRACTICES AN

CHANGES, WE DO MORE RCTs, BUT

WE'RE MISSING THE POINT THAT'S

NOT GOING THE CHANGE THE

BEHAVIOR, IT WILL BE SOMETHING

ELSE THAT CHANGE IT IS BEHAVIOR.

IT RAISES THE ISSUE AROUND THE

CONCEPT OF CLINICAL EQUIPOISE.

WE CAN GO INTO THIS MANY NCI

MORE DEPTH.

BUT JUST BECAUSE YOU SHOW 50% OF

PHYSICIANS DO A AN 50% DO B,

DOESN'T MEAN THEY'RE IN CLINICAL

EQUIPOISE.

COULD MANE THE ONES DOING A ARE

NOT UP TO DATE WITH WHAT THEY

SHOULD BE DOING AND EVERYBODY

OUGHT TO DO B WITH EXISTING

EVIDENCE.

YET THAT'S OFTEN CITED AS LOOK

THERE'S CLINICAL EQUIPOISE

THEREFORE WE SHALL DO ANOTHER

RCT WITHOUT RECOGNIZING THE

RCTs HAVE BEEN DONE.

WE NEED TO CONVINCE THE 50%

BEHAVING BADLY TO CHANGE THEIR

PRACTICE.

SO I THINK THAT IDEA OF CLINICAL

EQUIPOISE CAN BE MISINTERPRETED

IN THAT WAY.

THANK YOU FOR BRINGING THAT UP.

[APPLAUSE]

>> SO I WANT TO SAY AS YOU G OUT

TO GET COFFEE, THAT'S WHY WE'RE

TEACHING THIS COURSE SO THAT

Y'ALL CAN CHANGE -- THINK OF

THESE THINGS IN THE FUTURE AND

BE REFLEXIVE WHEN DESIGNING AN

CONDUCTING YOUR STUDIES.

BUT COFFEE AND COOKIES AN BACK

IN 15 MINUTES, PLEASE.

>> IN THE REMAINING TIME WE'RE

GOING TO BE AN IRB AND WE'RE

GOING TO REVIEW A STUDY THAT'S

VERY DIFFERENT FROM THE STUDY

THAT YOU JUST HEARD ABOUT IN THE

LAST SESSION.

CAN EVERYBODY HEAR ME OKAY?

I'M GOING TO PLAY A COUPLE OF

ROLES HERE.

I'M GOING TO START LET'S IMAGINE

ON THE PI.

I'M GOING TO PRESENT A FEW FACTS

ABOUT THE STUDY.

THEN ONCE ALL THE FACTS ARE OUT

THERE I HOPE YOU ALL READ IT SO

YOU HAVE SOME THINGS TO SAY.

BUT ONCE I GET A FEW FACTS OUT

OBJECT TABLE WE WILL THEN HAVE

-- ON THE TABLE WE WILL HAVE A

DISCUSSION AND I'LL TRANSFORM --

CHANGE MY HAT AND BE THE IRB

CHAIR.

SO BY THE END OF THE SESSION WE

WILL VOTE.

ABOUT WHETHER OR NOT THIS STUDY

SHOULD BE APPROVED.

AS Y'ALL KNOW BECAUSE YOU READ

IT, THIS IS A PHASE 1 STUDY TO

EVALUATE THE SAFETY AND

IMMUNOGENICITY OF E BEE LO DNA

PLASMID VACCINE AND A MARBURG

DNA VACCINE IN HEALTHY ADULTS.

AS YOU KNOW, EBOLA AND MARBERG

ARE PHYLOVIRUSES KNOWN TO INDUCE

HEMORRHAGIC FEVER, LARGE

NEGATIVE STRAND RNA VIRUSES

ENCODING PROTEINS INCLUDING A

SINGLE GLYCO PROTEIN.

TRANSMISSIONS TO HUMANS IS NOT

FULLY UNDERSTOOD BUT LIKELY

INCLUDE INCIDENTAL EXPOSURE TO

INFECTED ANIMALS.

HUMAN OUTBREAKS OF EBOLA AND

MARBERG HEMORRHAGIC FEVER ONLY

OCCUR THE DATE IN AFRICA.

A PREVIOUSLY UNSEEN STRAIN OF

EBOLA CAUSE AN OUTBREAK IN A

LABORATORY IN NORTHERN VIRGINIA

IN 1989.

AND THE VIRUSES AND POACHING

HAVE PUSHED POPULATION OF

GORILLAS IN SOME COUNTRY IN

AFRICA TO THE BRINK OF

EXTINCTION IN WESTERN AFRICA.

THE HUMAN DISEASE WITH EBOLA OR

MAR BEG IS DRAMATIC.

THERE'S A BRIEF INCUBATION

PERIOD, RAPID ONSET OF SYMPTOMS

INCLUDING FEVER, FATIGUE, GI,

ABDOMINAL PAINS, ANOREXIA,

HEADACHE MORE SEVERE SYMPTOMS

FOLLOW WITHIN A FEW DAYS.

AND CAN INCLUDE HEM RA JUDGE

RASH -- HEMORRHAGIC RASH,

MUCOSAL BLEEDING, HEME TOURIA,

HEMOPTASIST, MELANA,

(INDISCERNIBLE) CONFUSION,

SOMNOLENCE AND HEARING LOSS.

HIGH FATALITY RATE, 50 TO 90%

FOR EBOLA AND 25 TO 100% FOR

MARBERG USUALLY WITHIN DAYS

AFTER THE ONSET OF SYMPTOMS.

THE PROTOCOL DESCRIBES IT BUT

WITH THE EASE OF TRAVEL AND

FREQUENCY OF AIR TRAVEL THERE'S

A POTENTIAL THREAT OF SPREAD OF

HUMAN DISEASE OUTSIDE OF AFRICA.

BOTH AGENTS HAVE BEEN

CATEGORIZED BY THE CDC AS

CATEGORY A BIOTERRORISM AGENTS.

THE KIND OF ORGANISMS THAT

COMPOSE A RISK TO NATIONAL

SECURITY BECAUSE THEY'RE EASILY

DISSEMINATED OR TRANSMITTED FROM

PERSON TO PERSON RESULTS IN HIGH

MORTALITY RATES AND HAVE

POTENTIAL FOR MAJOR HEALTH

IMPACTS.

AND ALSO CAUSE PUBLIC PANIC AN

SOCIAL DISRUPTION.

SO THE OVERALL GOAL OF THE

PROGRAM AT THE VRC HERE IS THE

PHYLOVIRUS VACCINE DEVELOPMENT

PROGRAM IS TO DEVELOP A REGIMEN

EFFECTIVE IN PREVENTING BOTH

EBOLA AN MARBERG.

IN HUMAN SURVIVORS BOTH CELL

MEDIATED IMMUNITY ARE DETECTED,

HOWEVER THE RELATIVE

CONTRIBUTION TO PROTECTION FROM

EITHER OF THESE DISEASES IS

UNKNOWN.

PRE-CLINICAL STUDIES OF

CLASSICAL WHOLE KILL VARIANTS AN

LYE ATTENUATED VIRUSES AND

RECOMBINANT VECTOR BASED

APPROACHES DEMONSTRATE PARTIAL

PROTECTION IN ANIMALS BUT NO

CELL MEDIATED IMMUNE RESPONSES

HAVE BEEN GENERATED FROM THOSE

MODALITIES.

THERE ARE PRE-CLINICAL SAFETY

AND IMMUNOGENICITY DATA ON THESE

VACCINE CANDIDATES WE'RE

TESTENING THIS STUDY BUT NO

HUMAN DATA ON THESE TWO

PARTICULAR CANDIDATES.

HOWEVER, THERE ARE HUMAN SAFETY

DATA FROM EIGHT OTHER SIMILAR

DNA VACCINES FOR OTHER DISEASES

AND THOSE DATA SUGGEST THAT

THESE KINDS OF DNA VACCINES ARE

SAFE AND WELL TOLERATED IN

HEALTHY ADULTS AGE 18 TO 65

YEARS OLD.

THE HYPOTHESIS HERE IN THIS

STUDY IS EACH OF THE TWO

RECOMBINANT DNAS WILL BE SAFE

FOR HUMAN ADMINISTRATION AN WILL

ELICIT HUMORAL AND T-CELL

MEDIATED RESPONSE.

SO THE OBJECTIVES OF THE STUDY

TO EVALUATE THE SAFETY ANATOL

LERRIBILITY OF THREE DOSES,

THREE FOUR MILL GAM GOES --

MILLIGRAM DOSE OF HEALTHY

VACCINES IN AMENDED SUBSET OF

THE GROUP.

THE SECONDARY -- SECOND

OBJECTIVE IS TO EVALUATION THE

IMMUNOGENICITY OF EACH STUDY

VACCINE.

THIS IS AN OPEN LABEL FIRST IN

HUMAN PHASE 1 STUDY TO EVALUATE

SAFETY, TOLERABILITY AND

IMMUNOGENICITY OF TWO

RECOMBINANT DNA VACCINES, ONE

AGAINST MARBERG AND ONE AGAINST

EBOLA.

A LITTLE BIT ABOUT THE

CANDIDATES THEMSELVES THE

MARBERG DNA VACCINE IS COMPOSED

OF ONE CLOSED CELLULAR CIRCULAR

DNA PLASMID ENCODING THE GLYCO

PROTEIN FROM THE ANGOLA STRAIN

AND THE HE CAN EBOLA IS COMPOSED

TO TWO SURK LAR DNA PALACE MIDS,

ONE ENCODES FROM THE ZYER STRAIN

AND ONE FROM THE SUDAN STRAIN OF

EBOLA.

VOLUNTEERS CANNOT BECOME

INFECTED FROM THESE VACCINE

CANDIDATES.

EACH DNA VACCINATION WILL BE

GIVEN INTRAMUSCULARLY INTO THE

DELTOID MUSCLE USING A

BIOINJECTOR NEEDLE FREE

INJECTION MANAGEMENT SYSTEM

WHICH HAS BEEN USED BEFORE.

WE ARE RECRUITING 20 HEALTHY

ADULTS BETWEEN AGE 18 AND 60.

THEY WILL BE ENROLLED IN TWO

GROUPS OF 10 SUBJECTS EACH.

NO MORE THAN ONE 5 # TO

60-YEAR-OLD WILL BE IN EITHER

GROUP.

GROUP 1 GETS THE MARBERG DNA,

GROUP 2 -- THE MARBERG DNA

VACCINE CANDIDATE, GROUP 2, THE

EBOLA CANDIDATE AND ONLY ONE

WILL BE ENROLLED, ONE PERSON

WILL BE ENROLLED IN EACH GROUP

PER DAY UP TO THE FIRST THREE

PEOPLE.

AFTER THAT IF THERE ARE NO MAJOR

SAFETY ISSUES IN THE FIRST THREE

THEY WILL ROLE THE OTHER SEVEN

IN A MORE EXPEDITIOUS MANNER.

TO BE ELIGIBLE PEOPLE HAVE TO BE

BETWEEN 18 AND 60, AVAILABLE FOR

CLINICAL FOLLOW-UP FOR 32 WEEKS,

ABLE TO PROVIDE PROOF OF

IDENTITY, ABLE, WILLING AND

WILLING TO COMPLETE A CONSENT

PROCESS AND ASSESSMENT OF

UNDERSTANDING WHICH IS OUR

STANDARD PRACTICE IN THE VACCINE

CLINIC.

WILLING TO DONATE BLOOD FOR

STORAGE FOR FUTURE RESEARCH,

THEY HAVE TO BE IN GOOD GENERAL

HEALTH WITHOUT CLINICALLY

SIGNIFICANT MEDICAL HISTORY,

HAVE TO HAVE A PHYSICAL EXAM AND

LABORATORY RESULTS WITHIN NORMAL

LIMITS.

THE BODY MASS INDEX HAS TO BE

LESS THAN 40 WITHIN THE PRIOR 28

DAYS, THEY HAVE TO HAVE NORMAL

HEMOGLOBIN, WHITE BLOOD CELL

COUNT PLATELETS, SERUM,

CREATININE AND PN PTT, NEGATIVE

FOR HIV, HEPATITIS B AN C AND

NORMAL YOUR MALLSIS AND FEMALES

HAVE TO HAVE NEGATIVE PREGNANCY

TEST AND MUST EITHER NOT BE ABLE

TO REPRODUCE OR BE SEXUALLY

INACTIVE OR USE CONTRACEPTION

FROM 21 DAYS BEFORE THE STUDY

UNTIL WEEK 32.

THERE ARE LOTS OF EXCLUSION

CRITERIA, THEY CAN INDIVIDUALS

CANNOT HAVE HAD PRIOR VAIXAL

VACCINE, IMMUNOSUPPRESSIVE

PRODUCT, BLOOD PRODUCTS OR

IMMUNOGLOBULIN WITHIN 60 DAYS OR

OTHER RESEARCH AGENTS WITHIN 30

DAYS.

THEY CAN'T HAVE HAD RESENT

MEDICALLY INDICATED SUB UNIT OR

KILLED VACCINE LIKE INFLUENZA OR

PNEUMOCOCCAL OR ALLERGY

TREATMENT WITH ANTIGEN

INJECTION.

A LOT IS TO PREVENT CONFLICTING

IMMUNOLOGICAL DATA.

THERE CAN'T HAVE HAD A HISTORY

OF ADVERSE REACTIONS TO VACCINES

OF ANY TYPE OR ALLERGIC

REACTIONS TO IMMUNOGLIEK SIDE

ANTI-APTANTIBIOTICS.

NO PROPHYLAXIS OR THERAPY.

NO AUTOIMMUNE DISEASES OR

IMMUNODEFICIENCIES AS DIABETES,

THYROID DISEASE, MALIGNANCIES,

SEIZURE DISORDERS, EDEMA OR

UNCONTROLLED HYPERTENSION.

NO ESPLENIA, NO PSYCHIATRIC

CONDITIONS THAT MIGHT PRECLUDE

COMPLIANCE.

AND ANY OTHER MEDICAL

PSYCHIATRIC SOCIAL OR

OCCUPATIONAL REASON OR

RESPONSIBILITY THAT IN THE

JUDGMENT OF THE INVESTIGATORS IS

A CONTRAINDICATION MIGHT EXCLUDE

AN INDIVIDUAL.

THE STUDY REQUIRES NINE CLINIC

VISITS AND THREE TELEPHONE

FOLLOW-UP CONTACTS OVER 32

WEEKS.

EACH SUBJECT WILL RECEIVE THREE

INJECTIONS OF THE VACCINE AT

LEAST 21 DAYS APART.

AS I MENTION, THERE'S A PROTOCOL

AMENDMENT FOR SUBSET WHO WILL

RECEIVE A FOURTH INJECTION.

AND THEY HAVE ADDITIONAL

FOLLOW-UP TIME AFTER THAT FOURTH

INJECTION.

WHEN INDIVIDUALS WHO ARE

ENROLLED COME O THE CLINIC THEY

GET THE INJECTION IN THE CLINIC,

REMAIN IN CLINIC 30 MINUTES FOR

OBSERVATION.

THEY WILL COMPLETE A DAILY DIARY

CARD ANY SYMPTOMS AND

TEMPERATURE THEY HAVE FOR FIVE

DAYS POST INJECTION.

THERE WILL BE A PHONE CALL TO

THE STUDY NURSE ONE DAY AFTER

INJECTION TO REPORT ON SYMPTOMS

OR SIDE EFFECTS.

AND THEY ARE INSTRUCTED TO COME

TO THE CLINIC OR IF THEY HAVE A

RASH OR HIVES OR FEVER OF 38.7

OR HIGHER FOR MORE THAN 24

HOURS.

OR ANY OTHER DIFFICULTY IN THEIR

USUAL ACTIVITIES.

WHEN THEY COME TO THE CLINIC

THEY WILL PROVIDE INFORMATION

ABOUT ANY CHANGES IN HEALTH, ANY

MEDICATIONS THEY HAVE BEEN ON,

ANY PROBLEMS, BLOOD SAMPLES

DRAWN IN EACH CLINIC VISIT, TWO

TO NINE TABLESPOONS PER VISIT

WITH A TOTAL OF 970.

URINE SAMPLE AT SOME VISIT AND

BLOOD FOR GENETIC STUDIES AN HLA

TYPING.

THEY RECEIVE $275 FOR THE

VACCINE INJECTION

VISITS, $175TOR FOR CLINIC

VISITS THAT HAVE NO INJECTIONS

BUT JUST BLOOD DRAWS AND $75 IF

NEITHER BLOOD DRAW OR INJECTION.

WITH A TOTAL POSSIBLE

COMPENSATION FOR THEIR

CONTRIBUTION OF $1,875 BUT

PRORATED BASED ON WHAT THEY

COMPLETE.

ARE THERE ANY QUESTIONS FOR

PRINCIPLE INVESTIGATOR THAT

HOPEFULLY SHE CAN ANSWER?

ANY QUESTIONS?

YOU ALL READ THE STUDY.

ARE YOU READY TO DISCUSS IT AS

AN IRB?

I HAVE A QUESTION IN THE BACK.

>> IN THE PRE-CLINICAL SAFETY

DATA'S A PORTION THAT SAYS THE

ACTUAL VACCINE HAS BEEN TESTED

IN GLP STUDIES AN SECTION

FOLLOWING SAYS ONLY THE

COMPONENTS ARE TESTED IN THE

STUDIES BUT NOT THE FULL

VACCINE.

WONDERING WHAT ARE THE ACTUAL

VACCINES HAVE IN THE GLP SAFETY

STUDIES OF NON-HUMAN PRIMATES OR

IF ONE IS A TYPO.

>> IT'S A TYPO.

>> SO WHAT WAS NON-HUMAN -- A

PREVIOUS VACCINE?

>> A SIMILAR VACCINE, SIMILAR

DNA VACCINE FOR OTHER VIRUSES.

ANY OTHER QUESTIONS?

>> COULD I ASK A QUESTION FROM

THE PERSPECTIVE OF A

PARTICIPANT?

>> SURE.

>> REMEMBER YOU'RE TALKING TO

THE PI UNLESS YOU WANT TO TALK

TO THE IRB.

>> GO AHEAD.

>> WHAT ARE THE CHANCES OF

SOMETHING GOING HORRIBLY WRONG

AND ME BEING PERMANENTLY

DISABLED OR KILLED BY MY

INVOLVEMENT IN THE STUDY?

AN IN THE EVENT THAT I AM

INJURED IN SOME WAY, WHAT ARE

THE RESPONSIBILITIES OF THE NIH

WITH RESPECT TO LONG TERM

HEALTHCARE?

>> DOUG, YOU HAVE BEEN IN THE

DEPARTMENT TOO LONG.

THERE'S ALMOST NO CHANCE YOU'LL

HAVE PERMANENT DISABILITY.

THE DATA THAT WE HAVE IN OTHER

DNA VACCINES ARE THAT THEY'RE

VERYW

IF YOU WERE FOR SOME UNKNOWN

REASON HAVE SOME KIND OF SIDE

EFFECT WE WILL TAKE CARE OF YOUR

SHORT TERM MEDICAL CARE BUT NO

LONG TERM MEDICAL CARE.

LAST PI QUESTION.

>> SO I NOTICE THAT'S A STUDY

GOING ON NOW ASSUMING IT'S STILL

2009, USING THE POINT MUTATION

VIRUS FOR THE EBOLA AND THAT'S

STILL GOING ON AND SO FAR SHOWN

TO BE PROTECTIVE IN NON-HUMAN

PRIMATE STUDIES AB THERE WAS

SOME KIND OF SLIGHT DISCUSSION

THAT THE WILE TYPE SHOWS MORE IN

VITRO TOXICITY COMPARED TO THE

POINT MUTATION.

WHY ARE YOU PUSHING AHEAD WITH

THE WILD TYPE WHEN YOU DON'T

HAVE RESULTS BACK FROM THE POINT

MUTATION VACCINE?

>> I HAD NO IDEA.

I HAVE TO APOLOGIZE IN THAT

CASE.

THAT'S A SCIENTIFIC QUESTION

THAT I DON'T HAVE THE ANSWER TO.

WE COULD ASK THE REAL PI IF YOU

WANT TO BUT LET'S ASSUME FOR THE

MOMENT THAT THIS IS ANOTHER

DIFFERENT STRATEGY THAT HAS

MERIT EVEN BEFORE THOSE OTHER

DATA ARE IN.

LET'S JUST SAY.

SO NOW YOU'RE THE IRB.

PI IS ASKED TO LEAVE, IRB

DISCUSSES.

WHAT DO YOU THINK?

WHERE DO YOU DO YOU WANT TO
START?

IDEAS?

>> JUST TWO ISSUES THAT SEEM TO

JUMP OUT.

ONE WAS THE STUDY POPULATION

SIZE, DOESN'T SEEM TERRIBLY

ROBUST.

THAT WAS ONE QUESTION THAT CAME

TO MIND.

THE OTHER, MOST CLINICAL STUDIES

ATTEMPT TO ADDRESS THE ISSUES OF

GENDER AND IN DIFFERENT RACIAL

POPULATIONS BECAUSE NOT ALL

RESPOND EQUIVALENTLY.

>> SO THIS IS FIRST IN HUMAN

PHASE 1 AND IN GENERAL FIRST IN

HUMAN PHASE 1 WE TRY WERE SMALL

NUMBER OF PEOPLE BECAUSE WHAT

WE'RE LOOKING FOR IS HOW SAFE

THIS IS.

IF WE FINE IT'S SAFE IN THE

FIRST 20 PEOPLE THAT WE TEST IT

IN, THERE WILL BE FURTHER

STUDIES THAT WE WORRY ABOUT

DIFFERENCES IN TERMS OF GENDER,

RACIAL AND ETHNIC MINORITIES.

>> ONE OF MY CONCERNS WOULD BE

THEY'RE TESTING TWO DIFFERENT

VACCINES FOR SAFETY AND WHY IN

THE JUST TEST ONE FIRST AND BASE

THE NEXT STUDY ON WHATEVER THEY

FIND FROM THE FIRST ONE.

>> IS THAT A PROBLEM THAT WE

WANT TO SAY THE INVESTIGATOR

SHOULD WRITE TWO PROTOCOL?

SAY MORE ABOUT WHY YOU THINK

THAT'S A PROBLEM.

>> I THINK THAT I WOULD

RECOMMEND STARTING WITH ONE, NOT

WRITING TWO PROTOCOLS JUST DOING

A SAFETY STUDY ON ONE OF THESE

VACCINES.

THEY DONE KNOW WHAT EXPECT

BECAUSE IT'S FIRST IN HUMAN.

>> SO FOR SAFETY REASONS.

>> UH-HUH.

>> OKAY.

ANYBODY ELSE WANT THE SAY

ANYTHING?

I'M JUST ASKING IS THIS ONLY

DONE IN THE U.S. OR DO WE HAVE

RESEARCH SITES INTERNATIONALLY?

I'M ASKING BECAUSE OF THE

BIOINJECTOR, THERE MIGHT BE

CULTURAL ISSUES OF THE FEAR OF

HAVING THE BIOINJECTOR.

IS THERE AN ALTERNATIVE METHOD

THEN?

IF THEY'RE FEARFUL OF IT,

BASICALLY.

>> SO THIS IS JUST THE FIRST.

THIS IS THE FIRST IN-HUMAN PHASE

1 EXPERIMENT WITH THESE TWO

VACCINES.

IT'S GOING TO BE DONE IN THIS

BUILDING.

IF THEY'RE SAFE THERE WILL BE

FUTURE STUDIES.

SO THE DELIVERY OF THE VACCINE

COULD BE AN ISSUE THAT WE COULD

DISCUSS WHEN WE TAKE IT TO OTHER

AREAS IN THE WORLD.

BUT FOR NOW IT'S JUST GOING TO

BE DONE HERE TO SEE IF THEY'RE

SAFE.

SO I WANT TO SUGGEST THAT WE

SHOULD USE SOME KIND OF A

FRAMEWORK FOR HAVING A

DISCUSSION.

WE HAVE HAD A COUPLE THAT WE

HAVE TALKED ABOUT IN THIS CLASS

SO JUST TO PUT THEM UP HERE TO

GIVE YOU SOME WAYS TO THINK

ABOUT IT.

ONE POSSIBILITY IS TO USE

FRAMEWORK I PRESENTED THE FIRST

DAY, LET'S START AT THAT TIME

TOP AN WORK OUR WAY THROUGH THE

VARIOUS ELEMENTS OF WHAT WE

PROPOSE ANYWAY, MAKE RESEARCH

ETHICAL.

THE OTHER POSSIBILITY THE OTHER

CRITERIA IN THE REGULATIONS IN

THE COMMON RULE THATTISHs ARE

SUPPOSED TO USE TO DECIDE

WHETHER OR NOT A STUDY IS

APPROVABLE.

SO USING THESE KINDS OF

CRITERIA, LET'S START AT THE

TOP.

I'M GOING TO SKIP COLLABORATIVE1

PARTNERSHIP.

PHASE 1 STUDY, THE ASSUMPTION IS

ALREADY ALSO OF PEOPLE INVOLVED

IN THIS STUDY EVEN IF SMALL.

BUT THE SORT OF NOTION OF LARGE

COLLABORATIVE PARTNERSHIP

COMMUNITIES IS KIND OF DOESN'T

MAKE AS MUCH SENSE IN THE PHASE

1 STUDY AS IN LATER STUDIES.

SO I'M GOING TO SKIP THAT AND

SAY WHAT ABOUT SOCIAL VALUE?

THIS RESEARCH QUESTION HAS

SOCIAL VALUE.

ANYBODY WANT TO SAY ANYTHING

ABOUT THAT, ANYBODY THINK IT

DOESN'T?

SHOULD I TAKE A VOTE?

GO AHEAD.

IT COULD BE A BIOTERRORISM

WEAPON SO IS THAT MEANT TO

CONJURE UP MORE SOCIAL VALUE

THAN MAYBE REALLY WARRANTED.

SEEMS LIKE THE MOST SOCIAL VALUE

WOULD COME FROM THE USE OF THIS

VACCINE AS BEING TESTED HERE AND

THE ONLY SOCIAL VALUE FOR THE

PARTICIPANTS HERE WOULD BE

AGAIN, TERRORISM.

SO THE SOCIAL VALUE DOESN'T

ADHERE TO THE 20 PERSISTENCE

THAT WE'RE PUTTING IN PHASE 1

STUDY.

THAT IS WHAT YOU'RE POINTING

OUT.

THE QUESTION IS IS THERE

JUSTIFICATION FOR DOING THIS

STUDY?

IS THERE A REASON TO LOOK FOR A

VACCINE FOR E BELA AND MARBERG?

YOU POINTED OUT CERTAINLY IN

AFRICA WHERE THEY HAVE

EXPERIENCED HUMAN DISEASE, THIS

MAKES SENSE.

PART OF THE REASON THERE WAS

JUSTIFICATION ABOUT THE POSSIBLE

TERRORISM USE OF THESE VIRUSES

IS BECAUSE WE'RE HERE AT THE

NIH, WE'RE SPENDING NIH MONEY TO

DEVELOP THESE VACCINES SO THERE

MAYBE MULTIPLE REASONS.

THAT'S THE JUSTIFICATION.

ANYONE IN THE ROOM THINK THERE'S

NO REASON TO DO A STUDY LIKE

THIS, NO SOCIAL VALUE?

REASON I'M GOING THERE IS

BECAUSE I THINK MORE INTERESTING

DISCUSSIONS ARE YET TO COME.

SO IF NOBODY SAYS SOCIAL VALUE

IS AN ISSUE, LET'S GO TO THE

SCIENTIFIC VALIDITY.

WHICH BRINGS US HERE IN TERMS OF

DISCUSSIONS IN THE REGULATIONS

AB HOW YOU MAKE DECISIONS.

ONE OF THE THINGS HOW THE IRB

MAKES DECISIONS.

ONE OF THE THINGS YOU'RE TASKED

TO DO IS MAKE A DECISION WHETHER

OR NOT THE RISKS ARE CONSISTENT

WITH SOUND CONSISTENT WITH SOUND

DESIGN IN A WAY THAT MINIMIZES

RISK TO THE PARTICIPANTS AND

USING PROCEDURES THAT ARE

PLANNED FOR DIAGNOSIS OR

TREATMENT.

WHAT DO YOU WANT TO SAY ABOUT

THAT?

THIS IS PHASE 1 HEALTHY

VOLUNTEER.

>> WHAT ABOUT THE ISSUE OF

ESCALATING DOSE?

IT STARTED -- IT'S 4 MILLIGRAMS

FOR BOTH.

MY EXPERIENCE HAS BEEN THE WHOLE

PURPOSE IS YOU START LOW AND

PROCEED UNTIL YOU SEE POTENTIAL

TOXICITY, ET CETERA.

SO THAT'S AN ISSUE.

>> IT'S A GREAT QUESTION.

A LOT OF PHASE 1 STUDIES FOR

EXAMPLE ONCOLOGY WHICH I KNOW

YOU WORK IN, THAT'S THE PAIR

DIME.

PARADIGM IS DOSE ESCALATION

UNTIL YOU FINE TOXICITY,

SELF-LIMITING TOXICITY.

IN VACCINE IT'S A DIFFERENT

PARADIGM.

SO IN THIS CASE THE ESCALATION

IS PROPOSED ANYWAY BY ENROLLING

ONE PERSON A DAY AND LOOKING AT

THE SIDE EFFECTS OF SAFE ANY

THOSE PEOPLE ONE A DAY, AND

AFTER 3 ARE ENTERED THERE ARE NO

SAFETY INDICATIONS AT ALL.

THEN THE REST CAN BE ENROLLED.

THE WAY THE SAFETY CONCERNS ARE

DEALT WITH IS SLIGHTLY

DIFFERENCE THAN ONCOLOGY PHASE 1

TRIAL.

DOES ANYONE HAVE CONCERNS ABOUT

SCIENTIFIC DESIGN, THE WAY IT'S

SET UP, THE RISKS GIVEN THE

SCIENTIFIC DESIGN THEN WE'LL

TALK ABOUT WAYS OF MINIMIZING

RISK IN A MINUTE.

>> YOU SAID NO HUMAN DATA ON THE

VACCINE BUT WHAT WAS THE DATA IN

THE NON-HUMAN PRIMATE IF ANY?

>> IN THE NON-HUMAN PRIMATES, I

DON'T REMEMBER EXACTLY BUT IT'S

SAFE, WELL TOLERATED AND SOME

IMMUNOGENICITY INCLUDING T-CELL

IMMUNITY.

>> WAS THERE ANY MORTALITY AT

ALL?

>> I DON'T THINK SO.

EVERYBODY IS OKAY WITH PHASE 1

DESIGN.

DESIGN IS OKAY, SCIENTIFIC

VALIDITY, WE'LL GET SOME DATA

ABOUT SAFETY AND THE WAY PHASE

1s ARE -- THE PURPOSE OF A

PHASE 1 IS TO GET DATA ABOUT

SAFETY TO DECIDE WHETHER TO

DECIDE A PHASE 1, # TRIAL.

THIS IS THE FIRST --

>> MAYBE MORE INABILITY TO

RECOLLECT THIS, WHAT WAS THE

CONTROL GROUP?

>> NO CONTROL GROUP.

>> THERE DOESN'T NEED TO BE A

CONTROL GROUP FOR PHASE 1?

OKAY.

I'M NOT SURE WHAT YOUR

EVALUATING SAFETY AGAINSTCH IS

IT TEN RANDOM MEMBERS?

>> YEAH.

>> WHAT SIDE EFFECT THIS VACCINE

IS CAUSING.

DO YOU THINK THERE ARE

SUFFICIENT PROCEDURES BUILT INTO

THE STUDY DESIGN TO FIND AN

ANSWER TO THAT QUESTION?

WHAT SIDE EFFECTS WILL PEOPLE

EXPERIENCE?

I SEE HEADS NODDING.

NO CONCERNS ABOUT SAFETY.

>> YOU SAID THE FIRST THREE WILL

BE ENROLLED DAY 1, 2, 3.

THE FIRST IS IN WEEK 12.

IF YOU DON'T SEE SOMETHING IN 24

HOURS BUT TEN WEEKS YOU ENROLLED

TEN PEOPLE AND SIDE EFFECTS TO

STA SHOWING UP.

YOU CONCERNED?

>> ARE YOU CONCERNED ABOUT THAT?

>> YES.

>> HOW WOULD YOU DO IT INSTEAD?

>> MAYBE DO WHATEVER TESTS

THEY'RE GOING TO DO AT THE 24

MARK AND THE 48 HOUR MARK AN

BEFORE THEY ENROLL THE PEOPLE

START THE TIME POINT SOONER.

>> OKAY.

YOU'RE SUGGESTING THAT THEY

SPREAD PEOPLE OUT ?URT IN OTHER

WORDS, NOT -- FURTHER?

NOT THREE DAYS IN A ROW BUT ALSO

DO -- WHICH IS THE BLOOD TEST

YOU'RE SAYING THAT EAR DOING 20

WHATEVER IT IS LATER?

(OFF MIC)

>> THAT'S A TEST FOR

IMMUNOGENICITY.

THE STAGGERING ENROLLMENT IS FOR

SAFETY.

SO WHAT WOULD YOU LIKE THEM TO

DO AT THE FRONT END TO ENSURE

SAFETY BEFORE THEY ENROLL

SOMEBODY ELSE?

(OFF MIC)

>> WHAT REACTION YOU'LL HAVE

LOCAL, WHETHER OR NOT PEOPLE

WILL HAVE SYSTEMIC REACTION.

COULD BE AN ALLERGIC REACTION TO

THIS VACCINE.

COULD BE REALLY NASTY LOCAL

REACTION.

COULD BE THE KINDS OF THINGS YOU

GET IN VACCINE, FEVER.

HEADACHE.

(OFF MIC)

>> SO YOU WOULDN'T NECESSARILY

ADD TESTS BUT YOU WILL SAY AT

LEAST FOR THE FIRST THREE OR DO

YOU WANT TO DO MORE THAN THREE?

SPREAD THEM OUT.

SO LET ME -- I'M PUTTING YOU ON

THE SPOT SO MUCH BUT YOU RAISE

THE QUESTION.

YOU'RE THE IRB SO YOU'RE

DECIDING IS THIS DESIGNED IN A

WAY THAT YOU FEEL COMFORTABLE

THAT THE RISK TO SUBJECTS ARE

MINIMIZED AND THAT THE VALUE OF

THE STUDY WILL BE REALIZED, THEN

YOU'LL FIND AN ANSWER YOU CAN

USE.

>> ONE IS ALLO GENICITY, A

NEGATIVE RESPONSE TO THE

VACCINE.

SO DOING AN INTRAMUSCULAR

INJECTION SEEMS TO BE A VERY

AGGRESSIVE WAY OF TESTING FOR

THIS STARTING OUT WITH A MORE

INCREMENTAL APPROACH WITH+zV

INTRADERMAL INJECTION AT LOCAL

SITES SEEING IF REACTION ENSUING

THERE, BEFORE GOING TO MORE

AGGRESSIVE INJECTION STRATEGY.

>> ARE YOU SUGGESTING FOR SAFETY

REASONS YOU WANT TO START WITH

INTRADERMAL OR SUBCUTANEOUS AND

THEN IF THERE'S NO SIDE EFFECTS

THEN TO INTER-- INTRAMUSCULAR?

>>

>> CORRECT.

>> INTRAMISQUEUE LAR IS GOING TO

GET THE IMMUNE RESPONSE WE'RE

LOOKING FOR.

THAT'S ANOTHER POSSIBLE

SUGGESTION SAFETY WISE, ANYBODY

ELSE?

YOU CAN DEFEND THEIR CURRENT

PROPOSAL IF YOU WANT TO.

>> ANY RECENT EVIDENCE

SUGGESTING MALES AND FEMALES

REACTED THE SAME WAY INJECTION I

WOULD RATHER SEE EQUAL NUMBER OF

FEMALE MALE SUBJECTS ENROLLED IN

THIS STUDY.

>> SO YOU HAVE TO MANDATE THEY

HAVE TEN AND TEN?

SO FIVE IN EACH GROUP?

OKAY.

>> ON THAT TOPIC I'M CONCERNED

ABOUT THE PLANS FOR PREVENTING

WOMEN FROM GETTING PREGNANT.

BECAUSE I WORK WITH PREGNANT

WOMEN ALL THE TIME.

AND I DON'T KNOW IF THAT'S AN

ADEQUATE CONTROL THING THEY

AGREE FOT TO GET PREGNANT OR

AGREE -- EITHER SINCE THIS IS A

PHASE 1 HOW IMPORTANT IS IT TO

GET THAT MUCH FEMALE VERSUS MALE

DATA?

I UNDERSTAND THE SENSITIVITY TO

TO GENDER EQUALITY.

IF NOT TRY TO FIND WOMEN WITH

HYSTERECTOMIES, EVEN

UNFORTUNATELY HAVING TUBAL

LIGATION IS NOT A GUARANTEE FROM

PERSONAL EXPERIENCE.

NOT PERSONAL BUT PROFESSIONAL

EXPERIENCE.

SO I'M CONCERNED ABOUT THAT.

I DON'T KNOW IF THAT MAYBE

STANDARD FOR YOUR VACCINE

RESEARCH.

SOMETHING TO BE LOOKED AT.

>> SOMETHING TO BE LOOKED AT BUT

YOU'RE TELLING THE INVESTIGATOR

WHAT HE OR SHE CAN CAN CAN OR

CAN CANNOT DO WITH THE STUDY.

YOU'RE DECIDING IS THIS

SOMETHING THAT -- YOU JUST MADE

AN ARGUE FOR A DIFFERENT

PROPOSAL THAN WHAT IS THE

PREVIOUS PERSON SO THE PREVIOUS

PERSON WE NEED KNOW WHETHER

THERE ARE DIFFERENCES BETWEEN

MEN AN WOMEN, THEREFORE TEN AND

TEN.

WOMEN MIGHT BE AT HIGHER RISK IF

THEY'RE ABLE TO GET PREGNANT.

WE CAN'T TRUST THEY H NOT GET

PREGNANT.

THEREFORE WE SHOULD EXCLUDE THEM

IF THEY'RE OF -- IF THEY CAN

REPRODUCE.

THAT YOUR PROPOSAL?

(OFF MIC)

LIKE LOCK THEM UP IN THE

HOSPITAL?

(OFF MIC)

>> YOUR PROPOSAL IS BE STRICTER

ON THE REQUIREMENTS FOR THE TYPE

OF CONTRACEPTIVE PEOPLE WOULD

HAVE TO USE IN ORDER TO ENROLL

THATCH'S THE PROPOSAL.

(OFF MIC)

>> CAN I GET YOU TO GO TO MIC?

I'M SORRY.

>> I WAS JUST GOING TO SAY THAT

I THOUGHT IT WAS WELL THAT WOMEN

HAD TO BE INCLUDED IN A PHASE 1,

THAT IN THE INFORMED CONSENT

PROCESS THAT COULD BE STRESSED

AS OPPOSED TO EXCLUDING THEM

COMPLETELY.

>> NO LAW SAYS WOMEN HAVE TO BE

INCLUDED IN PHASE 1, CERTAINLY

THE NIH HAS ANY POLICY A

GUIDANCE THAT SAYS WOMEN SHOULD

BE INCLUDED IN CLINICAL

RESEARCH.

AND POLICY IS MUCH MORE SPECIFIC

ABOUT LARGER RANDOMIZED TRIALS.

PHASE 3 TRIALS, EFFICACY

TRIALSCH DOESN'T SAY ANYTHING

ABOUT PHASE 1.

HOWEVER AS WE TALKED ABOUT I

THINK AND WE'LL TALK AGAIN IN

THIS CLASS THERE'S THIS

INTERESTING QUESTION ABOUT

SUBJECTS SELECTION IN TERMS OF

FAIRNESS, HOW DO YOU ENROLL

PEOPLE IN -- WITH THE NOTION OF

FAIRNESS, ONE WAY TO THINK ABOUT

IT IS NOBODY SHOULD BE EXCLUDED

UNLESS THERE'S GOOD REASON.

CERTAIN RISK AND VULNERABILITY.

THE QUESTION IN THIS CASE IS THE

RISK OF HARM TO THE FETUS IF

SOMEBODY WERE PREGNANT, IS THAT

SUFFICIENT TO SAY WE EXCLUDE

PREGNANT WOMEN, WE EXCLUDE WOMEN

WHO CAN GET PREGNANT OR REQUIRE

A STRICT ADHERENCE TO CERTAIN

KINDS OF CONTRACEPTIONS OR DON'T

LET WOMEN IN AT ALL.

THOSE ARE THE THREE'b OPTIONS.

>> I THINK THAT ARGUMENT IS

BASED ON THE ASSUMPTION THAT

WOMEN ARE NOT ABLE TO MAKE AN

INFORMED CONSENT.

IT'S VOLUNTARY, THE INFORMATION

IS PROVIDED SO IF YOU'RE A WOMAN

OF CHILD-BARING AGE I DON'T SEE

WHY THERE HAS TO BE -- THE

CAUTIONS ARE THERE, THEY LAID IT

OUT AND STATED.

IT IS INFORMED CONSENT.

I MEAN, I DON'T THINK THE

ASSUMPTION IS THAT A WOMAN WHO

CAN HAVE INFORMED CONSENT IS NOT

-- THEY CAN'T MAKE DECISION

WHETHER SHE'S GOING TO

PREINVENTORY OR NOT GOING TO GET

PREGNANT.

THE OTHER THING ALONG WITH

SAFETY BECAUSE PART OF THE

PROTOCOL KEEPING A DIARY, WE CAN

ASSUME PEOPLE CAN GET D&O THAT

AND CALL INTO THE DOCTOR WE CAN

ASSUME A WOMAN THAT VOLUNTEERS

AN CONSENT TO BE IN A STUDY CAN

DO THAT.

>> YOU'RE COUNTERING THE OTHER

PROPOSE LES, LET THE WOMAN

DECIDE.

>> RIGHT.

>> SO WE'RE GOING TO VOTE ON

THAT IN A MINUTE.

WHAT ABOUT ANY OF THESE OTHER

THING?

YOU TALK SUBJECT COLLECTION.

INFORMED CONSENT, PLANS FOR

MONITORING PRIVACY AN

CONFIDENTIALITY, ANYBODY WANT TO

SAY ANYTHING ABOUT THOSE THINGS?

YOU'RE ALL HAPPEN HAPPY WITH THE

WAY THEY PROPOSE TO TO DO THAT.

>> LOOKING AT COMPENSATION

PROFILE THAT'S BEING SUGGESTED

STRIKES ME AS A LARGE AM OF

MONEY TO COMPENSATE THESE PEOPLE

AND I WOULD BE WORRIED WHETHER

THAT PRESENTS AN UNDUE

INDUCEMENT AND CAUSES THEM TO

IGNORE RISKS FOR SOME OF THE

RISKS IN THE INFORMED CONSENT

PROCESS SO I ASK THE

INVESTIGATOR TO JUSTIFYkO THAT
WHY

IT'S NECESSARY TO RERECRUIT THE

NUMBER OF PARTICIPANTS HE WANTS

OR OTHERWISE MAYBE THINK ABOUT

REDUCING THE COMPENSATION

SOMEWHAT JUST TO --

>> SO YOU WANT MORE

JUSTIFICATION, OR REDUCTION IN

THE AMOUNT OFFERED OR MORE

ASSURANCE TESTING UNDERSTANDING?

>> RIGHT.

I THINK THE UNDERSTANDING THE

TEST OF UNDERSTANDING ARE

SUFFICIENT, I WOULD BE WORRIED

ABOUT POTENTIAL OF SOMEBODY TO

SAY I'M MAKING I WOULD ALLOW A

LOT OF RISK TO MYSELF THAT I

WOULDN'T OTHERWISE DO.

>> ANYBODY ELSE AGREE?

DISAGREE?

IN THE LAST MINUTE WE HAVE TO

VOTE.

AS YOU MIGHT REMEMBER FROM LAST

WEEK THESE ARE OPTIONS.

SO FAR HERE ARE THE STIPULATIONS

THAT I HEARD PROPOSED.

ENROLL PEOPLE MORE SLOWLY.

NOT EVERY DAY -- NOT ONE A DAY

BUT SPREAD THEM OUT FURTHER.

I THINK WE HAVE TO DECIDE

WHETHER WE WANT TEN MEN AND TEN

WOMEN THAT CAN CONSENT FOR

THEMSELVES OR RESTRICT WOMEN WHO

ARE REPRODUCTIVE AGE IN SOME

WAY.

ARE THERE ANY OTHER -- AND THE

STIPULATION MAYBE THAT WAS JUST

PROPOSED ABOUT EITHER JUSTIFY OR

REDUCE THE AMOUNT OF MONEY.

THAT'S IT.

THREE STIPULATIONS.

DID I MISANY?

EVERYBODY IS HAPPY WITH THOSE?

ONE VACCINE AT A TIME.

CHANGE THE WHOLE STUDY TO BE

JUST ONE.

LET ME SAY ONE THING ABOUT THAT

AS A POINT OF CLARIFICATION.

THE FIRST THING THREE I

MENTIONED COULD BE STIPULATIONS

THAT WE CAN DECIDE TO APPROVE

THE STUDY WITH STIPULATIONS.

IF YOU WANT THEM TO SEPARATE

THEM TEST ONE VACCINE, IT'S

GOING TO EITHER HAVE TO BE A

DEFERRAL OR TABLELING SO THEY

CAN REVISE THE WHOLE PROTOCOL.

THOSE ARE YOUR OPTIONS.

WHO WANTS TO APPROVE WITH NO

STIPULATION?

COUPLE OF PEOPLE.

WHO WANTS TO APPROVE WITH

STIPULATIONS WE JUST TALKED

ABOUT.

MOST OF YOU.

WHO WANTS TO DEFER.

ANYBODY WANT TO TABLE WITH FOR

MAJOR REVISION?

ANYBODY WANT TO DISAPPROVE?

ONE.

DO EITHER WANT A TABLE OR JUST

WANT TO SAY WHY?

WHILE YOU'RE COMING UP I'LL SAY

BASICALLY WHAT JUST HAPPENED IN

THIS ROOM THEN IS THAT WILL

APPROVE STIPULATION.

IN THE MINUTES OF THE IRB WOULD

HAVE TO HAVE ANYBODY WHO VOTED

FOR DISAPPROVAL OR TABLELING

WOULD HAVE TO EXPRESS THEIR

RATIONALE, OTHERWISE THE SLIDES

WILL APPROVE WITH STIPULATION.

GO AHEAD.

REASON, IT IS PAST 11:30 SO IF

ANYBODY HAS TO LEAVE GO AHEAD.

>> I WOULD TABLE THE STUDY

BECAUSE FIRST OF ALL THE SUBJECT

POPULATION THAT'S BEING -- THE

RESEARCH BEING CARRIED ON IS

HERE IN STATE IN ACTUALITY WHEN

THE VACCINE IS TESTED, WHEN YOU

PASS THROUGH ALL THE SAFETY IT

WILL BE USED ON A POPULATION IN

AFRICA.

SO YOU WANT TO LOOK AT --

>> YOU WANT TO PROPOSE PHASE 1

FIRST IN HUMAN PHASE 1 STUDY IN

AFRICA INSTEAD OF BETHESDA?

>> YEAH.

GENE DIFFERENCES, ET CETERA, ET

CETERA.

THEN SO I KIND OF QUESTION THE

SCIENTIFIC VALIDITY THAT IN

OTHER ISSUES AS FAR AS

COMPENSATION THAT COULD BE AN

INDUCEMENT AND I ALSO DON'T

UNDERSTAND, I DON'T KNOW, MAYBE

I DIDN'T GET THE PICTURE RIGHT

BUT I DON'T UNDERSTAND WHY THEY

WOULD TIE IN SEXUAL OR

INACTIVITY WITH THE PROTOCOL, I

DIDN'T GET THAT PART.

THAT SEEMS LIKE -- IT'S A DANGER

TO POTENTIAL -- IS THE REASON.

YOUR FIRST POINT IS ONE THAT WE

DIDN'T DISCUSS, NOBODY BROUGHT

UP EARLIER BUT SOME HAVE IN

PREVIOUS YEARS.

>> IN THAT CASE IT'S NOT --

>> IN THAT CASE OFF VEEP

SOMEWHERE ELSE BESIDES HERE.

>> SO NOT FAIR SELECTION IN THAT

SENSE.

>> WE WILL HAVE A SESSION ON

INTERNATIONAL RESEARCH WHERE

THAT -- MAYBE THAT PROPOSAL CAN

BE ENTERTAINED.

OKAY.

THANK YOU.

SEE YOU NEXT WEEK.I