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IPPCR 2015: Overview of Clinical Study Design

MY NAME IS DR. LAURA LEE

JOHNSON, I'M THE ASSOCIATE

DIRECTOR OF THE DIVISION OF

BIOMETRICS 3 AT THE UNITED

STATES FOOD AND DRUG

ADMINISTRATION.

ALSO ONE OF THE CODIRECTORS FOR

IPPCR.

SO I WANT TO WELCOME YOU FOR

TAKING THIS CASE.

I'M GOING TO GIVE SEVERAL

BIOSTATISTICS CLINICAL DESIGN

LECTURES.

AND I ALSO WANT TO WARN YOU

THERE ARE OVER 6,000 PEOPLE IN

THE COURSE.

FOR THOSE IN FRONT OF ME YOU MAY

SAY WOW, THAT DOES NOT LOOK LIKE

HOW MANY PEOPLE ARE SITTING IN

THIS ROOM.

BUT BECAUSE WE HAVE 6,000 PEOPLE

I DON'T TAKE QUESTIONS DURING

THE LECTURE.

UNLESS I JUST SAID SOMETHING

REALLY STUPID IN WHICH CASE WAVE

ME DOWN.

I PROBABLY ACCIDENTALLY MISSPOKE

T RECENT I DON'T TAKE QUESTIONS

DURING THE LECTURE, YOU ALL HAVE

TO STOP, GET TO THE MICS OF

PEOPLE TRYING TO WATCH THIS, GET

A LOT OF DEAD AIR.

SOMETIMES THEY CAN'T HEAR.

UNLESS YOU REALLY THINK YOU'RE

GOING TO DIE AND NOT BE ABLE TO

UNDERSTAND SOMETHING, PUT ALL

THE QUESTIONS ONLINE.

THIS IS WHAT I PROMISE YOU WHICH

IS I WILL LOG IN ONLINE AND WE

WILL HAVE A REALLY ROBUST

DISCUSSION ON THOSE DISCUSSION

BOTHERS.

THAT'S WHERE -- BOARDS.

THAT'S WHERE I WANT THE

QUESTIONS TO COME.

NOT ALL THE DIFFERENT LECTURERS

WILL SAY THE SAME THING BUT IT

IS SOMETHING TO THINK ABOUT AS

YOU'RE SITTING THROUGH THE

LECTERS, THAT A LOT OF PEOPLE

ARE WATCHING US IN THE MIDDLE OF

NOWHERE.

THIS IS OUR DISCLAIMER, COURTTY

OF MY WORKING AT THE FDA.

THEY HIRE ME, THEY PAY ME, BUT

THEY ONLY WANT TO TAKE ACCOUNT

OF ANYTHING THAT THEY DECIDE

THEY LIKE AND DISOWN ANYTHING

THAT THEY DON'T LIKE.

FOR THOSE OF YOU THAT ARE IN

FRONT OF ME, I'M GOING TO POST

ALL THESE QUESTIONS ON THE

DISCUSSION BOARD ONLINE.

HOW MANY OF YOU ALL HAVE TAKEN A

CLASS OR HAVE A DEGREE IN

BIOSTAT, EPI, RESEARCH DESIGN?

ANYBODY IN HERE.

>> A FEW PEOPLE.

HOW MANY OF YOU HAVE USED

LOGISTIC REGRESSION IN THE LAST

TEN YEARS?

A FEW MORE HANDS.

HOW MANY HAVE YOU HAVE ALL HAVE

BEEN INVOLVED IN DESIGNING SOME

TYPE OF A PUBLIC HEALTH RESEARCH

PROJECT OUTSIDE A CLASSROOM

ENVIRONMENT?

OKAY.

SOME OF YOU.

HOW MANY HAVE YOU ACTUALLY

ACTIVELY BEEN INVOLVED IN

RUNNING A CLINICAL STUDY OR AN

ANIMAL STUDY?

LABORATORY STUDY OF SOME SORT?

OKAY.

HOW MANY HAVE YOU HAVE DONE DATA

ANALYSIS OUTSIDE THE CLASSROOM

ENVIRONMENT?

SOME OF THE HANDS KEEP COMING.

HOW MANY OF YOU HAVE ACTIVELY

WRITTEN PART OF A CLINICAL

RESEARCH PROTOCOL?

GOOD.

HOW MANY OF YOU HAVE ACTUALLY

HAD TO READ A CLINICAL RESEARCH

PROTOCOL?

AND HOW MANY HAVE YOU READ A

CLINICAL JOURNAL ARTICLE?

THAT WOULD BE THE VAST MAJORITY

OF FOLKS.

WE'RE GOING TO POST THESE

QUESTIONS ONLINE TONIGHT,

TOMORROW MORNING, AND I WANT

EVERYBODY WHO CAN TO ACTUALLY

GIVE AN ANSWER TO THAT, SO THAT

WAY WE'LL ALSO GET TO KNOW EACH

OTHER, WHO IS INVOLVED IN THE

CLASS.

BECAUSE PART OFF WHAT'S REALLY

IMPORTANT HERE IS THERE ARE A

LOT OF DIFFERENT PEOPLE WHO TAKE

THIS COURSE.

FROM ALL AROUND THE WORLD.

AND FOR SOME IT'S THE FIRST

INTRODUCTION, FOR OTHERS, WE

HAVE A PRETTY ADVANCED

UNDERSTANDING OF CLINICAL

RESEARCH.

SO PART OF WHAT I AIM FOR IN MY

LECTURES IS TO GIVE SOME OF THE

TREKS AND THE TIPS AND THE

CONCEPTS THAT I HAVE LEARNED

OVER THE YEARS, FROM THE VARIOUS

INVESTIGATORS I'VE WORKED WITH.

I'M GOING TO GET HITTING THESE

MIKERISHS, I'M SORRY -- MICS,

I'M SORRY.

WE HAVE A NEW SETUP THIS YEAR.

I TALK A LOT WITH MY HANDS.

EVEN THOUGH I TRY TO STAY STEADY

FOR THE CAMERA.

MY GENERAL OBJECTIVES HERE, I

WANT YOU TO BE BETTER CONSUMERS

AS A MEDICAL SCIENTIFIC

LITERATURE.

BECAUSE WHILE THIS COURSE IS

FOCUSED ON PRINCIPLES AND

PRACTICE OF CLINICAL RESEARCH,

THIS PRESIDENTIALS AND PRACTICES -- PRINCI PALS AND

PRACTICES ARE TRUE FOR NON

CLINICAL RESEARCH TOO.

THERE IS A HUGE PUSH RIGHT NOW,

ALSO FROM THE NIH AND MANY OTHER

GROUPS.

YOU'LL SEE MANY JOURNALS THAT

HAVE WRITTEN EDITORIALS SAYING

WE'RE NO LONGER GOING TO ACCEPT

REALLY BAD RESEARCH JUST BECAUSE

ITS PRECLINICAL.

AND ALL OF THESE STUDY DESIGNS,

MANY OF THEM, THEY HAVE

LABORATORY COMPONENTS.

NOT JUST BECAUSE -- MY BIGGEST

RANDOMIZATION PROBLEM HAPPENED

IN SOMEBODY WHO DID NOT

RANDOMIZE ON HER 96 WELL PLATE.

IT CAUSED A HUGE PROBLEM FOR HER

STUDY AND HER INTERPRETATION.

SO I WANT YOU TO BE BETTER

CONSUMERS. I WANT YOU TO BE

BETTER USERS.

AND I WANT TO ENHANCE THE

CONVERSATION INSIDE RESEARCH

TEAM.

AND IT MIGHT BE WITH YOUR STUDY

STATISTICIANS AND EPIDEMIOLOGIES

BUT ALSO WILL BE ACROSS AND

BETWEEN A LOT OF DIFFERENT

FOLKS.

REALISTICALLY, WHAT WE REALLY

WANT IS BETTER SCIENCE.

WITH THE INFORMATION YOU LEARN,

YOU'RE NOT GOING TO BE ABLE TO

DO YOUR OWN STATISTICAL

ANALYSES, LIKE SOME OF YOU

ALREADY CAN DO YOUR STATISTICAL

ANALYSES BASED WHEN YOU'RE

RAISING YOUR HANDS.

IF YOU WANT TO LEARN HOW TO DO

STATS, YOU WANT TO LEARN HOW TO

BE A DATA MANAGER, BREACH YOU

NEED TO GO TAKE -- YOU NEED TO

TAKE DIRECT COURSE WORK IN HOW

TO DO THAT.

BUT THIS AGE YOU TO IMPROVE YOUR

ABILITIES TO CRITICALLY EVALUATE

GRANT APPLICATIONS, PROTOCOLS,

AND THE LITERATURE.

NO ONE IS AN EXPERT IN ANY GIVEN

AREA.

WE DO ALL TRY TO COMBINE OUR

EXPERTISE.

IN THIS WORLD EVERYTHING IS A

TEAM SCIENCE WORK.

BECAUSE IT'S REALLY EASY TO

WRITE THAT YOU'RE STUDIES IS

GOING TO USE A RANDOMIZED DOUBLE

BLIND CONTROLLED PARALLEL ARM

DESIGN AND INTENT TO TREAT

ANALYSIS.

EASY TO SAY SUBJECTS AND

PARTICIPANTS WILL BE CONSENTED.

WHAT YOU ALREADY HEARD FROM THE

FIRST TWO LECTURES AND YOU'LL

LEARN THROUGHOUT THE ENTIRE

COURSE, IT'S REALLY NOT EASY TO

DO IT.

IT'S NOT EASY TO IMPLEMENT AND

MAINTAIN THE INTEGRITY OF YOUR

RANDOMIZATION.

AND PAMELA AND OTHER FOLKS HAVE

WRITTEN IN THE CHAPTER ON

RANDOMIZATION.

A LOT OF THE THREATS TO

INTEGRITY THAT SHOW UP.

VERY WELL MEANING PEOPLE TRYING

TO DO GOOD STUDIES, AND HOW THEY

WERE UNDERMINED.

IT'S HARD TO MAINTAIN BLINDING

AND MASKING.

ONE OF THE TRICKS ONE OF MY

INVESTIGATORS TAUGHT ME, SHE

ACTUALLY MADE BADGES FOR HER

STUDY STAFF AND THEY HAD BLINDED

WITH A LITTLE PERSON WITH A

LITTLE MASK ALMOST LIKE A

RACCOON LOOKING THING.

AND THEN UNBLINDED.

AND ALL OF HER STAFF WORE THESE

BADGES.

BECAUSE SHE WAS DOING A STUDY

WHERE IT WAS A PHYSICAL

INTERVENTION.

PEOPLE KNEW THAT THEY WERE DOING

YOGA, OR THEY WEREN'T DOING

YOGA.

BUT SHE DIDN'T WANT THEM TO TALK

ABOUT IT TO THE PEOPLE WHO WERE

ACTUALLY TAKING THEM THROUGH ALL

OF THEIR STUDY MEASUREMENTS.

THAT WAS AN INNOVATIVE WAY TO

TRY TO PROTECT THE BLINDING.

IT HELPED HER PARTICIPANTS

REMEMBER WHO THEY COULDN'T TALK

TO, BUT THEN WHO THEY NEEDED TO

COMPLAIN TO.

MULTIPLE STUDY ARMS.

HOW DO YOU MAKE SURE YOUR STUDY

ARMS AREN'T BLEEDING INTO EACH

OTHER.

DATA COLLECTION.

HOW DO YOU ACTUALLY MAKE SURE

THAT YOU STANDERIZE YOUR

COLLECTION PROCESS.

WE'LL TALK ABOUT THAT THROUGHOUT

THE SEVERAL LECTURES.

ALSO HOW DO YOU TRANSFER DATA TO

REGULATORY AND OTHER GROUPS.

IT MIGHT BE THAT YOU ARE STUDIES

DON'T FALL ISSUED FDA BUT THEY

MIGHT.

THERE IS A LOT OF REGULATORY

ORGANIZATIONS AROUND THE WORLD.

A LOT OF TIFF RULES THAT YOU

HAVE TO FOLLOW.

BUT MANY TIMES DIFFERENT PEOPLE

WANT YOUR DATA AND EVEN IF NONE

OF THE REGULATORY GROUPS DO,

THIS IS A TIME AND WORLD OF DATA

SHARING AND HOW DO YOU

ADEQUATELY SHARE THAT DATA AND

MAKE SURE IT'S USEFUL TO OTHER

PEOPLE.

THERE ARE A LOT OF DATA

STANDARDS YOU'LL HEAR ABOUT

LATER IN THE WINTER AND THOSE

WILL BE USEFUL FOR YOU, TOO.

BUT THAT'S THE LONG VIEW.

TONIGHT I'LL TALK TIE ABOUT

IDENTIFY STUDY ZONES, EPA,

PUBLIC HEALTH RESEARCH.

WE'LL COVER MOST OF THE

EPIDEMIOLOGY MONDAY.

I'M TALK ABOUT MASKING, BLINDING

DIFFERENT INTERVENTIONS AND

COMPARISON GROUPS.

IF YOU WANT TO KNOW WHAT CHAPTER

THIS IS COVERED UNDER, IT'S

CHAPTERS 19 AND 29.

NOW, YOU'LL NOTICE IN MY

OUTLINE, THERE IS SOMETHING

AFTER THE CONCLUSION.

SO WE HAVE ABOUT 20ISH SLIDES,

NOT QUITE, UNCONFOUNDING AND

EFFECT MOD.

I DON'T KNOW THAT WE'LL COVER IT

BUT I PUT IT IN THIS SLIDE DECK.

WE'LL COVER IT BETWEEN NOW AND

DECEMBER.

KEEP AHOLD OF THEM, PROBABLY

COVER THIS WEEK OR NEXT WEEK.

ALL RIGHT.

CERVICAL CANCER.

WHEN I WAS AT THE UNIVERSITY OF

WASHINGTON, MANY YEARS AGO, A

DOCTOR CAME UP TO ME.

SHE WAS ACTUALLY FROM PERU.

AND AT THAT TIME THE GOVERNMENT

HAD GIVEN MONEY AND SAID WHAT

WAS ONE OF THE NATIONAL PROBLEMS

THEY THEY HAD IN HEALTHCARE?

IT WAS CERVICAL CANCER, ONE OF

THEIR NUMBER ONE KILLERS, WOMEN

THAT WERE OF A ACTIVE

REPRODUCTIVE AGE.

THEY SAID OH, YOU KNOW HOW TO

LOOK FOR CERVICAL CANCER.

DO YOU PAP SMEARS.

WE CAN GIVE MONEY, WE'RE GOING

TO DO PAP SMEARS.

THE DECISION WAS TO DO PAP

SMEARS ON EVERY WOMAN IN PERU

EVERY 2 TO 3 YEARS.

PERU IS VERY MOUNTAINOUS.

THERE ARE PLENTY OF LARGE

CITIES.

THEY SAID WE KNOW HOW TO WORK

OUR PUBLIC HEALTH INFRASTRUCTURE

FOR THIS.

BUT HOW DO WE GET TO ALL OF THE

INDIGENOUS VILLAGES, TO ALL

THESE FAR AWAY PLACES?

THEY DEVELOPED A PLAN.

THIS ACTUALLY WHILE IT WAS

HAPPENING IN PERU, SIMILAR

ISSUES WERE COMING UP IN INDIA

AND SEVERAL OTHER COUNTRIES

AROUND THE GLOBE.

THEY SAID WE WILL HAVE TEAMS AND

THEY WILL GO TO ALL THESE REMOTE

PLACES.

AND THE GOAL WAS BASICALLY THEY

WERE GOING TO GO IN AND IN

SEVERAL DAYS, THEY WOULD SCREEN

EVERYBODY AND IF THEY SAW

DYSPLASIA THEY WERE GOING TO DO

TREATMENT ON SITE.

BASICALLY -- AND FOR OF THESE,

IT WAS LIKE YOU WERE HIKING IN,

LIKE THERE IS NOT -- YOU CAN'T

DRIVE A LITTLE MOBILE SOMEPLACE

TO TO IT.

SO THEN THEY FOUND OUT THEY HAVE

A PLAN TO ACCESS PHYSICALLY BUT

IN MANY OF THESE AREAS, THE MEN

SAID MY WIFE DOES NOT EXIST

BELOW THE WAIST.

NOBODY IS LOOKING AT HER.

MY DAUGHTERS, YOU ARE NOT

LOOKING AT THEM.

SO THEY HAD PROBLEMS IF THEY HAD

ANY MALES THAT WERE SUPPOSED TO

BE PYRIFORMING THE PAP SMEARS.

PERFORMING.

THEY SAID FINE, WE'LL GET WOMEN

TO DO THEM.

BY YOU STILL HAD TO OVERCOME THE

CULTURAL PART OF WHETHER -- EVEN

IF YOU HAD A FEMALE WHO IS GOING

TO BE PERFORMING THE

PROCEDURE, WERE THEY GOING TO BE

ALLOWED TO PERFORM THE

PROCEDURE?

AGAIN, A HUGE CULTURAL ELEMENT

HAD TO BE DEALT WITH ENSOME OF

THESE GROUPS.

SO THEY SAID FINE.

WE THINK WE KNOW HOW TO DO THIS.

WE'RE GOING TO BE ABLE TO GO TO

EVERY WOMAN, EVERY TWO TO THREE

YEARS.

NO BIG DEAL.

IF SHE'S MENSTRUATING, YOU'RE

NOT SUPPOSED TO DO A PAP SMEAR

WHEN SOMEONE IN MENSTRUATING.

CERVICAL CANCER IS SLOW.

WELL, THE PROBLEM WAS THEY FOUND

OUT NEXT TIME THEY GET TO THIS

REMOTE LOCATION, THE WOMAN WHO

WAS MENSTRUATING LAST TIME IS

MENSTRUATING AGAIN.

SO NOW I HAVE AN EVEN LONGER

PERIOD THAT I'M NOT SCREENING

THIS PERSON.

SO THE DOCTOR ASKED US, SHE SAID

CAN I CLEAN THE CERVIX IN

VINEGAR, AND THEN DO THE PAP

SMEAR?

WELL, HERE IS THE PROBLEM.

SO PAP SMEAR, WHAT WE CALL A

DIAGNOSTIC BIO MARKER.

WHAT SHE NEEDED WAS SOMETHING

THAT HAS A HIGH NEGATIVE

PREDICTIVE VALUE.

WHAT DOES THAT MEAN?

IF I TEST NEGATIVE THERE IS A

REALLY, REALLY GOOD CHANCE I

DON'T HAVE CERVICAL CANCER.

I NEEDED TO BE LOST COST.

I'M TRYING TO SCREEN EVERY WOMAN

WITHIN A VERY LARGE AGE RANGE IN

A COUNTRY.

AND I NEED IT TO BE FAST

BECAUSE, AGAIN, I'M TREATING ON

SITE AND THEN MOVING TO THE NEXT

VILLAGE.

I KNOW A LOT OF INFORMATION

ABOUT THAT PAP SMEAR.

I ALSO NEED TO DO IT IN PLACES

WHERE I MAY NOT HAVE

REFRIGERATOR, ELECTRICITY, ALL

THESE ISSUES.

BUT DO I HAVE -- CAN I TRANSFER

ALL THAT INFORMATION ABOUT THAT

PAP SMEAR?

IF I JUST CLEAN THE CERVIX WITH

VINEGAR?

SO WHAT WE REALIZED, WE HAD TO

RUN A TRIAL TO FIGURE THAT OUT.

THAT'S NOT THE TYPE OF TRIAL

YOU'RE NORMALLY THINKING ABOUT.

BUT THESE ARE THE DEEPS OF

ISSUES AND TOWARD THE VERY END

OF THE COURSE WE'LL TALK ABOUT

DISSEMINATION, IMPLEMENTATION.

THESE ARE THE TYPES OF ISSUES

THAT COME UP.

AND IT'S ALSO NOT REALLY WORDED

LIKE A STATISTICAL HYPOTHESIS

TEST.

THIS WAS A STORY, THIS WAS MY

BEING STOPPED IN THE HALLWAY

BEING ASKED A QUESTION.

AND THIS, HOWEVER, IS WHERE MOST

RESEARCH STARTS.

YOU HAVE TO COME UP WITH THE

QUESTION AND A LOT OF TIMES IT'S

A SITUATION TO BEGIN WITH.

AND THERE ARE ARE A LOT OF OTHER

EXAMPLES LIKE. THIS YOU CAN

THINK OF THE I HAVE A GENERAL

STORY, I'LL ALSO ADMIT EVERY

TIME I WALK INTO THIS BUILDING

MY NOSE STARTS TO RUN.

I APOLOGIZE.

CARDIOVASCULAR DISEASE.

LIKE WE HAVE THESE STRANGE

QUESTIONS ABOUT WEIGHT AND

HYPERTENSION BUT WE HAVE TO DIG

DOWN TO WHAT IS THE REAL

QUESTION SOCIETY NEEDS US TO

ANSWER.

WHEN YOU'RE THINKING ABOUT

SOMETIMES THE MODE OF

ADMINISTRATION OR DATA

COLLECTION, IN MOBILE HEALTH WE

SAY OH, I CAN GET ALL SORTS OF

INFORMATION FROM THEIR FACEBOOK

ACCOUNTS, I CAN HAVE THEM USE AN

APP AND PLUG IN INFORMATION.

I CAN TRACK THEIR GPS.

THERE IS A LOT OF INFORMATION WE

CAN GET BUT DOES IT ACTUALLY

ANSWER THE QUESTION WE NEED WITH

THE INTEGRITY THAT WE NEED AND

THE POPULATION THAT WE CARE

ABOUT.

THERE ARE LOTS OF THESE WEIRD

TESTS WE SOMETIMES HAVE TO DO IN

ORDER TO ACTUALLY ACCOMPLISH A

LARGER RESEARCH QUESTION.

AND TO ATTACK A LANER PUBLIC

HEALTH OR MEDICAL PROBLEM.

SO WHAT IS YOUR QUESTION OF

INTEREST?

ARE YOU TRYING TO INTERPRET WORK

IN SOME NEW POPULATION?

ARE YOU TRYING TO MAKE A

DECISION ABOUT AN INDIVIDUAL

CASE?

HOW MANY PEOPLE IN THE ROOM ARE

ACTIVELY CLINICALLY DOING WORK?

A HANDFUL, OKAY.

SO WHAT WE FIND OUT COMPARING

TWO GROUPS OF PEOPLE OR MULTIPLE

GROUPS OF PEOPLE MAY BE VERY

DIFFERENT.

WHEN YOU NEED 250 MAKE DECISIONS

ABOUT AN INDIVIDUAL PATIENT IN

FRONT OF YOU, FOR EACH OF US I

TALK TO YOUR DAD.

WHAT DRUG IS HE GOING TO USE.

THIS DOCTOR TALKS ABOUT THE

PLUSES AND MINUSES OF THESE

THERAPIES.

WHAT, IN THE END, IS THE

DECISION AND HOW DOES IT WORK

FOR HIM?

WE'RE LOOKING AT CHANGES A

POPULATION.

DIABETES MANAGEMENT, A LARGE

PORTION IS TRYING TO SHIFT THE

CURVE OF A POPULATION.

SOMETIMES CLASSILY WE LOOK AT

THOSE DIFFERENCES OF GROUPS IN A

STUDY.

BUT SOMETIMES WE'RE TRYING TO DO

BIOMARKER DEVELOPMENT.

WE HAVE 250 FIGURE OUT WHAT TYPE

OF BIOMARKER.

PEOPLE LOVE BIO MARKERS.

THEY FORGET TO GIVE OUT WHAT THE

BIO MARKER IS FOR SOMETIMES.

ARE YOU TRYING TO DEVELOP A NEW

OUTCOME?

PART OF MY JOB IS A PATIENT

REPORTED OUTCOME LIAISON.

I HELD PEOPLE DEVELOP ENDPOINTS

THAT INVOLVE THE PATIENT VOICE.

THE LEVEL OF EVIDENCE.

WHAT DID THAT WE'RE TRYING TO

ESTABLISH?

ARE WE FIGURING OUT WHAT THE

CURRENT LEVEL OF EVIDENCE IS?

YOU'RE GOING TO HEAR ABOUT MET

EYE ANALYSES AND OTHER TYPES OF

SECONDARY DATA REVIEW.

IS THAT WHAT WE'RE TRYING TO DO

INSTEAD?

REGARDLESS OF WHAT YOU'RE DOING,

ALWAYS REMEMBER THE ANALYSIS

FOLLOWS THE DESIGN.

YOUR QUESTION WILL ALWAYS COME

FIRST.

WE MAY HAVE TO EDIT IT, BECAUSE

IT MAY NOT BE DIRECTLY

ANSWERABLE.

BUT YOUR QUESTION COMES FIRST.

IF AT THE END OF THE DAY THEIR

ANSWERING SOMETHING THAT DOES

NOT ADDRESS YOUR QUESTION YOU

NEED TO SAY HOLD UP, PEOPLE

DESIGNING THE STUDY AND

ANALYZING THE DATA.

THAT IS NOT WHAT WE NEED TO DO.

BECAUSE YOUR QUESTION IS GOING

TO DRIVE THE HYPOTHESES, WE'RE

GOING TO DESIGN THAT

EXPERIMENTAL DESIGN FOR YOUR

STUDY.

IN ORDER TO MAKE SURE WE CAN

TEST THE HYPOTHESIS, WE'RE GOING

TO DO ALL OUR SAMPLING, ALL THAT

DATA COLLECTION IN LINE WITH THE

EXPERIMENTAL DESIGN.

YOUR DATA COMES FROM THE

SAMPLES, WE ANALYZE THE DATA, WE

DRAW CONCLUSIONS, THAT GENERALLY

LEADS TO MORE QUESTIONS AND WE

START OVER.

SOMETIMES I LOOK AT DATA

ANALYSES AND I READ PAPERS AND

I'M LOOK WHO CARES, YOU ANSWERED

A QUESTION THAT WAS ANSWERABLE

BUT IT WASN'T THE QUESTION OF

INTEREST.

SO ALL WE -- THE REASON

STATISTICIANS HAVE JOBS, NOT

JUST BECAUSE WE LIKE TO ANALYSIS

DATE, BUT TO SAY YOU HAVE A NEW,

COOL QUESTION AND WE DON'T HAVE

A METHOD TO DO IT.

SO WE NEED TO DEVELOP THE

METHODOLOGY TO ANSWER THE

PERTINENT QUESTION.

THE OTHER PROBLEM, THOUGH, YOU

NEED TO TAKE ALL YOUR DESIGN

INFORMATION TO A STATISTICIAN

EARLY AND OFTEN.

BECAUSE PART OF OUR JOB IS TO

GIVE GUIDANCE ABOUT SOME OF THE

ASSUMPTIONS FOR THE METHOD AND

TO TRY TO HELP MAKE SURE THAT

WE'RE GOING TO DO THE BEST JOB

POSSIBLE WITH THE FEWEST

SUBJECTS POSSIBLE TO ANSWER A

QUESTION.

BECAUSE, OF COURSE, YOU ASK A

STATISTICIAN HOW THEY RESEARCH A

RESEARCH STUDY.

THEY SAY EVERYTHING IMPACTS THE

STATISTICAL ANALYSIS.

I WILL ALSO SAY THAT'S NOT JUST

MY JOB SECURITY, THAT'S BECAUSE

SOMETIMES AT THE END OF THE DAY

INVESTIGATORS BRING THE

INFORMATION TO ME AND I SAY,

WELL, WE'VE UNDERMINED THE

INTEGRITY OF THE STUDY BY MAKING

THE FOLLOWING DECISION.

SO I CAN'T HELP YOU.

YOU COLLECTED ALL THAT DATA.

AND IT'S BASICALLY WORTHLESS.

YOU DON'T WANT THAT TO HAPPEN.

IT'S NOT GOOD FOR YOU, NOT GOOD

FOR YOUR STUDY TEAM AND NOT GOOD

FOR THE HUMAN BEINGS THAT AGREED

TO PARTICIPATE IN YOUR STUDY.

SO WE'RE GOING TO GO THROUGH A

LITTLE BIT OF VOCABULARY.

NONE OF YOU WANT THAT TO HAPPEN.

YOU DON'T WANT IT TO HAPPEN

BECAUSE YOU'RE HERE LATE AT

NIGHT LISTENING TO ME TALK.

SO WHEN I GO THROUGH VOCABULARY,

PART OF THIS IS TO GET US ON

SIMILAR FOOTING.

WE WILL TALK ABOUT ARMS.

I DO NOT MEAN MY APPENDAGE.

IN CLINICAL RESEARCH WE TALK

ABOUT STUDY ARMS OR SAMPLES OR

GROUPS.

WE USE THESE WORDS FAIRLY

INTERCHANGEABLY.

A LOT OF TIMES WE TALK ABOUT

WANTING TO DEMONSTRATE

SUPERIORITY.

JOHN POWERS TALKED ABOUT THIS A

LITTLE BIT LAST NIGHT.

WE WANT TO DEMONSTRATE

SUPERIORITY, YOU'RE TALKING

ABOUT DETECTING A DIFFERENCE

BETWEEN GROUPS OR BETWEEN

TREATMENTS OR STUDY ARMS.

THE IDEA IS THAT THERE IS A

DIFFERENCE IN SOME WAY, SHAPE OR

FORM.

SOMETIMES WE SAY WE WANT TO

DEMONSTRATE THAT THE DIFFERENT

ARMS ARE EQUALLY OR SIMILARLY

EFFECTIVE.

SO THAT IS AN EQUIVALENCE TRIAL.

SOMETIMES WE WANT TO DEMONSTRATE

THINGS ARE NON INFERIOR.

YOU HAVE TO BE CAREFUL.

SOMETIMES THEY STEP AWAY SO I

HAVE ONE NON INFERIORITY STUDY.

NOW I HAVE A NEW COMPOUND, I

NEED TO SHOW IT'S NOT INFERIOR.

THE FIRST THING YOU SHOWED, I

HAVE DO MAKE SURE IT'S NOT

INFERIOR TO GROUP ONE.

RIGHT?

SO NON INFERIORITY.

YOU CAN ALSO THINK OF THIS WHILE

IT'S NOT EXACTLY THE SAME, KIND

OF LIKE GENERICS.

RIGHT?

WHEN YOU THINK ABOUT EQUIVNESS,

I SOMETIMES THINK ABOUT GENERIC.

I COUGH ABOUT THE SAME AMOUNT

PLUS OR MINES, THAT'S EQUIVALENT

NON INFERIORITY IS IT MAY BE A

LITTLE BIT WORSE.

NOT ENOUGH THAT IT MATTERS.

FIGURING OUT THE MARGIN, BIG,

BIG DIFFICULT PROBLEM.

ALSO, I'M A VERY BAD LADY.

INTERACT AND USE OPATIENT VERSES

PARTICIPANT VERSES SUBJECT.

TRUTH BE TOLD WHAT YOU'RE

SUPPOSED TO DO IS SAY A STUDY

SUBJECT.

THAT HELPS DIFFERENTIATE WHEN

YOU'RE IN CLINICAL RESEARCH

YOU'RE A GUINEA PIG.

I SIGN UP FOR CLINICAL TRIALS, I

RECOMMEND ANYBODY WHO WORKS IN

CLINICAL RESEARCH, SIGN UP FOR

TRIALS.

YOU SHOULD UNDERSTAND WHAT IT

MEANS TO HAVE YOUR DATA POSSIBLY

OUT THERE AND BREACHED.

YOU SHOULD UNDERSTAND WHAT A

PAIN IN THE NECK IT IS TO FILL

OUT ALL THESE FORMS.

UNDERSTAND WHAT THE BURDEN IS.

BUT YOU ALSO SOMETIMES IN

LITERATURE, SOMETIMES MORE IN

THE BEHAVIORAL SOCIAL SCIENCES

RA TALKING ABOUT PARTICIPANTS.

YOU WANT PEOPLE TO FEEL LIKE

THEY'RE PARTICIPATING IN

RESEARCH, ACTIVELY ENGAGED.

I DO A LOT OF MY WORK WITH

PATIENT MEDICAL RECORDS.

SO THEY ARE LITERALLY PATIENTS

THAT WE ARE WORKING WITH.

BUT BECAUSE OF THAT, I HAVE A

TENDENCY TO FLIP IN BETWEEN ALL

THESE THREE WORDS.

WHAT I SHOULD ALWAYS BE SAYING

IS PARTICIPANT AND SUBJECT.

SO SHAME ON ME, DON'T MAKE MY

MISTAKE.

A LITTLE BIT ABOUT STUDY DESIGN

TAXONOMY.

BREAK THE WORLD INTO

INTERVENTIONAL AND OBSERVATIONAL

STUDIES.

INTERVENTIONAL MEANS I DO

SOMETHING TO YOU.

OBSERVATIONAL MEANS I WATCH THE

FILM OF YOUR LIFE.

OR THE PHOTOGRAPH, AS THE CASE

MAY BE.

WE ALSO BREAK THE WORLD INTO

LONGITUDINAL VERSES CROSS

SECTIONAL.

LONGITUDINAL IS THE FILM.

WHEN I LOOK AT YOU AS BASELINE

6, 7, 8 MONTHS, CROSS SECTIONAL

IS I GIVE YOU ALL ONE SURVEY

RIGHT NOW AND WE'RE DONE.

LIKE A STEM CELLS.

WE ASK SOMETHING ONCE, WALK AWAY

OPOST EXPECTATIVE VERSES

RETROSPECTIVE.

I'M GOING TO FOLLOW YOU INTO THE

FUTURE.

TAKE MY DATA REAL TIME.

RETROSPECTIVE MEANS I LOOK BACK

IN THE PAST.

SO I MAY BE LOOKING BACK AT

EMPLOYEE HEALTH RECORDS THAT

WERE GATHERED BY DEPARTMENT OF

DEFENSE OR AN ARMY.

SO RETROSPECTIVE IS LOOKING BACK

AT DATA THAT WAS ALREADY

COLLECTED.

MAY OR MAY NOT HAVE BEEN

COLLECTED THE WAY YOU WANTED IT

OR THE DATA YOU WANTED BUT

YOU'RE USING WHAT'S ALREADY

THERE.

PROSPECTIVE, YOU'RE MOVING

FORWARD AND COLLECTING DATA.

DON'T GET TOO HUNG UP ON THOSE.

BUT IT IS A LITTLE BIT

IMPORTANT.

IT'S LIKE IF YOU WERE

PROSPECTIVELY COLLECTING DATA

AND STORING IT AND YOU GO BACK

AND THAT WOULD YOUR STORED DATA,

STILL A PROSPECTIVE STUDY.

BLINDED, MASKED, SO THIS IS WHEN

THE INVESTIGATOR, THE PEOPLE

RUNNING THE STUDY, THE STUDY

PARTICIPANTS, DO NOT KNOW WHAT

INTERVENTION THEY'RE ON.

SOMETIMES WE ACTUALLY MASK THEM

INSTEAD TO THE HYPOTHESIS THAT

WE'RE TESTING.

SOMETIMES WE DO NOT BLIND OUR

MASK A STUDY AND IT'S CALLED AN

OPEN LABEL STUDY.

FOR SOME OF THE INTERVENTIONAL

TRIALS.

BUT DEPENDING ON WHO ALL IS

BLINDED OR NOT, SINGLE BLIND,

DOUBLE BLINDED, UNBLINDED.

I USED TO DO SOME WORK FOR THE

NATIONAL EYE INSTITUTE.

THEY DO NOT BLINDED, THEY PREFER

MASKS.

YOU CAN UNDERSTAND WHY.

DEPENDING WHERE YOU TRAIN YOU

WILL SEE DIFFERENT NAMES FOR

EACH.

RANDOMIZED OR NON RANDOMIZED.

WE'LL HAVE A LOCAL LECTURE ON

RANDOMIZATION.

PAUL GIVES A GREAT LECTURE ON

THIS.

THE IDEA, HOW AM I ALLOCATING

SUBJECTS?

IS THERE A RANDOM ELEMENT TO IT?

OR CAN I FIGURE OUT WHO IS GOING

TO BE GOING INTO WHICH TREATMENT

GROUP?

BUT REMEMBER KIND OF THIS BASIC,

THAT FIRST BULLET.

KIND OF TWO TYPES OF RESEARCH.

OBSERVATIONAL VERSES THIS KIND

OF EXPERIMENTAL

INHIBITVENTIONAL.

SO THE OBSERVATIONAL, MY GOAL IS

TO OBSERVE AND COLLECT DATA ON

CHARACTERISTICS OF INTEREST

WITHOUT INFLUENCING THE

PARTICIPANT, THE ENVIRONMENT OR

DISEASE COURSE.

I LITERALLY OBSERVE.

I DO NOT WANT TO INTERVENE IN

ANY WAY.

I WANT TO SEE NATURAL.

EXPERIMENTAL IS WHEN YOU'RE --

THE RESEARCHER ARE DELIBERATING

INFLUENCING THE COURSE OF EVENTS

OR AT LEAST YOU'RE HOPING TO,

AND INVESTIGATING THE EFFECT OF

THE INTERVENTION ON SOME

CAREFULLY SELECTED POPULATION OF

SUBJECTS.

SAY OBSERVATIONAL IS INITIALLY

CAREFULLY SELECTED SET OF

SUBJECTS.

WHEN WE DO EXPERIMENTAL STUDIES

ON HUMANS, WE CALL THEM CLINICAL

TRIALS OR CLINICAL STUDIES.

SIMILARLY, THOUGH, A LOT OF THIS

WORK, ALL OF THIS APPLIES TO

ANIMALS.

IT APPLIES TO A LOT OF DIFFERENT

PROJECTS.

SO WE'RE GOING TO COVER

OBSERVATIONAL STUDIES IN DETAIL

NEXT WEEK.

BUT THE GENERAL IDEA HERE IS

THAT YOU MAY HAVE CASE REPORTS

WHICH IS LITERATURE THE DOCTOR

WRITING DOWN A SET OF

INFORMATION, LIKE SOMETHING

LOOKS WEIRD.

I'M GOING TO WRITE IT UP

STRUCTURED TO SHARE IT WITH

OTHER FOLKS.

SEVERAL CASE REPORTS MAKE A CASE

SERIES.

THIS FUNDAMENTAL EPIDEMIOLOGY

101.

ALSO BECAUSE A PHARMACIST

NOTICED SOMETHING LOOKS ODD,

STARTED WORKING ON A SET OF CASE

SERIES AND CASE REPORTS.

THAT WE DISCOVERED, A.

SO YOU USED TO GET CDC NOW

PUBLISHED IT ELECTRONICALLY BUT

YOU HAD MORBIDITY, MORTALITY

WEEKLY REPORTS.

WHEN I WAS IN SCHOOL EVERY

FRIDAY WE WENT TO READ THIS

REPORT TO SEE WHAT LOOKED NEW

AND WEIRD AROUND THE COUNTRY.

WHAT WE SHOULD HAVE OUR EYES

OPEN FOR.

THOSE ARE USUALLY CASE SERIES.

YOU STILL SEE THEM PUBLISHED

TODAY IN A LOT OF JOURNALS.

CROSS SECTIONAL OR PREVALENCE

SURVEYS.

THIS IS A SNAPSHOT PICTURE.

THIS MIGHT BE THE NATIONAL

HEALTH INTERVIEW SURVEY IN THE

UNITED STATES.

CASE CONTROL STUDIES.

WE'LL TALK ABOUT THIS.

USUALLY, YOU GET A SERIES OF

DISEASE CASES AND TRY TO FIND

SOME MATCHED CONTROLS AND FIGURE

OUT WHAT'S DIFFERENT BETWEEN

THEM.

YOU HAVE A REALLY RARE DISEASE,

THIS IS A VERY USEFUL TYPE OF

STUDY TO DO, TRY TO FIGURE OUT A

LIST OF REASONS THAT YOU MIGHT

HAVE DISEASE.

COHORT DISEASED THAT ARE

LONGITUDINAL. -- STUDIES THAT

ARE LONGITUDINAL.

A LOT OF TIMES WHEN WE HAD MAJOR

DISASTERS, WE WILL FOLLOW THE

HEALTHCARE WORKERS OR THE PEOPLE

THAT ARE CLEANING UP THE

DISASTER SITES LONG TERM TO SEE

IF THEY HAVE PSYCHOLOGICAL

ISSUES, IF THEY HAVE RESPIRATORY

RELATED ISSUES.

OTHER PROBLEMS THAT COME UP.

NATURAL HISTORY DISEASED.

YOU MAY HAVE -- HISTORY STUDIES.

YOU MAY HAVE A GROUP OF

PATIENTS, AND YOU'LL FOLLOW

THEM, SEE HOW THEY AGE, HOW

THEIR CITIES PROGRESSES.

THE NIH AT THE CLINICAL CENTER

DOES QUITE A FEW OF THESE.

THEN THE HE CAN LOGICAL STUDIES.

THIS IS DATA ON A POPULATION

RATHER THAN INDIVIDUAL LEVEL.

LIKE I SAID WE'LL TALK MORE

ABOUT THESE NEXT WEEK.

THEN WE HAVE THESE KIND OF --

SOME GROUPS CALL THEM QUAZ

SIEXPERIMENTAL STUDIES, THESE

ARE SINGLE ARM NON RANDOMIZED

INTERVENTIONAL STUDIES.

DR. GALLIN TALKED ABOUT SEVERAL

OF THESE WHEN YOU THINK ABOUT

HIS HISTORICAL LECTURE.

YOU DON'T HAVE A CONTROL GROUP.

THEY TEND TO BE EARLY IN THE

INVESTIGATION.

SOMETIMES YOU MAY HAVE A

CONCURRENT CONTROL GROUP SO I

MAY DECIDE I'M GOING TO BATHE

ONE SIDE OF THE HOLE IN MY

HOSPITAL BUT NOT BATHE THE OTHER

SIDE OF THE HALL.

YOU CAN DO SOME WEIRD

INTERESTING THINGS BUT I'M NOT

RANDOMLY CHOOSING IT.

I JUST KIND OF ALLOCATE IT.

THEN YOU SOMETIMES HAVE THINGS

CALLED HISTORICALLY CONTROLLED

STUDIES.

PAEDIATRIC ONCOLOGY WE USED TO

DO THESE WHERE PATIENTS THAT --

WE BASICALLY ONLY HAD ENOUGH

PATIENTS.

EVERYBODY ON THE THERAPY.

SO WE SAID, WELL, WE'LL USE OLD

PATIENT INFORMATION AS KIND OF

OUR CONTROL GROUP.

SO THAT EARLY INTERVENTION BASED

RESEARCH SPECTRUM.

I TALK ABOUT EPI.

SOMETIMES IT'S INTERVENTIONAL,

SOMETIMES NOT.

BUT THAT QUASI EXPERIMENTAL,

PRECLINICAL STUDIES, PHASE 0,

THOSE ARE EARLY STUDIES.

THAT ALL OF THIS IS SETTING THE

FOUNDATION FOR TRYING TO DO

WHAT'S A PHASE 1 DECIDE OR THOSE

DOSE FINDING STUDIES MANY TIMES.

IN THIS PATIENT POPULATION,

WHAT'S TOLERABLE?

AND WHAT MIGHT BE SYSTEMS WE

ALSO LOOK TO SEE EARLY EFFICACY

THERE.

OR AT LEAST SOME CHANGE THAT

SAYS WE MIGHT THINK WE'RE -- WE

HAVE EFFICACY DOWN THE LINE.

THESE EARLY AND LATE PHASE 2

STUDIES, WE'RE LOOKING A LOT AT

SAFETY LIKE WE ARE IN PHASE 1

BUT STARTING TO GET A BETTER

IDEA OF THE DOZE, A BET IDEA OF

HOW TO DELIVER A MEDICATION.

OR SOME TYPE OF MEDICAL PRODUCT

OR THERAPY.

WE'RE TRYING TO GET AN IDEA OF

WHO SHOULD BE IN THESE STUDIES,

AND NOT.

PHASE 3 OR WHAT WE TYPICALLY

CALL PIVOTAL TRIALS.

THESE ARE YOUR MAJOR LARGE

EFFICACY STUDIES.

PHASE 4 FOR ME IN THE FDA WORLD

IS POST MARKET.

SO WE'VE KIND OF DECIDED THERE

IS EFFICACY, BUT IF I PUT THIS

OUT IN THE GENERAL POPULATION,

DO I STYLE SEE SAFETY AND

EFFECTIVENESS?

YOU ALSO GET INTO THESE

DISSEMINATION AND IMPLEMENTATION

STUDIES, GREAT.

YOU THINK THAT IF YOU MAKE THIS

CHANGE YOUR HOSPITAL PROCESS

THAT YOU WILL IMPROVE -- LET'S

SAY IT'S RATE OF SOME TYPE OF

HOSPITAL ACQUIRED INFECTION.

YOU'VE DONE THIS AT YOUR VERY

RIGOROUS FOCUS HOSPITAL.

IS THAT GOING TO WORK IN THE

MIDDLE OF NOWHERE HOSPITAL?

OR A BUSY PUBLIC HOSPITAL?

DISSEMINATION IMPLEMENTATION IS

CAN I TAKE ALL OF THE

INFORMATION ABOUT HOW TO DELIVER

A THERAPY AND HOW DELIVERING

INTERVENTION, AND ACTUALLY DO IT

EVERYWHERE IN THE REAL WORLD?

YOU ALSO, THEN, SEE COMPARATIVE

OR COST EFFECTIVENESS STUDIES.

SO THERE IS A LARGE STUDY DONE

MANY YEARS AGO BY THE NATIONAL

INSTITUTE OF MENTAL HEALTH, THEY

TOOK SEVERAL DIFFERENT THERAPIES

WHERE PEOPLE HAD MAJOR

DEPRESSIVE DISORDER.

WE'RE PUTTING THEM HEAD TO HEAD.

THAT'S THE COMPARATIVE STUDY.

BUT YOUR IDEAL STUDY IS A

PROBLEM THAT COMES UP, WE HAVE

THESE IDEALS, RIGHT?

WHENEVER ANYBODY LOOKS A THE

YOUR STUDY DESIGN, THEY'RE GOING

TO SAY I EXPECT TO HAVE A

TREATMENT AND CONTROL ARM.

WHAT ABOUT ALL THOSE STUDIES ON

CONTROL ARMS?

THEY EXPECT YOU TO HAVE A

PARALLEL GROUPS THAT YOU'RE

GOING TO HAVE RANDOMIZED PEOPLE

TO DIFFERENT TWO ARMS OF A STUDY

AND YOU'RE GOING TO WATCH THESE

FOLKS SIMULTANEOUSLY.

WELL, SOMETIMES THAT'S NOT

FEASIBLE.

THEY EXPECT YOU TO LOOK FOR

SUPERIORITY.

DRUG A IS BETTER THAN DRUG B.

WELL, MAIN DRUG A COSTS $30,000

A YEAR.

DRUG B COSTS 30 CENTS.

I MAY BE -- MAYBE IT'S MORE

ACCESSIBLE OR MAYBE THERE ARE A

LOT FEWER SIDE EFFECTS WITH DRUG

B THAN A.

PROSPECTIVE.

THEY EXPECT YOU TO BE FOLLOWING

PEOPLE INTO THE FUTURE.

ONLY 34 PEOPLE IN THE WORLD WITH

YOUR DISEASE.

YOU MAY NOT BE ABLE TO FOLLOW

THEM ALL PROSPECTIVELY IN A

RANDOMIZED PARALLEL ARM STUDY.

THEY EXPECT TO BE DOUBLE BLINDED

AND MASKED.

WELL, WHAT IF YOU'RE DOING

SURGERY VERSUS NON SURGICAL

INTERVENTION?

WE USED TO BLIND THOSE STUDIES

BUT YOU MAY NOT BE ABLE TO BLIND

THEM.

ALTHOUGH SOMETIMES YOU MAY SAY

WHAT AM I TRYING TO LOOK AT?

DO I WANT TO CONTROL FOR ALL THE

RISKS OF OPENING SOMEBODY UP IN

THE EXTRA NEVERTHELESS THEY MAY

GET FROM OPENING AND CLOSING

THEM OR DO I NOT?

WHAT IS YOUR EXACT QUESTION YOU

WANT TO ANSWER?

IF YOU'RE LOOKING AT A PILL

VERSES IV IN A PAEDIATRIC

POPULATION, YOU'RE PROBABLY NOT

GOING TO BE ABLE TO GIVE A FAKE

IV.

AND THEY EXPECT A RANDOMIZED

STUDY.

A LOT OF STUDIES CAN BE

RANDOMIZED IF YOU VENT INVENTIVE

AND YOU'RE WORKING IN THE RIGHT

POPULATION.

NOT ALL STUDIES CAN BE

RANDOMIZED.

IF I WANT TO LOOK AT LONG TERM

ANTI-RETROVIRAL THERAPY IN HIV

PATIENTS, IT WILL BE REALLY HARD

TO RUN A RANDOMIZED TRIAL.

SO WE HAVE THESE GOLD STANDARDS.

SOMETIMES WE HAVE TO EXPLAIN WHY

WE NEED TO BE A LITTLE BIT

[INDISCERNIBLE].

NOW, THE NEXT TWO SLIDES ARE A

HANDFUL OF STUDIES FROM BMJ BACK

IN 2013.

IT WAS ACTUALLY EASY DO LIFT THE

INFORMATION.

YOU'LL SEE ACTUALLY I GIVE A LOT

OF EXAMPLES FOR BMJ.

THAT'S BECAUSE YOU CAN ACCESS IT

PUBLICLY, OPEN FOR ANYBODY IN

THE WORLD.

WHAT I SHOW YOU IS SOMETHING I

WANT YOU ALL TO BE ABLE TO

ACCESS.

IF THERE ARE ARTICLES THAT ARE

NOT PUBLICLY AVAILABLE, WE WILL

PUT THEM UP AS PART OF THE

COURSE INFORMATION ALONG WITH MY

SLIDES.

IN BMJ, THEY HAD FOUR ARTICLES

IN THE RESEARCH SECTION.

THIS ONE WEEK.

NON INVASIVE VERSES INVASIVE

RESPIRATORY SUPPORT, A

SYSTEMATIC REVIEW META-ANALYSIS.

ANOTHER ONE, A MULTIPLE CENTER

RANDOMIZED CONTROL TRIAL

BLINDED.

RESEARCHERS WERE BLINDED.

YOU HAD A POPULATION BASED

COHORT STUDY AND A LARGE SCALE

SURVEY.

A LOT OF DIFFERENT RESEARCH

THERE.

ONLY ONE OF THOSE PROJECTS WAS

RANDOMIZED, DOUBLE BLIND

CONTROLLED TRIAL.

THERE IS A LOT OF DIFFERENT

TYPES OF RESEARCH YOU CAN DO

THAT'S MEANINGFUL.

BUT AS YOU'RE DOING IT, YOU

STILL HAVE TO DISTINQUISH THE

OBSERVATIONAL STUDIES FROM THE

RANDOMIZED STUDIES.

A LOT OF TIMES WE START DOING

THESE ANALYSES OF OBSERVATIONAL

STUDIES.

THINKING THAT THEY WERE A

CONTROLLED RANDOMIZED TRIAL.

BUT THAT TACIT ASSUMPTION OF

RANDOMNESS MAKES A LOT OF OTHER

ASSUMPTIONS WORK IN STATISTICS

LAND.

SO YOU REALLY HAVE TO DO A LOT

OF EXTRA WORK WHEN YOU'RE

ANALYZING OBSERVATIONAL TRIAL

DATA.

THE IDEA IS THAT IN A NON

RANDOMIZED STUDY YOU CAN ONLY

SHOW ASSOCIATION.

YOU'RE NEVER GOING TO KNOW ALL

POSSIBLE CONFOUNDERS.

IN A RANDOMIZED STUDY, YOU CAN

SHOW ASSOCIATION AND CAUSATION.

NOW, IN A WELL DONE NON ADAPTIVE

RANDOMIZATION, WE'LL GET TO THAT

IN A FEW WEEKS, THE UNKNOWN

CONFOUNDERS SHOULD NOT CREATE

PROBLEMS.

IF YOU'RE DOING AN ADAPTIVE

TRIAL, UNKNOWN CONFOUNDERS CAN

CAUSE A ROT OF PROBLEMS. -- LOT

OF PROBLEMS.

IN NON ADAPTIVE STUDIES, NON

ADAPTIVE RANDOMIZATIONS, THE

GENERAL IDEA IS UNKNOWN

CONFOUNDERS SHOULD NOT CREATE

PROBLEMS.

REMEMBER THAT YOUR QUESTIONS ARE

GOING TO COME FIRST.

SO AS YOU MAKE ALL THESE

CHANGES, ALL THESE THINGS THAT

YOU'RE THINKING ABOUT WITH YOUR

PATIENTS, WHAT'S GOING TO WORK,

ARE YOU STILL ANSWERING THE

FUNDAMENTAL QUESTION OF

INTEREST?

SO FOR THIS LECTURE, THE

REMAINDER OF THIS LECTURE WE'RE

GOING TO FOCUS ON INTERVENTION

STUDIES.

ON THE 26th OF OCTOBER WE'LL

TALK ABOUT NOT INTERVENTION

STUDIES AROUND EPIDEMIOLOGY.

WHAT ARE TYPES OF RANDOMIZED

DISEASED?

PARALLEL GROUP IS A CLASSIC

STUDY.

I MENTIONED THAT ALREADY A FEW

TIMES.

WE HAVE A SEQUENTIAL TRIAL, A

LIST OF OTHERS I'LL GO THROUGH

ALL OF THESE.

SO IN A PARALLEL GROUP DESIGN,

THE IDEA IS I'M GOING TO

RANDOMIZE PATIENTS TO ONE OF X

TREATMENTS.

ONE OF TWO, ONE OF FOUR

TREATMENTS HOWEVER MANY.

I'LL LOOK FOR A RESPONSE.

I'M GOING TO MEASURE THEM AT THE

END OF THE STUDY AND JUST

COMPARE HOW IS EVERYBODY AT THE

END OF ONE YEAR, I MIGHT LOOK AT

A CHANGE OR A PERCENT CHANGE.

FROM BASELINE.

SO HOW DID THEY CHANGE BETWEEN

BASELINE AND ONE YEAR?

I MAY LOOK AT REPEATED MEASURES,

MAYBE I ACTUALLY TAKE THEIR

BLOOD PRESSURE EVERY FOUR WEEKS.

I'M GOING TO LOOK AT THE CHANGE

IN SYSTOLIC BLOOD PRESSURE OVER

TIME LOOKING AT A CURVE OF

INFORMATION.

CALLED REPEATED AMERICANERS.

OR LOOK AT A FUNCTION OF

MULTIPLE MEASURES.

IF YOU THINK, BODY MASS INDEX,

BMI, IT IS A FUNCTION OF YOUR

HEIGHT AND WEIGHT.

SO THERE ARE A LOT OF VARIATIONS

ON PARALLEL GROUP DESIGNS.

WE SOMETIMES BUT NOT ALWAYS DO

DOSE TITRATION WITH MULTIPLE

DECIDE ARMS. THIS IS BECOMING

MORE POPULAR.

ESPECIALLY IF IT'S NOT A FIRST

IN HUMAN PRODUCT.

THE IDEA IS YOU WANT TO TITRATE

TO THE MAXIMUM TOLERATED DOSE

WITHIN A GIVEN SUBJECT.

DOSE ESCALATION STUDIES.

WITH A CONTROL ARM THAT YOU'RE

SIMULTANEOUSLY RANDOMIZING TO.

PEOPLE UNDERESTIMATE THE

IMPORTANCE OF CONTROLS IN REALLY

RESEARCH.

IT USED TO BE THE OLD WAY IS YOU

ONLY PUT EVERYBODY ON

INTERVENTION.

BUT ESPECIALLY WHEN YOU HAVE

SUBJECTS THAT A LOT OF BAD

THINGS MIGHT HAPPEN TO THEM, YOU

MAY SAY ONE OF MY SUBJECTS DIED.

IF YOUR SUBJECTS HAVE A 50%

MORTALITY RATE, KIND OF HARD TO

TELL, WAS IT THE TREATMENT OR

THE DISEASE THAT CAUSED THEM TO

DIE?

IF YOU HAVE A CONTROL ARM, EVEN

IN THOSE VERY EARLY STUDIES YOU

CAN START TO TEASE OUT WHAT ARE

THE DIFFERENCES IN THE ADVERSE

VOLUNTEERS IS THIS WHAT ARE THE

DIFFERENCES IN THE DEATH RATES,

ET CETERA?

SOME OF YOU ARE MAKING UGLY

FACES.

TO BE HONEST WITH YOU, THIS IS

REAL LIFE IN CLINICAL RESEARCH.

IF YOU DO INTERVENTIONAL

RESEARCH THERE IS A VERY GOOD

CHANCE YOU WILL KILL PEOPLE.

NOT THAT YOU MEAN TO.

BUT YOU MAY CAUSE HARM.

IF WE KNEW THE ANSWER, IF WE

KNEW THAT PEOPLE WERE OR WERE

NOT GOING TO BE HARMED, OR KNEW

THAT SOMETHING WORKED WE DIDN'T

NEED TO DO THE RESEARCH.

SO THIS IS SOMETHING THAT YOU

HAVE TO KIND OF IN YOUR GUT MAKE

A DECISION YOU'RE WILLING TO DO

OR NOT.

IF YOU HAVE THOUGHTS ABOUT THAT,

STEVEN STRAWS' CHAPTER IN THE

BOOK IS A GOOD ONE TO READ.

DR. STRAWS DIED SEVERAL YEARS

AGO.

HE TALKS ABOUT A PERSONAL

JOURNEY HE HAD WITH ONE OF THE

STUDIES HE DID.

THEY FOUND OUT VERY LATE IN THE

PROCESS, THAT THEY WERE CAUSING

HARM.

AND SOME OF THE PEOPLE THAT

WORKED ON THOSE STUDY DECIDED

THEY HAD TO LEAVE RESEARCH.

LEAVE MEDICINE COMPLETELY,

BECAUSE IT WAS SOMETHING THAT

THEY COULDN'T HANDLE.

IT'S NOT AN EASY THING BUT IT'S

SOMETHING TO CONSIDER.

NOW, BACK TO THE DESIGN.

I MEAN THE WHOLE GOAL OF THIS

COURSE IS TRY TO MAKE IT THAT

YOU HOPEFULLY FIGURE THIS OUT

BEFORE YOU EVER TOUCH A HUMAN

BEING, RIGHT?

YOU DO NOT WANT TO CAUSE HARM.

NOT ALL DOSE ESCALATION AND DOSE

TITRATION STUDIES ARE

RANDOMIZED.

SOME OF THEM, MORE ARE NOT.

IN SEQUEL TRIALS, SEQUENTIAL

TRIALS HAPPEN MORE IN

ENGINEERING.

IF YOU'RE DOING DEVICE

MANUFACTURING, YOU MAY ALSO DO

THIS.

YOU DON'T NECESSARILY HAVE A

FIXED SAMPLE SIZE OR PERIOD THAT

YOU'RE RUNNING THE STUDY.

THIS, OF COURSE, MAKES IT SCARY.

IRBs GO WHAT?

THOSE ARE YOUR INSTITUTIONAL

REVIEW BOARDS OR GROUPS THAT

APPROVE HUMAN SUBJECTS RESEARCH.

THE IDEA OF THE SEQUENTIAL TRIAL

IS THAT IT ENDS WHEN ONE

TREATMENT SHOWS CLEAR

SUPERIORITY OR UNLIKELY ANY

IMPORTANT DIFFERENCE IS GOING TO

BE SEEN.

COMPUTERS, CAPACITIERS, ET

CETERA.

VERY SPECIAL STATISTICAL DESIGN

METHODS ARE NEEDED WHEN YOU DO

THESE TRIALS.

ONE THAT YOU DO SEE COMMONLY

INCLINICAL RESEARCH IS GROUP

SEQUENTIAL TRIALS.

HERE IS WHAT WE'RE GOING TO TALK

ABOUT, TYPE ONE ERROR CAN BE

COMPUTENED.

YOU CAN'T DO THAT EASILY IN THE

STRAIGHT UP TRIALS.

THESE ARE VERY POPULAR, BECAUSE

THEE GROUP SEQUENTIAL TRIALS YOU

ANALYZE YOUR DATA AFTER

CERTAINLY PROPORTION OF THE

RESULTS OR INFORMATION FROM THE

TRIAL IS AVAILABLE.

THERE IS EARLY STOPPING,

DEPENDING ON HOW YOU SET THIS

UP.

IF ONE TREATMENT ARM IS CLEARLY

SUPERIOR, FIT LOOKS LIKE THERE

IS FUTILITY -- IF YOU GOT TO THE

END HAVE TRIAL YOU'RE STILL NOT

GOING TO HAVE SIGNIFICANT

RESULTS, MIGHT AS WELL STOP NOW.

YOU MAY ALSO STILL STOP FOR

ADVERSE VOLUNTEERS.

SO ALL TRIALS SHOULD BE

MONITORED TO SEE IF THEY NEED TO

BE STOPPED.

WE'LL TALK ABOUT THAT IN THE

SECOND PART OF THE COURSE.

THIS TAKES A LOT OF REALLY

CAREFUL PLANNING AND STATISTICAL

DESIGN WORK.

IT WILL IMPACT YOUR SAMPLE SIZE.

SO YOU HAVE TO ROLE THE FACT

THAT YOU'RE GOING TO BE

ANALYZING YOUR DATA BEFORE THE

STUDY IS DONE INTO THE PLANNING

OF THE STUDY INITIALLY.

BUT THIS IS AN EXAMPLE THAT WE

HAD FROM A TRIAL FROM NIAID, A

VERY OLD EXAMPLE.

THAT WAS ONE OF THE FIRST

STUDIES DONE IN PREGNANT WOMEN.

AT THE FIRST IN THE TRIM

ANALYSIS WHERE OH OH INTERIM

ANALYSIS, THE DATA

SAFETYMANTERING BOARD SAW THIS

PICTURE.

WE'RE GOING TO BACK TO THIS IN

THE SURVIVAL ANALYSIS LECTURE.

THIS WAS A RANDOMIZED TRIAL.

THEY RANDOMIZED THE MOTHERS TO

TAKE THE DRUG OR PLACEBO.

AND THEN THEY LOOKED AT THE

PROBABILITY OF TRANSMISSION OF

HIV TO THE INFANTS.

AND YOU CAN SEE HOW THE STUDY

ARMS WORKED OUT. THIS IS A

KAPLAN MEIER CURVE ON THE

SCREEN.

AND THEN THERE IS A P VALUE

ASSOCIATED WITH IT.

BUT A LOT OF WORK WENT INTO

TRYING TO DECIDE WHAT SHOULD THE

INTERVENTIONS BE?

WHAT SHOULD THE POPULATION BE?

WE -- THIS CLINICAL TRIAL GROUP

PROTOCOL 076 WAS LOOKING AT

SAFETY AND EFFICACY AND

PREVENTING TRANSPORTATION

MISSION OF HIV FROM INFECTED,

NOT NECESSARILY ADVANCED WOMEN,

TO THEIR BABIES.

NOW I HAVE TO FIGURE OUT, I HAVE

A DIFFERENT POPULATION.

NOT NECESSARILY ADVANCED.

GOT TO WORRY ABOUT NOT ONLY MOM,

GOT TO WORRY ABOUT INFANT.

BECAUSE MAYBE THEY DON'T GET HIV

BUT THEY HAVE SOME OTHER

HORRIBLE PROBLEM THAT HAPPENS TO

THEM.

YOU'VE GOT TO THINK ABOUT WHAT

ARE THE RAMIFICATIONS?

OF GIVING A DRUG TO SOMEBODY,

ESPECIALLY IF IT'S A PREGNANT

WOMAN OR IF IT'S A MALE WHO

MIGHT IMPREGNATE SOMEBODY.

THAT'S A LITTLE TRICK THEY

FORGET TO TELL YOU ABOUT.

EVERY ONE THINKS ABOUT LACTATION

AND PREGNANCY.

THEY FORGET THE GUY.

SO PREVENTING HIV TRANSMISSION,

THEY HAD TO POWER THIS STUDY TO

DETECT A 33% REDUCTION IN THE

TRANSMISSION RATE.

THE PLACEBO RATE, NORMAL NATURAL

HISTORY, I SHOULD SAY, RATE OF

TRANSMISSION WAS 30 PERCENTS.

THEY WANTED TO DROP IT TO 20

PERTS.

SO THIS STUDY THEY PLANNED WAS

GOING TO ACCRUE OVER 5 YEARS,

THEY EXPECTED 15% DROOP OUT.

SOME OF THE FOLKS WOULD NOT BE

ABLE TO FOLLOW THE ENTIRE TIME

FOR VARIETY OF REASONS.

INFANTS DIE FOR A LOT OF

REASONS.

SOMETIMES MOMS AND INFANT.

THEY GO SOMEWHERE ELSE.

YOU CAN'T TRACK THEM.

YOU HAVE TO THINK ABOUT ALL THIS

WHEN YOU'RE TRYING TO DESIGN

YOUR TRIAL.

ALSO, HIV TESTING, NOT ALL THAT

GREAT.

SO THEY HAD TO FIGURE OUT WHAT

WAS IN FACT A POSITIVE TEST.

IN ORDER TO DECIDE THAT THEY HAD

AN EVENT.

ANOTHER TYPE OF STUDY IS A CROSS

OVER DECIDE.

IN A CROSS OVER STUDY, LET'S SAY

TREATMENTS.

I'M GOING TO HAVE A TWO PERIOD

CROSS OVER.

EACH PATIENT ACTS AS THEIR OWN

CONTROL.

TRICK HERE IS THAT YOU NEED TO

ELIMINATE CROSS OVER EFFECTS.

SO IF I'M GOING TO HAVE YOU ALL

USE AN ASTHMA INHALER THAT,

THEN, CHANGES YOUR LONG

STRUCTURE IN SOME WAY, CHANGES

YOURSELF, I PROBABLY AM NOT

GOING TO WASH THAT OUT.

AT LEAST NOT FOR A WHILE.

I TEACH YOU MEDITATION.

I CAN'T -- I CAN'T UNTEACH IT

FROM YOU.

SOME THINGS YOU CANNOT DO IN A

CROSS OVER TRIAL.

BUT THE IDEA IS THAT A LOT OF

THINGS YOU CAN'T.

SO THE WOMEN'S ALCOHOL STUDY, WE

DID A 3, 8 WEEK DIETARY PERIOD.

EACH WOMAN WAS RANDOMIZED DO THE

ORDER IN WHICH THEY TOOK IN

DIFFERENT DOSES OF ALCOHOL.

30 GRAHAMS OF ALCOHOL A DAY,

ABOUT 2 DRINKS, 15 GRAHAMS A

DAY, ONE TRIANGLE.

0-GRAMS.

THEY GOT AN ALCOHOL FREE

BEVERAGE.

BASICALLY, THEY GOT ORANGE JUICE

AND EVER CLEAR.

THE ORDER OF THE ASSIGNMENT OF

THE THREE ALCOHOL LEVELS WAS

RANDOM.

SO THAT IS THE PART THAT GOT

RANDOMIZED.

EACH WOMAN GOT EACH OF THESE

THREE DOSES.

WHY?

WE EACH HAVE A DIFFERENT SET OF

HORMEANS, DIFFERENT

CARDIOVASCULAR RISK FACTORS.

AND WE'RE TRYING TO LOOK AT A

LOT OF CANCER RISKS.

IT'S BETTER DO IT INSIDE A

PERSON AND THEIR OWN DO THE, ALL

THEIR OWN STUFF THAT THEY ARE

BRINGING OUTSIDE OF THE ALCOHOL.

WE HAD WASHOUT PERIODS.

BECAUSE IT WAS SUCH A LONG STUDY

WE VARIED THE WASH OUT PERIOD.

WE HAD ONE GROUP OF PEOPLE,

PEOPLE PACKING THE LUNCH AT USDA

AND DINNER.

EVERY NIGHT THEY HAD A SNACK.

THAT INCLUDED THIS BEVERAGE.

AND THEY WERE TOLD TAKE IT AT

THE END, BEFORE YOU GO TO SLEEP,

DO NOT DRIVE, BLAH, BLAH, BLAH.

BUT YOU HAVE DIFFERING WASHOUT

PERIODS.

AND SOMETIMES WE HAVE THE SAME

WASHOUT PERIOD.

BUT AT LEAST WITH ALCOHOL WE

KNEW HOW LONG IT TOOK TO GET IT

OUT OF THE SYSTEM.

AND THIS WAS A DOUBLE BLIND

STUDY.

THE INVESTIGATORS WHO WERE CRAIG

THEIR BLOOD AND CHECKING THEIR

BLOOD PRESSURE 3 TIMES A WEEK,

THEY DID NOT KNOW WHAT THIS

PERSON WAS ON.

THE WOMEN DID NOT KNOW WHAT THEY

WERE ON.

SOME OF THEM SAID THEY THOUGHT

THEY KNEW THEY WERE GETTING

DRUNK AT NIGHT.

AND THIS WAS ACTUALLY IN A

WASHINGTON POST ARTICLE ON THE

STUDY.

AND SO AFTER THE STUDY WAS OVER,

THE PI SAID -- LOOKED BACK TO

SEE IF SHE HAD BEEN TAKING

ALCOHOL OR NOT.

TURNS OUT SHE WAS IN THE PLACEBO

PART OF IT AT THIS TIME IN DIME.

THAT'S ANOTHER TRICK I LEARNED.

PEOPLE WHO THINK THEY'RE HAVING

HUGE VIED EFFECTS, THEY KNOW

THEY THINK WHAT STUDY ARM

THEY'RE ON.

A LOT OF TIMES YOU DON'T.

BUT ANYWAY, SAME GOES FOR THE

CLIPPINGS TRYING TO GUESS WHAT

STUDY ARM SOMEBODY IS ON.

SO THEN YOU HAVE THESE FACTORIAL

DESIGNS.

FACTORIAL DESIGNS, EACH LEVEL OF

THE FACTOR OR TREATMENT OR

OCCURS WITH EVERY OTHER FACTOR.

SO THIS WAS A STUDY THAT MY NCI

COLLEAGUES WORKED ON.

WHERE THEY RANDOMIZED PEOPLE.

YOU EITHER GOT SALENIUM PLACEBO,

AND ANOTHER MR. OBAMA OR A

COMBINATION.

SO WHAT YOU'LL NOTICE IS THIS

BOTTOM BOX.

CELECOXIB ONLY.

THIS IS SELENIUM ONLY.

IN THE BOTTOM CORNER THEY'RE

GETTING BOTH.

HOW DOES THAT WORK?

WELL, IT WORKS IF YOU DONE THINK

THAT SELENIUM AND CELECOXIB

INTERACT, PARTICULARLY IN

RESPECT TO YOURO.

OUTCOME.

WHEN YOU DO THE ANALYSIS, I

COMPARE EVERYONE IN THE SELENIUM

PLACEBO ARM TO EVERYBODY GETTING

SELENIUM REAL.

IGNORING WHAT CELECOXIB THEY

GOT.

AND I COMPARED ALL THE CELECOXIB

IN THE PLACEBO CELECOXIB TO

CELECOXIB REAL, IGNORING THE

SELENIUM.

PROBLEM IS, A LOT OF TIMES I DO

THESE, AND THEN THE

INVESTIGATORS COME BACK AND SAY

CAN YOU TELL ME IF THERE WAS AN

INTERACTION?

IF YOU CARE ABOUT THAT

INTERACTION, IF YOU EXPECT IT

MIGHTPIST, YOU NEED 250 DO A 4

ARM STUDY.

NOT -- SO YOU CAN DESIGN -- IT

CAN LOOK LIKE THIS.

BUT WHEN YOU POWER THE STUDY,

YOU CANNOT POWER THE STUDY

ASSUMING THAT THESE TWO

INTERVENTIONS ARE INDEPENDENT OF

EACH OTHER.

SO YOU'VE GOT TO MAKE A

DECISION.

2, 2 ARM STUDIES OR 4 ARM STUDY.

THE MS FINANCIAL PLANNER STUDY

ALSO USED A -- MS FLASH STUDY --

THERE ARE A LOT OF THINGS I

DON'T LIKE ABOUT THE MS NASH

STUDY, BUT HEAR IT'S NOT EVENLY

RANDOMIZED.

THEY SAID WE'RE NOT GOING TO

COMPARE YOGA TO AEROBIC

EXERCISE.

THEY WERE COMPARING EACH TO

USUAL ACTIVITY.

WE'RE NOT GOING TO COMPARE THESE

THREE ARMS BUT THEY HAVE AN

UNEQUAL RANDOMIZATION BETWEEN

THE STUDY GROUPS TO ACHIEVE THE

STATISTICAL POWER THEY NEEDED.

THEN YOU RUN INTO THINGS LIKE

INCOMPLETE, PARTIAL, OR

FRACSHUNAL TRIALS.

DEPENDING WHERE TRAIN IT'S

LABELED ONE OF THESE THREE.

NUTRITIONAL INTERVENTION TRIAL

IS AN EXAMPLE.

THEY HAD 4 DIFFERENT TYPES OF

MICRONUTRIENTS THEY WERE LOOKING

AT.

WHAT THEY DID, THEY DIDN'T WANT

TO LOOK AT ALL POSSIBLE

INTERACTIONS.

THIS STUDY IN TEND, I WANT TO

SAY, HAD MANY LIKE 30 THOUGH, 20

PLUS THOUSAND PEOPLE IN IT.

YOU WILL SEE GROUPS THAT WILL DO

THIS, CHOOSES CERTAIN

COMBINATIONS TO LOOK AT AND YOU

HAVE DO MAKE SURE THAT YOU HAVE

THE ONES IN THERE THAT YOU NEED

IN ORDER TO DO THE ANALYSIS YOU

CARE ABOUT.

THE PROBLEM IS, YOU KNOW, IN THE

END PEOPLE WANT YOU TO LOOK AT

CERTAIN INTERACTIONS THAT YOU

DON'T HAVE IN, THERE CERTAIN

COMBINATIONS YOU DON'T HAVE.

YOU DO HAVE TO THINK PRETTY HARD

AND ADVANCED ABOUT WHAT YOU WANT

TO LEAVE OUT.

I'M GOING TO SPEND SEVERAL

MINUTES ON ADAPTIVE DESIGNS.

THEY'RE GAINING A LOT OF

POPULARITY.

MAYBE YOU HAVE 2-8 DIFFERENT

ARMS.

SOMETIMES THERE IS RANGE DOSE

RANGING, SOMETIMES NOT.

PEOPLE THINK YOU HAVE -- AND

YOU'LL SEE IT IN THESE CLINICAL

JOURNALS.

IF YOU DO ADAPTIVE DESIGNS,

YOU'LL HAVE A SMALL MUCH OVERALL

SAMPLE SIZE.

SOMETIMES YOU HAVE A LARGER

OVERALL SAMPLE SIZE.

BUT AT LEAST YOU'RE ABLE TO DO

IT IN ONE TRIAL.

A LOT OF THESE HAVE KIND OF A

RUN IN PERIOD AND YOU START TO

ANALYSIS DATA CONTINUOUSLY OR AT

6 POINTS. -- FIXED POINTS.

FOR ANY ADAPTIVE STUDY AND THERE

ARE LIKE 30 PLUS DIFFERENT

VERSIONS, YOU NEED TO BE CLEAR.

WHAT IS BEING ADAPTED?

THE NUMBER OF PEOPLE IN EACH

STUDY ARM?

IS IT SOMETHING ABOUT THE

RANDOMIZATION?

LIKE THE CHARACTERISTICS OF

PEOPLE, THE INTERVENTION

THEMSELVES?

WHAT IS BEING ADAPTED?

WHEN ARE YOU GOING TO ADAPT IT?

AND BASED ON WHAT EVIDENCE DOES

THIS ADAPTATION TAKE PLACE?

WHO DECIDES AN ADAPTATION IS

NEEDED?

AND HOW IS IT IMPLEMENTED?

SO THIS IS A SLIDE FROM ONE OF

PAUL'S LECTURES THAT HE GOT FROM

PAUL GALLOW, WHO IS IN THE

PHARMA WORKING GROUP.

BASICALLY, THE IDEA WITH

ADAPTIVE DESIGNS IS THIS IS A

CLINICAL STUDY DESIGN THAT USES

ACCUMULATING DATA FROM YOUR

TRIAL TO DECIDE HOW TO MODIFY

ASPECTS OF THAT SAME TRIAL, AS

IT CONTINUES.

BUT THE TRICK IS YOU'VE GOT TO

DO THIS IN A WAYS THAT DOESN'T

UNDERMINE THE VALTY INTEGRITY OF

THE TRIAL.

NOW, IF YOU LOOK AT MY EMPLOYERS

WORK ON THIS, WE'LL ALSO SAY AN

ADAPTIVE DESIGN IS DEFINED AS A

STUDY THAT INCLUDES

PROSPECTIVELY PLANNED

OPPORTUNITIES FOR MODIFICATION

OF ONE OR MORE ASPECTS OF THE

STUDY DESIGN AND HYPOTHESES

BASED ON ANALYSIS OF DATA

USUALLY INTERIM DATA FROM

SUBJECTS IN THE STUDY.

ONE OF MY STUDIES, THEY WANTED

TO DO ADAPTIVE STUDY.

WE THOUGHT IT WAS A GOOD IDEA.

THEN WE FOUND OUT BASICALLY HAD

TO FOLLOW PATIENTS FOR 3 YEARS

BEFORE THEY HAD ANY GOOD

INFORMATION.

ON THEIR OUTCOMES.

THEY WERE GOING TO ENROLL OVER A

4 YEAR PERIOD.

SO THE QUESTION WAS, WHAT TYPES

OF ADAPTATIONS MADE SENSE?

LIKE MAYBE WE COULD LOOK EARLY

TO DECIDE IN FACT PATIENTS

SHOULD FINISH THE TRIAL, BUT WE

HAD TO ACTUALLY GET SOME OF THAT

LONG TERM DATA IN ORDER TO MAKE

THAT DETERMINATION.

YOU HAVE TO THINK ABOUT WHAT

ADAPTATIONS MAKE SENSE.

DOES IT ALSO MAKE SENSE TO ADAPT

RANDOMIZATION, MIGHT MAKE SENSE

TO STOP EARLY.

SO YOU HAVE A ADAPTIVE

RANDOMIZIZATIONS, ADAPTIVE DOSE

FINDINGS WHERE WE MAY TURN ON

AND OFF DIFFERENT DOSES BASED ON

CHARACTERISTICS WE'RE SEEING.

DROP THE LOADSER PICK THE

WINNER.

YOU HAVE TO BE CAREFUL, THERE IS

REALLY BAD EXAMPLES WHERE THEY

MADE A DECISION TO DROP A STUDY

ARM BUT THAT ONLY -- THAT ARM

ONLY HAD ONE PATIENT IN IT.

IT WAS THE PATIENT THAT WAS THE

SICKFULIST OF EVERYBODY.

THAT'S KIND OF A PROBLEM.

WE ALSO DO THESE ADAPTIVE

SEAMLESS PHASE 2 AND 3 TRIALS.

BIOMEDICALER ADAPTER TRIALS.

SOMETIMES BASED ON THE BIO

MARKER WE MAY PUT YOU IN

DIFFERENT STUDY ARMS OR MAY

CHANGE YOUR STUDY ARM.

YOU HAVE SEQUENTIAL METHODS

REALISTICALLY THAT GROUP

SEQUENTIAL PARALLEL DESIGNS THAT

I TALKED ABOUT AT FIRST IS

BASICALLY AN ADAPTIVE TRIAL.

WE ALSO DO THESE SAMPLE SIZE

RECALCULATIONS.

WE'LL TALK ABOUT VARIANTS AND

ISSUES LIKE THAT, HOW YOU CAN

USE TO -- USE -- A LOT OF FOLKS

LIKE ADAPTIVE TRIALS.

THIS IS NOT NILLY WILLIE T RULES

HAVE TO BE PRESPECIFIED IN THE

PROTOCOL.

CHANGES ARE MADE BY DESIGN.

THIS IS NOT AD HOC.

BECAUSE YOU SEE SOMETHING AND

YOU WANT TO MAKE A LITTLE

CHANGE.

THIS IS NOT A WAY TO FINANCE A

BADLY DESIGNED TRIAL.

FIX A BADLY DESIGNED TRIAL.

GOING DOWN THE TUBES, YOU WANT

TO FIX IT.

THAT THE OAGS A SALVAGE

OPERATION.

NOT AN ADAPTIVE DESIGN.

ADAPTIVE DESIGNS REQUIRE A LOT

OF UNDERSTANDING.

THEY ARE HARD TO DO FOR

INVESTIGATORS, REVIEWERS, DSMB

MEMBERS, JOURNAL EDITORS.

NOT ALL STATISTICIANS KNOW HOW

TO DO ALL OF THEM.

THERE ARE A LOT OF ADVANTAGES

AND DISADVANTAGES.

YOU ACTUALLY -- WHILE YOU HAVE

FLEXIBILITY, IT COMES AT A

PRICE.

YOU NEED A LOT MORE

QUANTIFICATION OF STATISTICAL

RISK.

YOU HAVE TO UNDERSTAND MORE

INFORMATION TO ACTUALLY PLAN

THESE ADAPTATIONS.

A LOT OF THEM HAPPEN AND THEY

HAPPEN BATED ON STATISTICAL

RULES.

IT WILL BE FOLLOWING THE DATA

AND MAKE A CHANGE.

YOU DON'T MAKE A DECISION THAT

IT SHOULD MAKE A CHANGE.

THAT MEANS YOU HAVE TO KNOW WELL

ENOUGH WHAT MIGHT HAPPEN.

YOU ALSO HAVE THESE COVARIATE

EMBALLS.

I MENTIONED HOW THE CONFOUNDERS

ARE NOT A PROBLEM UNLESS YOU

HAVE AAN CAPTIVE RANDOMIZATION.

THIS IS PART OF YOUR PROBLEM.

IT'S A LOT MORE WORK UP FRONT.

BUT THEY CAN BE VERY USEFUL.

IF YOU HAVE THE INFORMATION.

YOUR BIG NEGATIVE FOR ANY TRIAL,

THOUGH, IS THAT WHENEVER YOU

MAKE A DECISION TO CONTINUE OR

TO MAKE A CHANGE, THAT

INFORMATION ABOUT THE STUDY MY

BE PROVIDED TO INVESTIGATORS,

THE PUBLIC, INVESTIGATORS, WHEN

YOU HAVE A DATA SAFETY

MONITORING MEETING AND DECIDE TO

CONTINUE A TRIAL, IT CAN CHANGE

STOCK PRICES.

THAT IS VERY SAD BUT VERY TRUE

AND PROBLEM THAT WE HAVE TODAY.

SO ENRICH ENROLLMENT DESIGN.

THIS IS AIERIANT OF CROSS OVER

END OF ONE STUDIES.

N OF ONE IS WHEN I TAKE A

PATIENT AND RANDOMLY DECIDE WHEN

TO ASSIGN THEM.

EXPANDED CROSS OVER STUDY BUT

WITH A GIVEN PATIENT.

ENROLLED ENRICHMENT DESIGNS I

TRY TO IDENTIFY POTENTIAL

RESPONDERS TO THE TREATMENT.

I ENTER THE RESPONDERS INTO A

SECOND PROSPECTIVE COMPARISON

STUDY.

AND PEOPLE THINK THIS IS GREAT.

I HAVE A BETTER CHANCE OF A WIN.

ACCEPT THIS IS NOT GENERALIZABLE

TO YOUR GENERAL PATIENT

POPULATION.

SOMETIMES, THOUGH, CLINICIANS

TELL ME, WELL, IT ACTUALLY IS.

I ACTUALLY TRY MY PATIENTS THAT

THEY SEEM TO BE RESPONDING.

WE STAY ON THE DRUG.

IF THEY DON'T, I SWITCH THEIR

DRUG.

WELL, AGAIN, YOU NEED TO THINK

ABOUT EVERY CLINICAL TRIAL

WITHIN LARGE SITUATIONS.

HOW ARE YOU GOING TO ACTUALLY

IMPLEMENT THIS THERAPY?

AND HOW CAN YOU WORK THAT

IMPLEMENTATION PROCESS INTO YOUR

ACTUAL TRIAL STRUCTURE?

RESULTS TEND TO NOT BE

GENERALIZABLE.

YOU GET THIS THING CALLED

REGRESSION TO THE MEAN. SO THE

PROBLEM WHEN YOU TRY TO ENROLL,

LET'S SAY I HAVE A HOT FLASH

STUDY.

AND I WANT TO ENROLL PEOPLE THAT

ARE HAVING HOT FLASHES TO SEE IF

HE CAN DECREASE THEIR NUMBER OF

HOT FLASHES.

PROBLEM IS I WILL GET -- THEY

WILL BE HAVING TEN HOT NASHS A

WEEK.

I PUT THEM ON THE MAIN STUDY.

RANDOMIZE THEM, AND LIKE IN MY

CONTROL GROUP I'M SEEING 2 HOT

FLASHES A WEEK.

THAT'S BECAUSE A LOT OF TIMES WE

ENTER TRIALS WHEN WE ARE FAIRLY

SING SICK.

IT'S A NATURAL EASTBOUND AND NO

FOR A LOT OF -- EASTBOUND AND

KNOW FOR A LOT OF DISEASE.

THEN WE GO BACK TO NORMAL LOW,

AND NOW MY PEOPLE THAT ARE

TRYING TO ANALYZE THE DATE SAY

WE DON'T HAVE ENOUGH VOLUNTEERS.

I SAW THIS -- EVENTS.

YOU SEE THIS HAPPEN IN A LOT OF

STRAINING STUDIES.

HERPES STUDIES, THEY'RE HAVING

THESE OUTBREAKS, NOW THEY HAVE

NONE.

GOOD FOR THE PATIENTS, NOT GOOD

FOR MY STUDY INVESTIGATOR.

GROUP OR CLUSTER RANDOMIZED

STUDIES.

WE HAVE A UNIT OF RANDOMIZATION

THAT'S NOT THE -- NORMALLY WHEN

WE RANDOMIZE, WE RICHMOND THE

INDIVIDUALS IN THE STUDY.

BUT I WANT TO RANDOMIZE AN

ENTIRE SCHOOL, AND GIVE ALL THE

KIDS IN THAT SCHOOL AN

INTERVENTION, I'M GOING TO

RANDOMIZE A COMMUNITY, VACCINATE

EVERYBODY IN A COMMUNITY, FOR

EXAMPLE, IF I'M GOING TO CHANGE

PRACTICE WITHIN A CLINIC, AND

THEN OBSERVE WHAT HAPPENS TO THE

INDIVIDUALS WHO ARE THE PATIENTS

OR PROVIDERS IN THE CLINIC, THEN

MY UNIT OF RANDOMIZATION IS THE

SCHOOL OR THE COMMUNITY OR THE

CLINIC.

IT'S NOT THE INDIVIDUALS INSIDE

OF IT.

NOW, THIS COULD BE REALLY

IMPORTANT BECAUSE SOMETIMES

YOU'RE TRYING TO MAKE A CHANGE

WHERE I CAN'T GIVE PAMPHLETS OF

INFORMATION IN THE WAITING ROOM

TO ONE PERSON VERSES ANOTHER.

IF WE'RE IN THE SAME WAITING

ROOM THEY CAN ALL PECULIAR UP

PAMPHLETS.

SOMETIMES PROVIDERS SAY IT'S

HARD TO CHANGE MY TREATMENT

ACROSS DIFFERENT PEOPLE.

WHEN THIS IS AN OPEN STUDY.

SO OTHER TIMES ALSO LIKE WE WERE

LOOKING AT CHARGES FOR BED NETS,

THIS WAS A GROUP OUT OF MIT.

EVERY ONE SAID YOU NEED TO

CHARGE SO THAT PEOPLE ARE

FEELING LIKE THEY'RE EMPOWERED,

THEY SPENT THEIR MONEY, USE THE

BED NETS.

AND A COUPLE OF FEMALE

ECONOMISTS WERE SITTING AROUND

LOOKING AT WHAT WAS GOING ON AND

THEY'RE LIKE, NO.

I CAN'T REMEMBER THEIR NAMES BUT

THEY GAVE A REAL GREAT TALK ON

THIS.

AND SO THEY ACTUALLY RANDOMIZED

DIFFERENT CLINICS, DIFFERENT

PRICING STRUCTURES.

SOME CHARGED NONE, SOME CHARGED

DIFFERENT PRICES.

AND THEN THEY LOOKED TO SEE HOW

MANY BED NETS GOT PECKED UP.

OR SOLD.

AND THEN HOW MANY GOT USED.

THEN HOW MANY GOT USED

APPROPRIATELY.

BUT OVERALL THEY SAID ALL THE

OTHER ECONOMIC ANALYSES, LOOK AT

ALL THOSE.

WHAT WE CARE ABOUT IS INFANT

MALARIAL CASES.

THEY LOOKED TO SEE WHAT THE

INFANT MALARIAL CASE COUNT WAS.

PEOPLE WHO BUY A BED NET ARE

MORE LOOK LIKELY TO USE IT.

BUT SO MANY MORE PEOPLE PECKED

UP THE FREE BED NETS THAT THAT,

IN FACT, WAS WHAT LOWERED THE

INFANT MALARIA CASES.

WHAT THEY ALSO DID IS THEY WENT

AND VISITED DIFFERENT HOUSES,

THEY NOTICED THESE BED NETS TAKE

UP THE ENTIRE STRUCTURE.

AND PEOPLE WERE DECORATING THEM.

THEY ALSO HEARD THAT ONE OF THE

MAIN REASONS PEOPLE DIDN'T PUT

THEM TOGETHER, THEY STILL DIDN'T

UNDERSTAND THE INSTRUCTIONS.

TO THEIR CREDIT, THOSE

INVESTIGATORS THOUGHT THERE WAS

INSTRUCTS AND TRIED TO PUT

TOGETHER THE BED NET, THEY

COULDN'T FIGURE IT OUT.

THEY CAME UP WITH THE EQUIVLENT.

IF YOU KNOW THE STORE IKEA, THEY

CAME UP WITH IKEA PICTURE

INSTRUCTIONS, THEY TOOK THE

INSTRUCTIONS WITH SOME FOLKS,

FIGURED OUT HOW TO HELP THEM

UNDERSTAND IT AND THEY ALSO MADE

PRETTIER BED NETS.

THIS IS YOUR CENTRAL FINANCIER

IN THE HOUSE -- FIXTURE IN THE

HOUSEHOLD, MAKING IT PRETTY.

SO PRETTY BED NETS FOR FREE

VERSES STANDARD BET NEEDS FOR

FREE.

IT LOWERS INFANT MALARIA CASES.

YOU CAN TEST PRETTY MUCH

ANYTHING.

YOU HAVE TO FIND THE PLACE AND

MAKE SURE IT'S A WORTHWHILE

QUESTION.

A FEW MORE THINGS ABOUT STUDY

DESIGN.

YOUR NUMBER ONE QUESTION IS HOW

GOOD IS YOUR PRIMARY RESEARCH

QUESTION?

AT THE END OF THE DAY WHEN YOUR

RESEARCH IS DONE AND YOUR DATA

IS ANALYZED, WILL THE ANSWER

REGARDLESS OF WHAT THE ANSWER

IS, TO THE PRIMARY RESEARCH

QUESTION, ADVANCE SCIENTIFIC

KNOWLEDGE OR CLINICAL PRACTICE?

IF IT DOES NOT ADVANCE

SCIENTIFIC KNOWLEDGE OR CLINICAL

PRACTICE, IF IT DOES NOT AT

LEAST LAY THE NECESSARY

FOUNDATION THAT'S MISSING TO

ADVANCE IT, YOU HAVE FAILED AND

YOU DON'T HAVE A GOOD PRIMARY

RESEARCH QUESTION.

I'M NOT SAYING THAT YOU ANSWERED

THE QUESTION THE WAY YOU HOPED

IT WOULD BE ANSWERED BUT DOES A

FAILED -- IF YOU GET THE EXACT

OPPOSITE ANSWER, DOES THROUGH

STILL ADVANCE SCIENCE?

IT'S AN IMPORTANT THING.

IF YOU GET A NEGATIVE RESULT,

NOT THAT POSITIVE RESULT YOU'RE

HOPING FOR, THAT'S STILL

IMPORTANT.

THE SECOND MOST IMPORTANT

ELEMENT IS GOOD PRIMARY

OUTCOMEMISHER IS COLUMNLY

MEANINGFUL AND SIMPLE.

I NOW HAVE TO WRITE THESE END

OPPONENTS FOR STUDIES INTO

LABELS THAT THE AMERICAN PUBLIC

CAN READ.

AND THAT THE PREVENTING

DESCRIBERS CAN UNDERSTAND. --

PREDESCRIBERS CAN UNDERSTAND.

IT'S HARD TO INTERPRET THESE

ENDPOINTS.

IT MAKES SENSE TO COMBINE THIS

TOGETHER, BUT AS YOU GET INTO

THE DISCUSSIONS OF MEASURES AND

ENDPOINTS IN THIS COURSE, YOU'LL

REALIZE IT CAN BE VERY HARD TO

ACTUALLY EXPRESS IT AND EXPLAIN

IT TO SOMEBODY.

I WANT TO GIVE A LITTLE BIT MORE

INFORMATION HOW YOU WANT TO

START DESIGNING ONE OF THESE

LOVELY STUDIES WE WERE JUST

TALKING ABOUT.

YOU'VE GOT STUDY AIMS, YOUR

BACKGROUND, RATIONALE.

THEN YOU'LL TALK ABOUT THE

ENDPOINTS, THE OUTCOME

VARIABLES, ANY ASSESSMENT YOU'RE

GOING TO TAKE ON THE PEOPLE IN

YOUR CLINICAL TRIAL, THE ANIMALS

IN YOUR TRIAL.

WHATEVER IS IN THE TRIAL.

WHAT ARE YOUR ASSESSMENTS.

BE SPECIFIC, DON'T TELL ME

YOU'RE PLEASURING SLEEP. --

MEASURING SLEEP.

HOW ARE YOU MEASURING IT?

THINK ABOUT THIS SPECIFIC

ELEMENTS, IS IT SENSITIVE IS TO

CHANGE?

DO NOT TAKE A WOODEN RULER AND

TRY TO MEASURE MY WAIST LINE.

THAT IS NOT A GOOD WAY TO TAKE

THE MEASUREMENT.

YOU WANT SOMETHING THAT'S

RELIABLE.

YOU WANT SOMETHING THAT'S VALID.

YOU NEED TO KNOW THIS CATEGORY

ABOUT THOSE MEASURES YOU'LL USE.

BECAUSE THE MEASURES ARE WHAT

YOU'RE GOING TO USE IN SOME

COMBINATION TO GET THAT ACTUAL

FINAL ENDPOINT.

THINK ABOUT INCLUSION EXCLUSION.

CAN YOU MEASURE THESE THINGS ON

THE PEOPLE IN YOUR STUDY?

WE'LL TALK ABOUT THIS AND WENDY

WEBBER WILL TALK MORE WHEN SHE

TALKS ABOUT PROTOCOLS, TOO.

YOU HAVE TO MAKE SURE PEOPLE ARE

LEGAL TO BE IN THE STUDY,

SOMETIMES I SEE SO MANY

EXCLUSION CRITERIA, I'M LIKE

THERE IS NOBODY LEFT IN THIS

WORLD THAT CAN BE IN YOUR STUDY.

SO YOU'VE GOT TO BALANCING, I

THINK ABOUT SAFETY.

CAN THEY NOT ETHICALLY BE IN

YOUR TRIAL?

AND AFTER THAT, YOU MIGHT WANT

TO LET EVERYBODY ELSE IN.

HOW DO YOU START DESIGNING,

THINK ABOUT THAT ACCRUAL PLAN.

THINK ABOUT THE PREPARE TORRE

TESTS.

WHAT'S THE TIMELINE FOR YOUR

OVERALL STUDY AND FOR THE

INDIVIDUAL PARTICIPANTS?

DO THEY HAVE TO COME BETWEEN

9:00 A.M. AND 4:00 P.M. ON DAYS

THEY'RE LIKELY TO WORK?

THAT IS GOING TO MAKE IT A BIG

PROBLEM.

SOMEONE IS RAISING THEIR HEAD.

YES, THAT'S RIGHT.

IT'S A PROBLEM.

TREATMENT.

WHAT ARE THE PARTICIPANT

IMPLICATIONS?

I WAS IN A TRIAL AND I COULDN'T

TAKE CERTAIN ANTIBIOTICS, SO OF

COURSE I GET SICK.

AND I NEED AN ANTIBIOTIC.

SO THERE WAS A BACK AND FORTH

ABOUT WHAT DRUG I COULD TAKE.

BUT YOU HAVE TO THINK ABOUT

IMPLICATIONS ON YOUR

PARTICIPANTS.

WHAT IS THE EXACT PRODUCT, THE

EXACT DOSE, WHAT ABOUT THE

QUALITY, HOW IS IT ADMINISTERED?

CAN YOU REPRODUCE THE

INTERVENTION?

WHETHER IT IS A DRUG OR WHETHER

IT IS YOGA, CAN YOU ACTUALLY

REPRODUCE THAT INTERVENTION?

SO IF I SAY YOGA, WHAT TYPE OF

YOGA IS IT?

HAPPENING I DOING IT ONCE A

WEEK, 6 TIMES A WEEK?

WHAT'S GOING ON?

DOES IT INTERFERE WITH PATIENT

MANAGEMENT?

AGAIN, KIND OF MY BEING IN THAT

TRIAL INTERFERED WITH MY DOCTOR

TRYING TO GIVE ME A MEDICATION.

GENERALIZABILITY, OFTEN LOST IN

THIS QUEST FOR SPECIFICITY.

SO YOU HAVE TO DECIDE AND

BALANCE.

DIFFERENT PARTS OFF YOUR

SCIENTIFIC KNOWLEDGE YOU MAY

DECIDE TO HAVE MORE OR LESS

GENERALIZABILITY.

SPECIFY THE CRITERIA FOR

WITHDRAWAL FROM STUDIES OR A

DEVIATION FROM THE PROTOCOL

DEFINITION.

IF THEY DO NOT SHOW UP, AT

EXACTLY DAY 72, DOES IT MATTER?

OR IS IT DAY 72 PLUS OR MINUS 7

DAYS.

WHAT ARE THE WINDOWS?

SOMETIMES YOU HAVE TO BE PRETTY

PRECISE, SOMETIMES LOSER.

SOMETIMES SOMEONE MAY NEED TO GO

OFF INTERVENTION BUT DO NOT NEED

TO LEAVE YOUR STUDY.

YOU CAN FOLLOW THEM AND TAKE THE

ASSESSMENT.

YOU WANT TO HAVE A LIST OF ALL

THE CONCURRENT MEDICATIONS,

PROCEDURES, ET CETERA THAT ARE

PROHIBITED, PERMITTEDENED AND

HOW YOU'RE GOING TO RECORD THEM.

DO REMEMBER IT'S NOT JUST

MEDICINE.

THESE PEOPLE ARE DRINKING TEA,

TAKING SUPPLEMENTS.

THEY ARE TAKING OVER THE COUNTER

MEDICATIONS.

DO YOU WANT THEM TO STILL DO TAI

CHI OR GO TO PENNING CLASS IF

YOU'RE STUDYING YOGA?

YOU HAVE TO THINK ABOUT ALL THE

DIFFERENT THINGS THEY COULD BE

DOING THAT MIGHT INTERFERE WITH

WHAT YOU'RE STUDYING.

BUT ALSO YOU HAVE TO THINK ABOUT

SOMETIMES PEOPLE ARE GOING TO

GET HEADACHES, AND WHAT ARE THEY

GOING TO TAKE?

DON'T TELL THEM TO DISAVOW AND

NOT DO ANYTHING.

YOU'LL GET NOBODY IN YOUR STUDY

OR THEY'LL DO IT ANY WAY AND NOT

TELL YOU.

WHAT IS THE DOSE?

MIGHT BE THE NUMBER OF SESSIONS,

PILLS OR TREATMENT.

COULD BE SOCIAL MEDIA.

SOME OF THESE STUDIES TRYING TO

ACTUALLY TELL YOU, LIKE ALREADY,

WE WANT TO GIVE YOU INFORMATION

ABOUT YOUR CIGARETTE SMOKING.

WELL, DO I GIVE YOU ONE TEXT

MESSAGE A DAY, SEND YOU 6?

TO TRY TO KEEP YOU SO THAT

YOU'RE STILL -- YOU HAVE NOT

STARTED SMOKING AGAIN.

WHAT IS THE AMOUNT?

FREQUENCY.

DO I GO TO THE CHIROPRACTOR ONCE

A WEEK, 7 DAYS A WEEK, HOW

FREQUENTLY DO I GO?

AND HOW MANY WEEKS.

>> AND HOW MUCH TIME?

THIS WAS A STUDY THEY LOOKED AT

30, 60, 90 MINUTE MASSAGE.

ONCE, TWICE, THREE TIMES A WEEK.

WE'RE NOT GOING TO STUDY 3 TIMES

A WEEK 90 MINUTE MASSAGE.

PEOPLE WILL NOT GO TO THAT.

THERE HAVE BEEN THESE VERY

INTERESTING DOSING STUDIES, NOT

JUST OF DRUGS, BUT A LOT OF

OTHER INTERVENTIONS.

IF YOU'RE TALKINGS ABOUT A LOT

OF PSYCHOLOGICAL INTERVENTIONS.

HOW MUCH PRACTICE, WHAT DO

PEOPLE NEED TO DO OUTSIDE OF A

CLASSROOM?

WHO IS THE LEADER?

WHO IS THE SURGEON?

WHO IS THAT PERSON, HOW MUCH

CONTACT IS THERE.

HOW WELL TRAINED ARE THEY?

THERE ARE A LOT OF COMBINATIONS.

YOU CAN ONLY TEST OF THESE

POSSIBLE DOSES.

IT'S IMPORTANT TO LOOK AT IT.

AS I MENTIONED AT THE VERY END

YOU HAVE TO THINK ABOUT YOUR

PRACTITIONER IMPACT.

THERE COULD BE A LOT OF FALSE

NEGATIVES AND POSITIVES.

THAT COME UP HERE.

BECAUSE WE HAVE SOME PEOPLE THAT

ARE JUST -- GOOD THINGS HAPPEN.

BUT SOMETIMES YOU SAY LISTEN

MUCH, I'M DOING A PROOF OF

PRINCIPAL STUDY.

IF THE BEST MASSAGE THERAPIST,

REALLY WELL TRAINED, TRAINS

OVERS, IF THAT PERSON CANNOT

GIVE A MASSAGE THAT IMPROVES LOW

BACK PAIN, PROBABLY NOBODY CAN

DO IT.

MY BEST SURGEON CANNOT FIX THIS,

MAYBE NOBODY CAN BE TRAINED TO

DO THAT.

SO SOMETIMES WE ACTUALLY GO FOR

REALLY WELL TRAINED FOLKS IN A

PROOF OF CONCEPT MODAL, AND THEN

BROADEN THAT OUT.

BUT AGAIN YOU PROBABLY WANT TO

CHOOSE TECHNIQUE THAT CAN BE

GENERAL LIED IF YOU'RE GOING TO

DO THAT.

BUT OTHER TIMES SUCH AS THE

PEARLMAN STUDIES THAT WERE

HOOKING AT MASSAGE FOR ASTEO

ARTHRITIS OF THE KNEE, HE CHOOSE

SWEDISH MASSAGE.

HE SAID THAT'S WHAT EVERYBODY IS

TRAINED IN THE MOST OF THE

COUNTRIES HE WAS LOOKING AT.

THAT'S THE FOUNDATION THAT THEY

HAVE.

WE WANT TO BUILD ON THAT.

SO THE STUDY ANALYSIS

POPULATION.

YOU HAVE THIS MECHANISTIC PROOF

OF CONCEPT.

WE SOMETIMES CALL THESE THE

PROTOCOL ANALYSES THAT WE DO

BECAUSE WE ONLY USE THE PATIENT

THAT BEHALVES.

THE STUDY SUBJECTS THAT DO

EVERYTHING WE TELL THEM, WE'LL

ANALYZE THEM.

THAT'S ALONG THE IDEA IN THE

PERFECT WORLD WHAT MIGHT BE

EXPECT?

BUT GENERALLY, JUST LIKE THESE

INTENT TO TREAT ANALYSIS, THAT'S

EVERYBODY.

YOU TELL A PATIENT TO TAKE A

DRUG, THEY DON'T NECESSARILY

TAKE IT.

YOU RANDOMIZE A PATIENT TO A

STUDY ARM, THEY DON'T

NECESSARILY COMPLY WITH YOUR

INTERVENTION.

SO INTENT TO TREAT VERSES THESE

DIFFERENT COMPLETERS ANALYSIS.

THIS DOWN TO WHAT IS YOUR DATA

ANALYSIS POPULATION.

WE COULD SAY I.T.T., OR INTENT

TO TREAT, ONCE RANDOMIZED,

ALWAYS ANALYZED.

OBSERVATIONAL TRIAL WE'RE LIKE

ONCE YOU'RE IN THE TRIAL WE

FOLLOW YOU IN THE TRIAL.

YOU ASSUME THAT ALL STUDY

PARTICIPANTS ARE ADHERING TO

YOUR STUDY REGIMEN AND THEY

COMPLETE THE STUDY.

SO THEY -- YOU ASSUME THEY

BEHAVE PERFECTLY REGARDLESS OF

WHAT THEY DO.

MOST OF YOUR REGULATORY AGENCIES

WILL SAY WE EXPECT YOU TO DO

INTENT TO TREAT ANALYSIS.

MOST HIGH QUALITY RESEARCH

REGULATED OR NOT, WE ASSUME YOU

SHOULD BE DOING INTENT THE TREAT

ANALYSIS.

BUT THEN PEOPLE KIND OF WENT

ASKIRT THE EDGES.

THEY DO SOMETHING CALLED A

MODIFIED OR MITT ANALYSIS.

MODIFIED INTENT TO TREAT.

THEY MAY ONLY INCLUDE PATIENTS

WHO START THE INTERVENTION

THEY'RE ASSIGNED TO.

THEY INCLUDE THE STUDENT

SUBJECTS, WHO START THE

INTERVENTION.

WELL, IF I RANDOMIZE YOU TO GO

TO PSYCHO THERAPY VERSES NOT,

YOU DECIDE YOU DON'T LIKE WHAT

YOU'RE RANDOMIZED TO AND YOU

DON'T START, THAT'S STILL

TELLING ME SOMETHING.

SO SHOULD I REALLY THROW THOSE

PEOPLE OUT OF MY ANALYSES?

DEPENDS ON THE QUESTION YOU'RE

TRYING TO ANSWER.

SOMETIMES PEOPLE SAY IF THEY

DON'T MAKE IT TO THE FIRST OR

THE SECOND POST BASELINE

ASSESSMENT, THEN I DON'T COUNT

THEM.

WELL, AGAIN, YOU CAN'T REALLY

COMPARE BOTH GROUPS OF PATIENTS

THEN.

YOUR STUDY SUBJECTS MAY NO

LONGER BE COMPARABLE.

YOU HAVE UNDERMINED THE

RANDOMIZATION.

SO THAT'S WITH A PROBLEM WITH

MODIFIED INTENT TO TREAT

ANALYSIS.

YOU HAVE TO BE VERY CAREFUL WITH

THOSE.

BUT SOMETIMES WE DO THESE

COMPLETERS, THAT AGAIN YOU'RE

ONLY DEALING WITH THE WELL

BEHAVED AND THAT'S A PROBLEM.

SO AS JOHN DESCRIBED LAST NIGHT

WE HAVE THIS KIND OF SUPERIORITY

IN EQUIVALENCE.

I WANTED TO PUT THIS IN A

PICTURE.

EQUIVALENCE OR NO DIFFERENCE.

EVERYTHING IS INSIDE THIS LITTLE

TINY REALM, KIND OF IN THE

MIDDLE.

LIKE WHERE THIS IS NO

DIFFERENCE.

THIS IS A NORMAL DISTRIBUTION

CURVE.

AND THIS LINE IS THE MIDDLE IS

THE 0.

THE MIDDLE OF THE BELL CURVE.

SO IF YOU'RE IN A TIGHT AREA

HERE THERE IS NO DIFFERENCE

BETWEEN YOUR STUDY ARMS.

IF YOU'RE IN THE ORANGE AREAS ON

EITHER END YOU HAVE SUPERIORITY.

WHEN I TEST TWO ARMS, I COULD

COME UP WITH A VALUE ALONG THIS

CURVE.

AND IF I'M FAR ENOUGH OUT,

THAT'S SAYING THAT BASICALLY,

THESE TWO GROUPS ARE

STATISTICALLY DIFFERENT AND

PROBABLY NOT JUST A RANDOM

ERROR.

NON INFERIORITY, THEY COULD BE A

LITTLE INFERIOR OR THEY COULD BE

SUPERIOR.

GIVES ME A HUGE AREA TO BE IN.

SO WHAT ARE THE COMPARISON

GROUPS I MIGHT USE TO TRY TO GET

THERE?

WELL, I'VE GOT EXPERIMENTAL

INTERVENTIONS VERSES CONTROL.

SOMETIMES I'M IN EPIDEMIOLOGY

LAND.

JUST BECAUSE IT'S A CONTROL

GROUP DOESN'T MEAN YOU HAVE A

RANDOMIZED CONTROL ARM.

SOMETIMES COMPARING THE EXPOSED

TO UNEXPOSED.

SO AT THE WORLD TRADE CENTER

SITE, THEY TOOK PEOPLE WHO WERE

DOING CLEANUP THERE, WHO HAD

BEEN EXPOSED TO THAT WORK AND

COMPARE THEM TO A GROUP OF

PEOPLE NOT DOING CLEANUP, DID

NOT HAVE THE EXPOSURE.

THAT IS A STUDY THAT THE CENTER

FOR DISEASE CONTROL PREVENTION

HAS BEEN RUNNING.

WE MAY HAVE VARIOUS LEVELS OFF

EXPOSURES THAT WE WANT TO

COMPARE.

MEN VERSES WOMEN.

COMMON COMPARISON YOU SEE.

THE OLD VERSES THE YOUNG.

MAYBE BMI OVER 25, TO 25 AND

UNDER.

YOU HAVE THE USUAL STANDARD OF

CARE, PRACTICE, STANDARD OF

CARE, NOT ALWAYS THAT

STANDARDIZED, BY THE WAY,

THOUGH.

AND SOMETIMES WE'RE DOING THIS

HISTORY.

SOMETIMES DO I PREPOST.

I TAKE SOMEBODY'S BASELINE

MEASURES, INTERVENE ON THEM AND

LOOK AFTER WARD.

OR MAYBE IT'S NATURAL HISTORY.

I LOOK, WHEN I DIAGNOSE THEM AND

SEE HOW THEY'VE CHANGED OVER 12

MONTHS OR 2 YEARS.

WHEN YOU TALK ABOUT PLACEBO,

STANDARD OF CARE, ATTENTION

CONTROLS, YOU MIGHT HAVE SOME

TYPE OF EXPERIMENTAL TREATMENT

THAT YOU MIGHT OFFER SUPPORT OF

CARE, OR SOME OTHER CURRENT

TREATMENT.

SO SUPPORT OF CARE IS NOT NO

CARE HAVE IT'S NOT A TRUE

PLACEBO.

IF YOU HAVE A YOGA INTERVENTION,

WHAT SHOULD THE CONTROL GROUP

BE.

MAYBE EXERCISING OR STRETCHING,

MAYBE IT'S COOKING CLASS.

YOU WANT PEOPLE IN A GROUP, NOT

REALLY INTERACTING WITH EACH

OTHER.

MAYBE IT'S A BOOK CLUB BECAUSE

YOU WANT THEM TO ACTUALLY GO

SOMEPLACE AND BE SOMEPLACE FOR

90 MINUTES.

MAYBE YOU DO NOTHING.

MAYBE YOU SAY, AGAIN, PROOF OF

CONCEPT TRIAL.

DOES ANYTHING CHANGE IF THEY GO

TO YOGA?

SOMETIMES THEY'LL DO SOMETHING

CALLED A WEIGHTLESS CONTROL.

WE SAY WE WANT YOU TO DO NOTHING

NEW FOR THE NEXT 12 WEEKS.

AND THEN YOU CAN DO THE YOGA.

BUT CONTROLS COST MONEY.

YOU WILL SEE IN THE SAMPLE SIZE

LECTURE, YOU HAVE MUCH HIGHER

SAMPLE SIZES.

WHEN WE HAVE CONTROL ARMS.

YOU WANT TO CONTROL EVERYTHING

EXCEPT THE SMALLEST ELEMENT OF

THE INTERVENTION YOU WANT TO

TEST.

BE CAREFUL, HOWEVER, IT'S NOT

TOO SMALL OF A DIFFERENCE.

I HAD THIS ONE MEDITATION STUDY,

AND THEY REALLY WANTED TO TEST

THE MINDFULNESS ASPECT OF

MEDITATION.

AND CONTROLLED FOR EVERYBODY

ELSE ABOUT THE MEDITATION.

EVERYTHING ELSE ABOUT THE

MEDITATION. THIS IS A VERY

SMALL DIFFERENCE.

AND VERY HARD TO DO.

LIKE WHY DON'T YOU JUST TEST

LIKE THE MEDITATION AS A WHOLE

VERSUS SOMETHING?

BUT THERE ARE CONSEQUENCES WHEN

YOU HAVE MORE CONTROL IMPOSED,

YOU CAN HAVE LARGER SAMPLE

SIZES.

YOU MAY MISS A DIFFERENCE.

IF YOU HAVE A LESS SENSITIVE

OUTCOME MEASURE YOU MAY NOT PICK

THAT DIFFERENCE UP.

SO PLAN ACCORDINGLY.

WHAT ARE THE DIFFERENCES?

AGAIN, YOU'VE GOT TO THINK ABOUT

EVERY DIFFERENCE BETWEEN YOUR

STUDY ARMS, BASICALLY DEFINING

YOUR INTERVENTION.

IF SOMEBODY IS SPENDING ONE HOUR

A WEEK WITH YOUR STUDY

PARTICIPANTS VERSES 3, THAT IS

SOMETHING THAT IS DIFFERENT.

IF YOU TELL PEOPLE TO SPEND 15

MINUTES AT HOME, WORKING ON THAT

MEDITATION VERSES 60 MENS A DAY

AT HOME WORKING ON IT, AGAIN,

THIS IS DEFINING YOUR

INTERVENTION AND SO WHEN YOU SAY

TO ME IF YOU JUST HAVE 2 STUDY

ARMS AGAINST EACH OTHER, WELL, I

NEED TO FIGURE OUT IF IT'S THE

PARTICIPANT CONTACT TIME OR THE

TIME THEY SPEND AT HOME AND SAY,

WELL, ONE HAD ONE HOUR OF

CONTACT AND 15 MINUTES AT HOME,

THE OTHER ONE HAD 3 HOURS OF

CONTACT, 60 MINUTES AT HOME.

I CAN'T TEASE IT APART, FOLKS.

YOU HAVE TO PLAN ALL YOUR

INTERVENTIONS TO FIGURE OUT IF

YOU CAN TEASE THAT OUT.

SO YOUR CONTROL GROUP MIGHT BE

PLACEBO, STANDARD TREATMENTS,

ALWAYS MAKE SURE THAT THESE TWO

BULLETS ARE WELL DEFINED.

YOU'LL HAVE TO RECORD IT DURING

YOUR STUDY.

MOST ACCEPTED PREVENTION

INTERVENTION.

ARE YOU GOING TO DO AN HIV

PREVENTION INTERVENTION, NOT

TALK ABOUT CONDOMS?

WHAT IS IT THAT YOU'RE GOING TO

DO?

AGAIN, USUAL CARE.

NOT ALL THAT USUAL ACROSS SITES.

YOU HAVE TO RECORD WHAT IT IS.

WHAT ARE THE ACCEPTED MEANS OF

DETECTION?

WHAT IS THAT DIAGNOSTIC TEST?

IF I THAT PAP SMEAR FOR CERVICAL

CANCER, AM I GOING TO GET THE

SAME RESULTS AS IF I SWIPE WITH

VINEGAR AND THEN DO THE TEST?

NON DISEASE POPULATION.

SOMETIMES WE COMPARE DISEASE TO

NON DISEASE POPULATIONS.

ESPECIALLY TO TRY TO FIGURE OUT

SPECIAL DIFFERENCES.

ALL CONTROL GROUPS, ESPECIALLY

WHEN YOU'RE DOING INTERSENSAL

STUDIES, NEED TO BE ETHICAL.

IF YOU'RE GOING TO ASSIGN

ANYBODY TO A GROUP, ANYONE

MEETING THE STUDY CRITERION HAS

TO BE ABLE TO BE IN ANY STUDY

GROUP.

THAT'S NOT THE CASE.

YOU NEED TO MAKE SURE YOUR

RANDOMIZATION THAT FIGURE THAT

OUT.

I SET UP ALGORITHM, FOLKS.

I LIBERAL KNOW ASERN MEDICINE

THAT YOU HAVE IMPARTED TO ME IN

SETTING THAT UP.

INCLUSION EXCLUSION CRITERIA

SHOULD KEEP PEOPLE FROM BEING IN

STUDY ARMS THAT YOU KNOW ARE I

DON'T THINK FOR THEM.

IF YOU HAVE QUESTIONS ABOUT

THAT, CHUCKNATESON HAS A WHOLE

LECTURE ON MISTAKES THAT HAVE

BEEN MADE IN RANDOMIZIZATIONS.

STANDARD OF CARE, IS IT REALLY

STANDER?

CONTROLSCANNOT ALWAYS BE MASKED.

SOMEBODY ASKS THIS EVERY YEAR

AND IT'S NOW ON THE SLIDE.

TRY, YOU MAY NOT BE ABLE TO DO

IT.

PEOPLE DO TEND TO BE BETTER

AFTER RECEIVING ANY TYPE OF

THERAPY PLACEBO OR NOT.

CARE MATTERS, DO NOT

UNDERESTIMATE THAT WHEN YOU PLAN

YOUR TRIALS.

COMPARING POPULATION INCIDENT

RATES, THE BEGINNING OF

PROGRAMS.

DOES NOT TAKE INTO ACCOUNT A LOT

OF FACTORS.

I HAD SOMEONE, JUST DO PREPOST.

WELL, IF YOU TAKE INTO CONTROL

THE CONTROL GROUP, WHILE THEY'RE

PREPOST, THE POST LOOKED WORSE

THAN BASELINE, EVERYBODY ELSE

LOOKED A LOT WORSE THAN THAT.

SO IF I HADN'T HAD THAT CONTROL

ARM, YOU WOULDN'T HAVE KNOWN

THAT THEY ACTUALLY SALVAGED THE

SLIDE.

EVERYBODY ELSE IS GOING LIKE

THIS, THEY'RE ALL GOING

DOWNHILL.

THEY KIND OF -- THEY WENT DOWN,

BUT NOT BY AS MUCH.

IT'S IMPORTANT TO UNDERSTAND

THIS.

NO CONTROL GROUP, YOU HAVE A LOT

OF PROBLEMS, RESEARCHERS AN

PARTICIPANTS TEND TO INTERPRET

FINDINGS IN FAVOR OF NEW

TREATMENTS, INVESTIGATOR AND

PARTICIPANT BIAS.

WHEN YOU DON'T HAVE

RANDOMIZATION, YOU CANNOT

DISTINGUISH EFFECT AND TIME.

IF I WAIT TEN TO 14 DAYS WE WILL

ALL GET OVER OUR COLDS.

SO WHAT'S THE RIGHT CONTROL

GROUP?

THERE IS NO RIGHT CONTROL GROUP.

YOU JUST HAVE TO CHOOSE ONE.

AGAIN REMEMBER, CONTROL GROUPS

MAY HAPPEN IN NON RANDOMIZED

STUDIES.

WE'LL TALK MORE ABOUT THIS NEXT

WEEK.

BUT YOU HAVE TO CONSIDER ALL

YOUR EFFECTS, POSITIVE,

NEGATIVE, YOUR EFFECTS GOING TO

PLATEAU, WHEN DO I MEASURE

THINGS?

ARE YOU LOOKING AT LONG TERM

DIFFERENCES?

GOING TO BE THATER OAGS GOING TO

SEE A CHANGE, IT WILL STRICT

TRICKLE WEIGH.

DELAYED RESPONSE, DO I HAVE TO

WAIT 6 MONTHS BEFORE I SEE A

CHANGE?

GOT TO CONSIDER ALL THIS STUFF

WHEN YOU'RE PLANNING A TRIAL.

SO TEN IS MY FAVORITE CONFOUNDER

IN UNCONTROLLED STUDIES.

YOU HAVE CHALLENGE DROPOUT

BETWEEN STUDY -- DIFFERENTIAL

DROPOUT BETWEEN STUDY ARMS.

BONE DENSITY CHANGES THROUGHOUT

THE YEAR.

YOU HAVE TO MAKE SURE YOU

MEASURE THEM ON THE 12 MONTH

MARK, NOT 9 MONTHS.

SOCIAL SUPPORT.

EMPATHY IN TALKING TO PEOPLE

REALLY MATTERS.

EXERCISE, WE KNOW CONTROL

STRESS, CARDIOVASCULAR RISK

FACTORS, A LOT OF ISSUES, YOU

SEE IMMUNE RESPONSES WITH ALL OF

THESE.

SO WHAT'S YOUR STUDY ABOUT?

WHAT DO I NEED TO CONTROL AND

NOT CONTROL?

WHEN IN DOUBT WHEN YOU CAN ASK

NOBODY ELSE, MASK THE PEOPLE

CORRECTING YOUR DATA, TO THE

HYPOTHESIS OF THE STUDY.

BUT YOU NEED TO SPECIFY IN YOUR

PROTOCOLS WHO IS MASKED, I

CAN'T, HOW, AND TO WHAT?

-- WHY, HOW AND TO WHAT.

IF I BREAK MY ANKLE AND I'M IN A

MEDICAL PRODUCT STUDY, THE PI

MAY NOT NEED TO KNOW WHAT STOWED

ARM I'M IN.

THE SAFETY OFFICER MIGHT NEED TO

KNOW, THE PERSON DOING THE

SURGERY MIGHT NEED TO KNOW IF I

HAVE TO ADJUST MY ANESTHESIA.

A LOT OF PEOPLE DON'T NEED TO

KNOW.

EVERYTHING ABOUT BLINDING IS

THIS IDEA LIKE PLAYING SECRET

SPY.

NEED TO KNOW INFORMATION.

ALL STUDIES SHOULD BE

REPRODUCIBLE.

REGARDLESS OF YOUR STUDY DESIGN.

REGARDLESS OF YOUR STUDY.

YOU NEED A WELL DEFINED STUDY

POPULATION.

WELL DEFINED INCLUSION EXCLUSION

CRITERIA.

IF I HAD 7 PEOPLE IN THE ROOM

YOU SHOULD ALL DECIDE THE SAME

THING IF SUBJECT A SHOULD BE IN

OR OUT OF THE STUDY.

NEEDS TO BE WELL UNDERSTOOD.

THE STUDY -- SOMEONE IS HAVING

FUN IN BACK.

STUDY CONDUCT NEEDS TO BE WELL

DESCRIBED, HOW ARE YOU GOING TO

DO YOUR STUDY?

AND IF SOMEBODY IS INJURED AND

HAS TO LEAVE QUICKLY, SOMEONE

HAS TO WALK IN, ARE THEY GOING

TO WALK IN AND DO IT THE SAME

WAY?

EVERY ONE FROM THE NURSE

COORDINATORS TO STATISTICIANS TO

DATA MANAGERS.

YOU HAVE TO KNOW THAT THE LABS

WILL BE PROCESSED THE SAME WAY,

THAT YOU'RE GOING TO GET PEOPLE

FROM THE SAME PLACE, AND THAT

EVERY LITTLE STEP OF THAT STUDY

WILL FOLLOW THE SAME WAY.

CAN I REPRODUCE THE OUTCOME

MEASURES?

HOW ARE YOU COLLECTING THOSE?

HOW ARE YOU DOING IT?

WE'LL TALK ABOUT THAT LATER.

AND ALSO THAT DATA ANALYSES.

THERE ARE A LOT OF POTENTIAL

BIASES IN CLINICAL TRIALS AND A

LOT OF POTENTIAL REMEDIES.

SO THINK ABOUT THESE.

SOMEBODY SAYS HERE IS A PROBLEM,

WELL, TRY TO FIND YOUR SOLUTION.

AND YOU ALSO HAVE TO THINK, WE

HAVE THE BIAS OF WHO IS IN THE

STUDY ANYWAY.

YOU'RE TRYING TO GENERALIZE TO

THIS BEG LIGHTER BOX OVER HERE.

REALISTICALLY, YOU HAVE THOSE

THAT ARE INTERESTED IN

PARTICIPATING, MEET THE

CRITERIA, CONSENT, AND GET

RANDOMIZED.

SO A MUCH SMALLER GROUP, MAY NOT

BE AS REPRESENTATIVE AS YOU'D

LIKE IT TO BE.

THAT'S PART OF WHY IT'S REALLY

HARD WORK TO BE A TRIALIST.

ALL OF OUR STUDIES AREN'T GOLD

BUT WE CAN SHUR TRY FOR IT.

SO SOME CONCLUSIONS.

IN THE NEXT MINUTE AND A HALF.

WHAT IS THE QUESTION?

YOU'VE GOT POPULATION OR

DISEASE, P.

SO SOME PEOPLE CALL IT PICO.

THE INTERVENTION OR VARIABLE OF

INTEREST.

COMPARISON GROUP, OUTCOME AND

TIME.

AND YOU WANT TO WRITE THIS

SENTENCE.

THIS IS AN EXAMPLE.

LIKE IN THIS POPULATION, HOW

DOES THIS INTERVENTION OR

VARIABLE OF INTEREST COMPARED TO

THIS CONTROL INFLUENCE THE

OUTCOME DURING THIS TIME PERIOD?

PHRASE, EVERY SINGLE STUDY

QUESTION LIKE THIS.

THIS IS YOUR STUDY SUMMARY.

I ASK YOU FOR A ONE SENTENCE

SUMMARY OF YOUR STUDY, WRITE IT

LIKE THIS.

IF YOU CANNOT FILL IN THOSE

LETTERS YOU HAVE A PROBLEM.

THE OTHER PART OF YOUR STUDY

QUESTION IS WHO CARES?

ABOUT YOUR STUDY QUESTION?

OTHER THAN YOU.

YOUR QUESTION IS ALWAYS GOING TO

COME FIRST.

BUT YOU'VE GOT TO CONSIDER THE

QUESTIONS YOU WANT TO ASK, THE

HYPOTHESIS IRRELEVANT OAGS

TRYING TO TEST.

I HAVE TO TURN YOUR QUESTION

INTO SOMETHING TESTABLE. WHAT

ARE THE KEY FACTORS.

THOSE ETHICAL ISSUES,

CONSTRAINTS.

WHAT CAN BE SAID, MAYBE I NEED

MULTIPLE CONTROL GROUPS IN ORDER

TO ACTUALLY ANSWER YOUR

QUESTIONS OF INTEREST.

SO I'M GOING TO STOP THERE FOR

TONIGHT.

WE'LL PUT UP THE OTHER

QUESTIONS.

IF YOU HAVE ARTICLES YOU WANT US

TO DISCUSS, ISSUES THAT YOU WANT

US TO DISCUSS LET ME KNOW AS

SOON AS YOU CAN ON THE CHAT

BOARDS.

WE'LL TRY TO WORK THOSE IN FOR

THE LATER FEW MONTHS OF THE

COURSE.

WE'LL TALK ABOUT EFFECT

MODIFICATION NEXT WEEK.

THANK YOU VERY MUCH.

HAVE A LOVELY WEEK.

TAKE CARE.