>> GINA: WELCOME TO EVERYONE
WHO HAS JOINED TODAY, EITHER ON
ZOOM OR ON VIDEOCAST. WELCOME
TO OUR FIRST OF SEVERAL
LECTURES FOR THE ANNUAL NINDS
SERIES ON STATISTICAL SERIES
AND I AM GINA NORATO. I WILL
BE TALKING THIS WEEK ABOUT
GIVING A BRIEF OVERVIEW FOR
CLINICAL TRIALS DESIGN.
ON WHATEVER PLATFORM YOU ARE
ON, PLEASE FEEL FREE TO SEND US
QUESTIONS. AND I CAN TRY TO
ADDRESS THEM AS WE GO. IF YOU
FEEL COMFORTABLE ASKING
QUESTIONS VERBALLY, FEEL FREE
TO DO THAT. THIS WILL BE
RECORDED. SO KEEP THAT IN MIND.
SO, THE FIRST THING THAT I WANT
TO DO IS GIVE A GENERAL OUTLINE
FOR WHAT WE ARE GOING TO BE
TALKING ABOUT.
FIRSTLY, I WANT TO GO OVER THIS
GENERALLY WHAT A CLINICAL TRIAL
IS. THE DIFFERENT PHASES OF
CLINICAL TRIALS AND ETHICAL
CONSIDERATIONS YOU SHOULD THINK
ABOUT YOU CONSIDER WHETHER OR
NOT CLINICAL TRIAL IS RIGHT FOR
YOU. AND HOW TO START BUILDING
IT.
WE GOING TO GO INTO KEY
PRINCIPLES OF TRIAL DESIGN, AND
THINGS YOU NEED TO MAKE
DECISIONS ON AS YOU DESIGN YOUR
TRIAL. THOSE ARE GOING TO BE
CHOICE OF CONTROL, CONTROL ARMS.
CHOICE OF ENDPOINTS, CONTROL
OF BIAS AND COMMON DESIGNS.
AND ALSO GOING TO TALK ABOUT
STATISTICAL ANALYSES AND THE
ROLE OF THE STATISTICIAN IN
THIS PROCESS. THIS IS GOING TO
BE REALLY A BROAD OVERVIEW.
EACH OF THESE THINGS COULD BE
GIVEN A FULL HOUR LECTURE.
THIS IS GOING TO BE KIND OF
CLINICAL TRIALS INTRO CRASH
COURSE. SO HOPEFULLY THIS
GIVES EVERYBODY WHO'S LISTENING
AN IDEA OF WHAT ULTIMATELY IN A
LOT OF WAYS ARE STATISTICAL
SORT OF DECISIONS ABOUT BIAS,
AND DECISION-MAKING, FOR
ANALYTICAL COMPARISONS AND
DEFINITION OF ENDPOINTS. AND
GIVING US A GOOD FRAMEWORK FOR
US TO START FROM.
SO, AGAIN FIRST I WANT TO TALK
ABOUT A BROAD OVERVIEW. NIH
GRANTS AND FUNDING DESIGNS
CLINICAL TRIALS AS A RESEARCH
STUDY IN WHICH ONE OR MORE
HUMAN SUBJECTS ARE
PROSPECTIVELY ASSIGNED TO ONE
OR MORE INTERVENTIONS, WHICH
MAY INCLUDE PLACEBO OR OTHER
CONTROL, TO EVALUATE THE
EFFECTS OF THOSE INTERVENTIONS
ON HEALTH RELATED BIOMEDICAL OR
BEHAVIORAL OUTCOMES.
AND THEY ALSO PROVIDE KIND OF A
HELPFUL SET OF QUESTIONS. SO
YOU CAN DETERMINE IF YOUR STUDY
IS A CLINICAL TRIAL. THIS IS
GOING TO BE IMPORTANT, NOT ONLY
FOR ANALYTICAL REASONS, BUT FOR
REPORTING REASONS. IF YOUR
STUDY IS A CLINICAL TRIAL WE
HAVE TO REPORT TO CLICK THE
TRIALS DOT GOV, MANAGED IN
OTHER WAYS, MORE RIGOROUS THAN
OTHER SORTS OF TRIALS OR
DESIGNS.
YOU CAN ASK YOURSELF, DOES THE
STUDY INVOLVE HUMAN
PARTICIPANTS? ARE THE
PARTICIPANTS PROSPECTIVELY
ASSIGNED TO AN INTERVENTION? IS
THE STUDY DESIGNED TO EVALUATE
THE EFFECTS OF THE INTERVENTION
ON THE PARTICIPANTS? AND,
FINALLY, IS THE EFFECT BEING
EVALUATED HEALTH-RELATED
BIOMEDICAL OR BEHAVIORAL
OUTCOME?
AND THERE ARE GENERALLY FOUR
PHASES OF CLINICAL TRIALS.
PRIOR TO THIS, THE DRUG WOULD
BE IN WHAT IS CALLED IN THE
ZERO OR PRECLINICAL FACES,
WHERE IT WOULD BE APPROVED FOR
FURTHER HUMAN TESTING. PHASE 1
ASKS ABOUT THE SAFETY. SIDE
EFFECTS, HOW DOES IT AFFECT OR
MOVE THE BODY? IS A SAFETY USE
AT THE SAME TIME AS OTHER
MEDICATIONS? GENERALLY THIS IS
DONE ON A VERY SMALL GROUP OF
PEOPLE. USUALLY DONE IN HEALTHY
PEOPLE FOR AFFECTED
INDIVIDUALS. ALSO DONE IN THE
DISEASE GROUP OF INTEREST
DEPENDING ON THE AVAILABLE
COHORT AND THE SPECIFIC GOALS.
AND WHETHER OR NOT THIS KIND OF
LEADS INTO BEING PHASE 1, PHASE
2 STUDY.
PHASE 2 IS MORE INTERESTED IN
ANSWERING QUESTIONS ABOUT
EFFICACY. SO WHILE WE STILL
ASK QUESTIONS ABOUT SAFETY, AND
REVIEW THROUGHOUT THE DIFFERENT
PHASES OF CLINICAL TRIAL
DESIGN, ADVOCACY IS A LITTLE
BIT MORE ANSWERED AT THIS
STAGE. IT IS MORE COMMONLY
USING THE ACTUAL POPULATION OF
INTEREST, OR INVESTIGATING THE
CONDITION BEING STUDIED. SO
ASKING QUESTIONS ABOUT, DOES
THE TREATMENT OF INTEREST
RELIEVE OR STOP THE PROGRESSION
OF THE CONDITION? ASKING
QUESTIONS ABOUT USAGE WOULD
ALSO BE A GOOD PHASE TO
QUESTION. GENERALLY IN A LARGER
SAMPLE. AND THE NUMBERS ARE
GOING TO VARY, THE NUMBERS
LISTED ON THIS FIGURE. THESE
ARE GOING TO BURY BASED ON YOUR
AVAILABLE COHORT AND FOR US, WE
SEE A LITTLE BIT SMALLER THAN
THIS BUT TO GIVE YOU AN IDEA OF
HOW CAN IT CAN ESCALATE AS YOU
PROCEED THROUGH THE PHASES.
PHASE 3 IS CONSIDERED MORE OF A
CONFIRMATORY PHASE OF TRIAL.
FURTHER EFFECTIVENESS, AND
ADVERSE EFFECTS, ASKING BROADER
QUESTIONS ABOUT SURVIVAL,
LONG-TERM QUESTIONS, QUALITY OF
LIFE, LONG-TERM ADVERSE
EFFECTS, AND AGAIN LARGER
SAMPLE SIZE. BEING ABLE TO
REACH MORE QUESTIONS, WITH
LARGER SAMPLES.
AND PHASE 4 IS GOING TO BE
ABOUT AS BIG AS YOU CAN GET IN
TERMS OF LOOKING AT THE
INVESTIGATIONAL PRODUCT. IN A
VERY LARGE COHORT, OVER LONG
PERIODS OF TIME. TO ANSWER
QUESTIONS ABOUT VERY LONG-TERM
RISKS AND BENEFITS AND OFTEN
THIS CAN BE AFTER THE DRUG IS
APPROVED. COLLECTING FURTHER
INFORMATION AS PEOPLE USE THE
DRUG, IN KIND OF A FOLLOW-UP
PHASE.
SO, AS YOU DESIGN, AS YOU START
TO THINK ABOUT DESIGNING,
THERE'S GOING TO BE A HANDFUL
OF KEY ETHICAL CONSIDERATIONS
YOU NEED TO THINK ABOUT AS YOU
DESIGN THE TRIAL. AND YOU
REALLY WANT TO THINK ABOUT
THESE EARLY ON AS WELL. TO
ENSURE YOU ARE DOING THIS IN
THE BEST WAY POSSIBLE.
FIRST IS GOING TO BE SOCIAL AND
CLINICAL VALUE. YOU REALLY WANT
TO MAKE SURE THAT THE RESEARCH
QUESTION IS IMPORTANT OR
VALUABLE ENOUGH TO JUSTIFY
ASKING PEOPLE TO TAKE RISKS, OR
INCONVENIENCE TO PARTICIPATE IN
YOUR STUDY. THE STUDY SHOULD
CONTRIBUTE TO SCIENTIFIC
UNDERSTANDING AND IMPROVE THE
TREATMENT AND PREVENTION OF
DISEASE.
NEXT SCIENTIFIC VALIDITY. WE
WANT TO MAKE SURE WE CAN ANSWER
THE RESEARCH QUESTION THAT WE
ARE TRYING TO ASK. ARE THE
METHODS VALID AND FEASIBLE TO
CONDUCT? IS THERE A VERY CLEAR
OBJECTIVE, AND VALIDATED
PRINCIPLES FOR CONDUCTING THE
STUDY?THUS THE STATISTICAL PLAN
OUTLINED AND WELL POWERED? SO
WE CAN MAKE SURE THE STUDY IS
DESIGNED IN A SCIENTIFICALLY
VALID WAY. MINIMIZING RESEARCH
WAYS AND ALL THESE THINGS.
AND THEN WE HAVE FAIR SUBJECT
SELECTION. WE SHOULD BE
CAREFUL TO CHOOSE PEOPLE IN
WITH MINIMIZE RISKS AND
ENHANCES BENEFITS TO
INDIVIDUALS AND SOCIETY. AND
AS MANY OF US KNOW WHO HAVE
GONE THROUGH THESE TYPES OF
TRAININGS BEFORE, SPECIFIC
GROUPS SHOULD NOT BE EXCLUDED
FROM THE OPPORTUNITY TO
PARTICIPATE WITHOUT GOOD
REASON.
WE SHOULD HAVE A FAVORABLE
RISK-BENEFIT RATIO. TO MAKE
SURE EVERYTHING HAS BEEN DONE
TO MINIMIZE RISK, AND MAXIMIZE
THE POTENTIAL BENEFITS THAT WE
MIGHT SEE.
WE SHOULD HAVE SOME INDEPENDENT
REVIEW. SO ARE THOSE
INDIVIDUALS, THE RESEARCH,
STATISTICIANS, STUDY TEAM, ARE
THEY SUFFICIENTLY FREE OF BIAS?
OR ARE WE TAKING ALL THE STEPS
TO MAKE SURE OUR STUDY HAS BEEN
LOOKED AT BY OTHER SOURCES? AND
THIS GOES THROUGH A REVIEW
PROCESS, BUILT IN TWO MOST OF
THE REPORTS AT NIH.
WE ALSO NEED TO MAKE SURE THAT
WE ARE ADHERING TO GOOD,
INFORMED CONSENT PRINCIPLES.
SO THE INDIVIDUALS MUST BE
INFORMED OF THE PURPOSE,
METHODS, RISKS, BENEFITS AND
ALTERNATIVES TO THE STUDY. AND
THEY REALLY NEED TO BE ABLE TO
MAKE THEIR OWN EDUCATED
DECISIONS ABOUT WHETHER TO
PARTICIPATE.
AND FINALLY, WE NEED TO RESPECT
POTENTIAL AND AND ROLLED
SUBJECTS AND RESPECT
CONFIDENTIALITY. PATIENTS
SHOULD BE ALLOWED TO WITHDRAW
FROM THE STUDY AT ANY POINT.
PARTICIPANTS ALSO HAVE THE
RIGHT TO BE INFORMED OF THE
RESULTS OF THE TRIAL AT THE
CONCLUSION OF THE STUDY. THIS
IS ALL PACKAGED HERE.
SO THERE'S A LOT OF DIFFERENT
ASPECTS THAT GO INTO ALL OF
THIS. AND AGAIN, THIS IS JUST A
BROAD OVERVIEW OF ALL THESE
THINGS THAT WE NEED TO THINK
ABOUT, EVEN BEFORE WE START TO
ACTUALLY DESIGN THE TRIAL.
NEXT I WANT TO GET INTO THE KEY
PRINCIPLES. SO COVERING A LOT.
THIS IS THE MEAT OF THE LECTURE
HERE. COVERING HOW WE THINK
ABOUT MAKING CHOICE OF
DECISIONS. WHAT THESE THINGS
ARE. LOOKING AT THIS FROM THE
STATISTICAL LENS. AND AGAIN,
THIS IS A LOT OF MEAT HERE. A
LOT OF DETAIL IS MISSING FROM
THIS PORTION OF THE
PRESENTATION. BUT I WANTED TO
TRY TO GIVE US A GENERAL SCOPE
AS TO HOW WE NEED TO THINK
ABOUT THESE ASPECTS WE DESIGN
THE TRIAL.
SO, FIRST IS CHOICE OF CONTROL.
A LOT OF TIMES, WHEN WE THINK
ABOUT CLINICAL TRIALS, WITH
THING ABOUT RANDOMIZED,
PLACEBO-CONTROLLED TRIALS. AND
IN FACT THIS IS ONLY ONE OF A
FEW TYPES OF TROUT THAT WE
MIGHT SEE. PLACEBO TRIALS,
USING PLACEBO-CONTROLLED IS A
SCENARIO WHERE WE HAVE A
TREATMENT THAT IS MORE AROUND
INVESTIGATIONAL PRODUCT OR
DRUG, OR WHATEVER ELSE WE ARE
INVESTIGATING. BUT IT IS
CONSIDERED TO BE INACTIVE. SO
PLACEBO BY NAME, IS GOING TO BE
THE MOST COMMON CASES WHERE WE
ARE IN THIS DRUG FORMAT. WHERE
WE HAVE SIMILARLY FORMATTED
PILLS, OR REGIMENTS. THIS IS
THE TREATMENT THAT SOME OF THE
PEOPLE A RANDOMIZED TO RECEIVE.
THERE ARE OTHER TYPES OF
CONTROL GROUPS AS WELL BUT WE
CAN CHOOSE TO USE FOR OUR
TRIALS. AND EACH IS GOING TO
HAVE ITS OWN CONSIDERATIONS,
AND PROS AND CONS TO WHEN THESE
COULD BE INDICATED FOR USE.
WE CAN ALSO HAVE A CONTROL ARM
THAT IS NO TREATMENT OR
STANDARD OF CARE. MANY OF YOU
HAVE SEEN TRIALS LIKE THIS AS
WELL. WHERE PERHAPS WE ARE
INVESTIGATING LIKE AN EXERCISE
INTERVENTION, FOR EXAMPLE. IT
WOULD OBVIOUSLY BE PRETTY HARD
TO COME UP WITH A PLACEBO FOR
THAT. LIKE SOME KIND OF OF THE
TREATMENT THAT IS NOT THE
EXERCISE REGIMEN THAT YOU ARE
INVESTING FOR YOUR PATIENT.
SO WE WOULD OFTEN TIMES IN
THOSE SCENARIOS USE KIND OF THE
STANDARD OF CARE. MAYBE THEY
WOULD KEEP GOING TO THE DOCTOR,
USING ALL THEIR USUAL DRUGS TO
MANAGE THEIR SYMPTOMS. AND THE
TREATMENT GROUP IS RECEIVING AN
ADDITIONAL, YOU KNOW, EXERCISE
REGIMEN FOR EXAMPLE.
IN A LOT OF CASES THERE IS NO
TREATMENT OR STANDARD OF CARE.
YOU ARE NOT ABLE TO BE BLINDED
BECAUSE YOU'RE BASICALLY
TELLING THE PERSON YOU'RE GOING
TO BE DOING THE SAME THINGS
YOU'RE GOING TO BE DOING. OR
WE ARE NOT PROVIDING YOU AN
ADDITIONAL TREATMENT. SO WE
WILL TALK MORE ABOUT BLINDING
AS WELL. THIS IS ONE DRAWBACK
OF THIS PARTICULAR TYPE OF
CHOICE OF CONTROL.
WE CAN ALSO HAVE ACTIVE CONTROL.
SO THIS IS MOST COMMON IN DRUG
TRIALS, SPECIFICALLY WHERE WE
ARE ASKING QUESTIONS ABOUT BIO
EQUIVALENCE OR EQUIVALENT IN
GENERAL, OR OTHER SIMILAR TYPES
OF INVESTIGATIONS WERE MAYBE WE
ARE TRYING TO COMPARE TWO
TREATMENTS TOGETHER. MAYBE THEY
ARE RECEIVING -- THEY ARE BEING
RANDOMIZED TO TREATMENT, BUT IT
IS NOT GOING TO BE THE ONE
UNDER INVESTIGATION. THIS IS
WHAT WE WOULD CALL AN ACTIVE
CONTROL.
WE CAN ALSO HAVE HISTORICAL
CONTROLS. SO, THIS IS SOMETHING
I THINK THAT COMES UP A LITTLE
BIT FOR US AT NINDS. THIS IS A
SCENARIO WHERE MAYBE WE HAVE A
RARE DISEASE, AND MAYBE WE
DON'T HAVE A WHOLE LOT OF
PATIENTS TO PULL FROM. MAYBE IT
IS DIFFICULT TO GET PEOPLE TO
ENROLL IN TRIALS, WHERE THEY
MUST BE RANDOMIZED AND SO IT IS
DIFFICULT TO HAVE A CONTROL
GROUP AS PART OF THE TRIAL. SO
THERE ARE SOME SCENARIOS WHERE
WE HAVE HISTORICAL CONTROL. IT
IS GOING TO BE A GROUP OF
PATIENTS WITH THE DISEASE OF
INTEREST FROM AN EARLIER TIME
PERIOD MAY BE THESE ARE
CROSS-SECTIONAL OBSERVATIONAL
COHORTS. MAY BE NATURAL HISTORY
STUDY, WHERE WE HAVE SOME
INFORMATION ON THIS PEOPLE OVER
TIME. THIS IS BASICALLY GOING
TO BE ASYNCHRONOUS. SO THE
PEOPLE WERE INVESTIGATED AT A
TIME OUTSIDE OF THE TRIAL THAT
YOU ARE DESIGNING.
AND THEN FINALLY, WE CAN HAVE
MULTIPLE CONTROL GROUPS. YOU
CAN USE MORE ONE OF THE ABOVE
IN ORDER TO DESIGN YOUR TRIAL
AS WELL. YOU CAN HAVE BOTH A
STANDARD CARE, AN ACTIVE
CONTROL OR A VARIETY OF
DIFFERENT COMBINATIONS OF THESE
AS WELL. SO YOU ARE NOT ALWAYS
LIMITED TO ONE CHOICE OF
CONTROL. IT WILL AFFECT YOUR
REQUIRED SAMPLE SIZE, QUITE A
BIT AND THEY MIGHT INCREASE THE
COMPLEXITY OF THE DESIGN.
CHOICE OF CONTROL IS IMPORTANT
BECAUSE WE NEED TO DETERMINE
HOW MUCH OF THE MEASURED EFFECT
WE SEE IS DUE TO THE PART OF
THE STUDY RECEIVING ANY
PRODUCT. INCLUDING CONTROL ALL
RECEIVING THE INVESTIGATIONAL
TREATMENT.
SO THIS FIGURE FROM HOWICK ET
AL IS A GOOD REPRESENTATION OF
WHY WE USE THESE CONTROLS ARE
ALL. ILLUSTRATED THE
DIFFERENCES OF THE TYPES OF
CONTROL.
THE FIRST PORTION OF THE
FIGURE-- I WILL REVEAL THE REST
OF THE CLICK THROUGH-- THE
MAGNITUDE OF THE EFFECTS THAT
WE SEE JUST FROM BEING IN A
STUDY. EVEN JUST BEING IN A NO
TREATMENT GROUP. THERE IS A
NAME FOR THIS. HAWTHORNE
EFFECT. JUST BEING PART OF THE
INVESTIGATION HAVING CONTACT
WITH CLINICIANS, GOING TO
APPOINTMENTS. I HESITATE TO
CALL THIS THE PSYCHOLOGICAL
EFFECT, BUT IT IS THE EFFECT OF
BEING OBSERVED AS A PATIENT.
IN THIS BAR INHERENTLY IS ALSO
THE TRUE UNDERLYING PROCESSES.
WHEN AND WHATEVER ADDITIONAL
FACTORS ARE INCURRED FROM BEING
OBSERVED.
AND THEN WE HAVE IN THIS CASE
WHERE WE HAVE A PLACEBO, WE
HAVE THE ADDITIONAL EFFECT OF
OBTAINING A TREATMENT, THAT IS
THE PLACEBO TREATMENT. THIS IS
THE PLACEBO EFFECT THAT WE
TALKED ABOUT. AGAIN THIS IS
STILL ON TOP OF THE EFFECT OF
BEING IN A STUDY AT ALL.
AND THEN FINALLY IS OUR
TREATMENT EFFECT HERE AT THE
TOP, WHICH DEMONSTRATES THE
ADDITIONAL EFFECT ON TOP OF
BOTH THE PLACEBO AND THE EFFECT
OF BEING IN A NO TREATMENT
GROUP. SO WE CAN SEE HOW THESE
THINGS KIND OF STACK. AND I
THINK STATISTICALLY IT CAN BE
REALLY IMPORTANT TO MAKE SURE
THAT YOU ARE OBTAINING AS MUCH
CONTROL OVER THIS PROCESS AS
POSSIBLE. SO YOU ARE ABLE TO
REALLY ISOLATE AS MUCH AS YOU
CAN THIS TREATMENT EFFECT THAT
YOU ARE INTERESTED IN, TO
REALLY UNDERSTAND THE EFFECT OF
THE DRUG OR WHATEVER TREATMENT
YOU ARE INVESTIGATING.
THE ONLY WAY WE CAN DO THAT IS
BY THOUGHTFUL CHOICES CONTROL.
NEXT I WANT TO TALK ABOUT
CHOICE OF ENDPOINTS. THIS IS
GOING TO BE PRIMARILY ABOUT THE
PRIMARY ENDPOINT. BUT
OBVIOUSLY WE HAVE A LOT OF
OTHER ENDPOINTS IN OUR STUDY
THAT WE NEED TO DEFINED. SO
THIS MIGHT BE PERTAINING TO OUR
PRIMARY ENDPOINT FOR THE STUDY
AS WELL AS OTHER KEY ENDPOINTS
THAT WE MIGHT BE INVESTIGATING
AS PART OF THE TRIAL. THESE
THINGS ARE GOING TO INFORM THE
SAMPLE CALCULATION, THE PRIMARY
ANALYSIS YOU ARE UNDERTAKING,
GENERALIZABILITY OF WHAT YOU
FIND IN THE STUDY AND HOW
APPLICABLE THE STUDY IS. AND
HOW USEFUL IT IS IN PRACTICE.
SO THIS CASE OF STUDY DESIGN
AND TRIAL DESIGN IS REALLY
IMPORTANT. AND I THINK WORKING
WITH THIS AS WELL CAN HELP YOU
FINE-TUNE THESE THINGS.
I WANT TO WALK THROUGH SOME OF
THESE FORMULATIONS OF ENDPOINTS
LOOK LIKE. AND HOW YOU MIGHT
CHOOSE DIFFERENT TYPES OF
DEFINITIONS OF ENDPOINTS HERE,
WITH THE UNDERSTANDING THAT OUR
CHOICE OF THESE THINGS CAN
REALLY DICTATE THE DIRECTION OF
OUR TRIAL. AND THE CHOICE OF
THESE THINGS SHOULD BE INFORMED
BY THE PILOT DATA, OR PRIOR
RESEARCH, OR THE LITERATURE
HELP YOU FINE-TUNE WHAT IS
GOING TO BE THE MOST USEFUL
FORMULATION OF ENDPOINT. WHAT
IS GOING TO BE THE MOST
INTERPRETABLE. AND HOW CAN WE
USE THIS IN THE MOST DIRECTED
AND COMPLETE WAY?
SO CONTINUES FORMULATION OF
ENDPOINT, FORMULATION OF A
METRIC THAT YOU'RE INTERESTED
IN FOR YOUR PRIMARY ANALYSIS
MIGHT BE SOMETHING LIKE A
DISTANCE WALKED, TIME TO WALK
EXAMS, ANOTHER COMMON METRIC TO
USE. PERCENT, VOLUME, AND SOME
LARGE RANGE SCALE, LIKE STROKE
SCALE SOMETIMES IS BIG ENOUGH.
OR IF THERE ARE OTHER LARGER
RANGE SCALES. SO MEASURES ARE
GOING TO BE PRIMARILY ON A
FINE-GRAINED NUMERIC SCALE.
WHERE YOU CAN THINK ABOUT
INTUITIVELY TAKING MEANS, OR
BEING ABLE TO DESCRIBE
VARIABILITY, AND ALL OF THE
METRICS YOU MIGHT THINK OF AS
BEING ABLE TO DO THAT WITH,
WOULD BE CONSIDERED CONTINUES
ENDPOINTS. THIS IS EVEN OUTSIDE
OF THE CHOICE OF WHICH OF THESE
METRICS SHOULD WE USE TO
INVESTIGATE? DO WE WANT TO USE
LIKE A LESION COUNT? OR JUST
PRESENCE OF LESIONS? SO MANY
DECISIONS THAT GO INTO CHOOSING
PRIMARY ENDPOINT OF TRIAL ON
TOP OF HOW WE MEASURE AND HOW
WE ARE GOING TO EXTRACT THAT
INFORMATION. BUT THIS IS JUST
ONE PIECE OF THE PUZZLE HERE.
BINARY ENDPOINTS, INTUITIVELY
YES/NO MEASUREMENTS, OR IN SOME
CASES A BINARIZED CONTINUE
SCALE SO YOU CAN USE A CUTPOINT
ON A CONTINUOUS SCALE OR IF YOU
THINK ABOUT BMI BEING CONTINUE
SCALE AND BINARIZE ITS WEIGHT
OR NOT ARE GOING TO BE OF
INTEREST TO YOU. ALL OF THIS
WILL BE THINGS LIKE THE
PRESENCE OR ABSENCE OF LESIONS,
ALL OF THESE ARE CONSIDERED
BINARY MEASURES OF AN POINTS.
A NOMINAL ENDPOINT IS AN
ENDPOINT WHERE WE HAVE NAMED
GROUPS. WHERE WE KNOW INHERENT
QUANTITATIVE ORDERING.
SOMETHING LIKE A TUMOR TYPE, OR
A GENETIC MUTATION TYPE
ETHNICITY AND NONE OF THESE
THINGS HAVE A GENERIC ORDER
TYPE. YOU CAN HAVE A PRIMARY
OUTCOME AS NOMINAL FOR EXAMPLE.
AND
AGAIN ALL OF THESE CHOICES OF
FORMULATION OF ENDPOINTS ARE
DIRECTLY RELATED TO THE TYPES
OF ANALYSIS THAT YOU DO. THEY
ARE DIRECTLY RELATED TO THE
TYPE OF POWER CALCULATIONS THAT
YOU WOULD DO. AND THE REQUIRED
SAMPLE SIZE YOU WOULD USE FOR
YOUR TRIAL. THIS IS A VERY
IMPORTANT SET OF DECISIONS THAT
YOU NEED TO MAKE HERE AS WELL.
ORDINAL FROM RELATION OF AN
ENDPOINT ARE NAMED GROUPS THE
HAVE AN INHERENT ORDER. LIKE
LABELS MILD/MODERATE/SEVERE.
EDUCATION LEVELS, DESCRIPTION
OF THE DATA. PUTTING MARKERS
ARE GOING TO BE THE MOST COMMON
TYPES OF FORMULATIONS FOR
ORDINAL ENDPOINT. AND YOU CAN
ALSO THINK ABOUT THE LIKERT
SCALE. NOT A CONTINUE SCALE
BECAUSE THERE ARE SO FEW
GROUPS. AND THERE IS THE
ACKNOWLEDGE GROUP DATA, NOT
NOMINAL BECAUSE THEY HAVE AN
INHERENT ORDERING. SOMETHING
LIKE A LIKERT SCALE WOULD ALSO
BE CONSIDERED AN ORDINAL
OUTCOME.
YOU CAN ALSO HAVE A TRIAL WITH
THE PRIMARY ENDPOINT OF TIME TO
EVENT. TIME TO EVENT DATA IS A
LITTLE TRICKY, IN THE SENSE
THAT IT IS TWO TYPES OF
ENDPOINTS TOGETHER. AND SO THE
FIRST IS A CONTINUOUS TIME
VARIABLE. WHICH WOULD BE THE
TIME ELAPSED FOR OBSERVATION
FOR THAT PERSON. AND OF BINARY
EVENT MARKER OF WHETHER OR NOT
THEY HAVE THE EVENT OR THEY
WERE CENSORED DURING THE COURSE
OF THE TRIAL.
THIS WILL BE LIKE THE TIME TO
DEATH IN YOUR DIFFERENT GROUPS,
OR IN YOUR SINGLE GROUP OF
INTEREST. TIME TO RELAPSE OR
TIME TO SYMPTOM RECURRENCE. AND
SOME TUMOR METRIC PERHAPS AS
WELL. THOSE ARE ALL SORTS OF
TIME TO EVENTS AND ENDPOINTS
YOU CAN USE. AND AGAIN TIME TO
EVENT, PRIMARY ENDPOINT WELL IT
MIGHT BE THE MOST INTERESTING.
POWERING THE TRIAL, AND THE
LENGTH OF THE TRIAL YOU WOULD
NEED TO PROPERLY INVESTIGATE
THIS. DO YOU NEED A LONGER
TRIAL? YOU PROBABLY NEED MORE
PATIENTS TO DO THIS THE RIGHT
WAY. AGAIN THIS IS WHERE ALL
OF THESE THINGS ARE
INTERRELATED IN TERMS OF HOW
YOU PICK ALL OF THESE PIECES TO
DEVELOP YOUR TRIAL.
YOU CAN ALSO HAVE COMPOSITE
ENDPOINTS. WHICH ARE BASICALLY
MULTIPLE DIFFERENT ENDPOINT.
USUALLY BINARY, GROUP TOGETHER
INTO A SINGLE ENDPOINT. YOU
CAN HAVE A SINGLE ENDPOINT OF A
COMBINATION OF PRESENCE OF
STROKE AND/OR DEATH. IF A
PERSON HAS ANY OF THOSE, YOU
WOULD CALL THAT AN EVENT. IF
THEY DID NOT HAVE IT YOU WOULD
HAVE YOUR COMPOSITE OUTCOME.
AND THIS CAN BE TRICKY AS WELL,
BECAUSE YOU'RE MAKING A LOT OF
ASSUMPTIONS ABOUT CLUSTERING
THESE THINGS TOGETHER. BUT
THIS IS ANOTHER TYPE OF
OUTCOME.
AND FINALLY, WE HAVE SURROGATE
ENDPOINT. USUALLY USED IN
CASES WHERE WE HAVE A LOT OF
VERY GOOD PRIOR INFORMATION ON
THE PROPER PATHWAY OF THE
SYMPTOMOLOGY AND THE DISEASE
THAT YOU ARE LOOKING AT. AND
WE WOULD HAVE TO BE ABLE TO
VERY WELL UNDERSTAND THE
CONNECTEDNESS BETWEEN THE
OBSERVABLE ENDPOINT, AND THE
SHORT RANGE ENDPOINT, AND THE
LONGER-RANGE ENDPOINT THAT
PERHAPS WE ARE NOT ABLE TO
OBSERVE. SURROGATE ENDPOINT
CAN BE REALLY NICE BECAUSE THEY
CAN MAKE YOUR TRIAL MORE
EFFICIENT. BUT YOU HAVE TO HAVE
REALLY GOOD SCIENTIFIC BACKING
FOR THE USE OF THESE.
AGAIN YOU ARE JUST USING LIKE
THE NAME ALLUDES, YOU'RE USING
ONE METRIC FOR SOMETHING ELSE
THAT IS PRESUMPTIVE TO BE
PREDICTIVE OF CLINICAL EVENT.
IN HIV, WE USE CD4+ COUNT AS A
SURROGATE FOR DEVELOPMENT OF
AIDS OR DEATH. A METRIC WOULD
USE TO SEE IF OUR TREATMENT IS
EFFECTIVE. ASSUMING THAT IF WE
CAN IMPROVE CD4 COUNT, WE CAN
IMPROVE THESE OTHER
LONGER-RANGE OUTCOMES.
SIMILARLY IN CARDIOVASCULAR
DISEASE OR TRIALS THAT WE ARE
INVESTIGATING, THESE SORTS OF
THINGS AND AFFECTED TREATMENT
MIGHT HAVE A GOOD IMPACT ON
BLOOD PRESSURE THAT COULD BE
INVESTIGATED MUCH FURTHER DOWN
THE LINE.
AND THE CHARACTERISTICS OF
THESE ENDPOINTS SHOULD HAVE,
REGARDLESS OF WHAT YOU CHOOSE
HERE, THEY SHOULD ALL BE
OBJECTIVE. THEY SHOULD BE--
WHEN YOU ARE MEASURING THIS
THING-- THEY SHOULD BE ABLE TO
BE OBJECTIVELY MEASURED IN YOUR
TRIAL. THE MEASUREMENT SHOULD
BE REPRODUCIBLE. YOU SHOULD
HAVE GOOD INTER AND INTRA
RELIABILITY. FOR EXAMPLE YOU
SHOULD UNDERSTAND THE
VARIABILITY OVER TIME AS WELL
IN TERMS OF INTERNALLY, OVER
TIME, ASIDE FROM WHAT IS
HAPPENING IN THE DISEASE
PROCESS, IS IT UNBIASED? IS IT
OBJECTIVE? IS IT GETTING AT
WHAT WE WANT TO KNOW UNDERLYING
THE DISEASE? IS THIS CLINICALLY
RELEVANT?
MAYBE THIS ENDPOINT THAT WE ARE
INTERESTED IN SOUNDS NICE. BUT
MAYBE IT DOESN'T ANSWER WHAT WE
WANT TO KNOW. WE NEED TO MAKE
SURE ALL OF THESE THINGS ARE
OUTLINED AS WE CHOOSE THESE
PIECES OF OUR DESIGN.
IT SHOULD BE FEASIBLE TO
COLLECT. THOUGH SOMETIMES WHAT
WE WANT TO KNOW ISN'T WHAT WE
CAN ACTUALLY COLLECT EASILY,
WITHIN THE SCALE OF THE TRIAL.
MAYBE WE REALLY WANT TO DO AN
EVENT INVESTIGATION. BUT WE
DON'T HAVE THE FUNDING, OR THE
DURATION OF TIME TO CONDUCT THE
TRIAL THAT WE WANT TO DO WITH
THE TYPE OF DESIGN AND OUTCOME.
WE NEED TO THINK ABOUT THAT AS
WELL.
THIS MAY SEEM OBVIOUS BUT, WE
HAVE CHOSEN A PRIORI. THERE
SHOULD NOT BE REFORMULATING OF
ENDPOINTS AT SOME POINT IN THE
TRIAL WHILE WE TALK ABOUT
ADAPTING DESIGNS LATER. I WILL
TOUCH ON THAT A LITTLE BIT AS
WELL. WE CAN CHANGE SAMPLE
SIZE. WE CAN CHANGE SOME OF
THE PIECES OF DESIGN. WE CAN
DROP INTERVENTIONS FROM THE
TRIAL. BUT CHANGING PRIMARY
ENDPOINTS IS A LOT TRICKIER.
BECAUSE THIS REALLY-- YOUR
PRIMARY ENDPOINT OF INTEREST IS
DIRECTLY RELATED TO WHETHER OR
NOT YOU HAVE A POSITIVE OR
NEGATIVE TRIAL. SO YOU NEED TO
MAKE SURE YOU THINK CAREFULLY A
PRIORI ABOUT THE OUTCOMES AND
YOUR PRIORITIES. THOSE SHOULD
NOT CHANGE.
MAYBE IN OUR LAB WE ARE REALLY
INTERESTED IN LIKE A TIME
DOESN'T GO GAP. BUT MAYBE OTHER
INVESTIGATORS IN OTHER PLACES
DON'T REALLY USE THIS AS MUCH.
FOR OUR TRIAL WE WANT TO MAKE
SURE THAT POSITIVE TRIALS WITH
PRIMARY ENDPOINTS, IT NEEDS TO
BE SOMETHING THAT OTHER PEOPLE
WILL FIND CONVINCING. SO, THAT
PRIMARY ENDPOINT THAT YOU
CHOOSE FOR YOUR TRIAL SHOULD
HAVE APPLICABLE IMMEDIATELY TO
OTHER INSTITUTIONS AND SHOULD
HOLD ITS OWN IN THE LITERATURE.
NOW WANT TO TALK ABOUT BLINDING.
AND OVERALL KIND OF CONTROL OF
BIAS HERE. BLINDING IS A
REALLY POPULAR TOPIC FOR
CONTROLLED TRIALS. OBVIOUSLY
THIS IS ONE OF THE KEY BENEFITS
OF TRIAL DESIGN. BEING ABLE TO
BLIND PEOPLE. IT CAN BE REALLY
IMPORTANT DO THIS. WE WILL TALK
ABOUT EACH PIECE OF BLINDING
AND WHY THIS MATTERS.
THERE ARE MULTIPLE PEOPLE IN
THIS PROCESS THAT CAN BE
BLINDED OR MASKED. SOMETIMES
YOU CAN USE THE TERM "MASKING"
AS WELL.
SO FIRST YOU CAN HAVE BLINDING
OF THE PATIENT. HOW WOULD WE
POSSIBLY BLIND THE PATIENT TO
WHAT TREATMENT THEY ARE BEING
RANDOMIZED TO? YOU WANT TO MAKE
SURE THEY ARE RECEIVING THE
SAME VISIT SCHEDULES, COMPARED
TO THE ST. TAMMANY THEY ARE
RECEIVING DRUGS. WE WANT TO
MAKE SURE THE DRUGS LOOK THE
SAME AND ARE SHAPED THE SAME IN
COLOR. THIS WOULD BE THE FIRST
STEP IN BLENDING OF THE
PATIENT.
WHY DO WE CARE ABOUT BLINDING
PATIENTS OR MASKING THE
PATIENTS? THIS COMES DOWN TO
PARTICIPANTS THAT NO WHAT
TREATMENT THEY ARE GETTING
WOULD BE MORE LIKELY TO CHANGE
THE BEHAVIOR INTENTIONALLY OR
UNINTENTIONALLY. AND PERHAPS TO
SAY NO THEY ARE RECEIVING THE
CONTROL, OR NOT RECEIVING THE
TREATMENT THEY WILL BE MORE
LIKELY TO WITHDRAW FROM THE
STUDY AND SEEK TREATMENT
ELSEWHERE ESPECIALLY IN CASES
WHERE THEY COULD BE RECEIVING
OTHER SORTS OF TREATMENT.
UNINTENTIONALLY THEY MIGHT BE
MORE OR LESS LIKELY TO REPORT,
IF THEY THINK THEY ARE
RECEIVING TREATMENT IS
BENEFICIAL THEY ARE LIKELY TO
REPORT POSITIVE SYMPTOMS. IF
THEY DON'T THINK THEY ARE
RECEIVING THE ACTIVE TREATMENT
THAT MIGHT BE MORE DOMESTIC
ABOUT THE DISEASE COURSE AT THE
SYMPTOMOLOGY THEY ARE RECEIVING.
SO IT IS IMPORTANT TO BLIND
THE PATIENTS. THIS IS SOMETIMES
THE MOST IMPORTANT ONE, BECAUSE
THIS IS REALLY THE FIRST STOP.
YOU CAN ALSO HAVE BLINDING OF
THE INVESTIGATOR. HOW WE BLIND
AND INVESTIGATOR IN THE COURSE
OF THE STUDY? WE DO THIS
THROUGH RANDOMIZATION. WILL
TALK ABOUT THAT TOO. WE DO
THIS BY CONCEALING THE DRUG
ASSIGNMENTS ARE CALLING
TREATMENT A AND B, USING
ENVELOPES AND LABELED VIALS,
AND THINGS LIKE THIS. AND WHILE
WE DO THAT?
INVESTIGATORS WHO KNOW WHAT
TREATMENT THE INDIVIDUAL
RECEIVED MIGHT TREAT THE
PATIENTS DIFFERENTLY. THEY
MIGHT INSINUATE THAT THEY ARE
NOT IMPROVING; OR THEY ARE MORE
BIASED IN THE WAY TO COLLECT
INFORMATION. WE LIKE TO THINK
WE ARE NOT DOING THESE THINGS.
BUT IT IS EASIER TO BE ABLE TO
BLIND YOURSELF AND NOT HAVE TO
WORRY ABOUT WHETHER YOU ARE
DOING A GOOD JOB OF BEING
UNBIASED OR NOT. SO THIS IS
ALSO VERY IMPORTANT.
THIRDLY WE WE CAN ALSO HAVE
BLINDING OF THE ANALYTICS TEAM,
OR OTHER INDIVIDUALS INVOLVED
IN THE ANALYSIS PROCESS, LIKE
PHYSICIANS, ETC. I THINK WE
DON'T THINK ABOUT THIS PART AS
MUCH. BUT IT IS A TYPE OF
BLINDING WE CAN HAVE OUR
TRIALS.
HOW WOULD WE BLIND AN
ANALYTICAL TEAM FOR THE TRIAL?
WE CAN MAINTAIN THE BLINDING
TREATMENT LABELING TO THE FINAL
DATA FILE. AND THERE IS A CODE
ELSEWHERE AND UNMASK THEM AT
THE FINAL POINT. SO THAT IN
THE COURSE OF ANALYSIS THE
STATISTICIAN ONLY KNOWS THERE
ARE TWO GROUPS OR THREE GROUPS,
ALL LABELED A, B, C, ETC.
THEY VIEW THE ANALYSIS AS
PRESPECIFIED. AND THEY DON'T
NEED TO KNOW WHICH GROUP. YOU
ARE DOING ALL THE DESCRIPTION
OF THINGS, EVEN IF YOU KNEW.
AND IN THIS ANALYSIS, IN MOST
CASES THE STATISTICIAN IS
SOMEWHAT MORE REMOVED FROM
BIAS, IN TERMS OF WHAT THEY
DESIRE TO BE THE OUTCOME THAT
PERHAPS THE INVESTIGATOR OR THE
PATIENT. BUT THIS IS NOT ALWAYS
THE CASE BUT IT IS AN IMPORTANT
PART OF THE PLANNING PROCESS.
WE CAN ALSO MEASURE BLINDING OF
THE PATIENT. AND YOU CAN ASK
THEM AT THE TRIAL WHAT THEY
BELIEVED THEY RECEIVED. YOU
CAN ASSUME THIS TO BE MORE THAN
A 50-50, COIN FLIP GUESS. BUT
YOU CAN SEE IF PEOPLE REALLY
STARTING TO UNDERSTAND WHAT
THEY RECEIVED, WHETHER MAYBE
THE PEOPLE WHO RECEIVED
TREATMENT HAD A VERY SPECIFIC
TYPE OF RASH THEY GOT. AND THE
RECEIVED MORE THIS SORTS OF
THINGS THAN YOU ANTICIPATED,
EVEN IF YOU TRY TO BLIND THEM.
THIS IS A SIMPLE DIAGRAM WHICH
SHOWS HOW WE FLOW THROUGH THE
BLINDING. AND WHAT WE CALL THE
STUDY IN THOSE CASES.
IF THE SUBJECTS WERE NOT
BLINDED DUE TO TREATMENT
ASSIGNMENT, WE CALL IT NOT A
BLINDED STUDY. EVEN IF WE
MANAGED TO BLIND THE
INVESTIGATORS OR THE
STATISTICIANS, WE STILL CALL IT
AN UNBLINDED STUDY.
IF WE BLINDED THE SUBJECT AND
THE INVESTIGATORS, WE CALL IT
THE DOUBLE-BLIND STUDY. WE
ADDITIONALLY BLINDED THE
ANALYTICAL TEAM WE CALL IT A
TRIPLE BLIND STUDY. YOU ARE
ABLE TO REPORT IN YOUR
PROTOCOLS AND FINAL REPORT AND
PAPER, EXACTLY WHO WAS BLINDED
AND AT WHAT PHASES. THIS GIVES
YOU THE TERMINOLOGY FOR THAT.
NOW WANT TO TALK ABOUT
RANDOMIZATION. SO THIS IS
AGAIN ANOTHER REALLY MEATY
TOPIC THAT IS VERY IMPORTANT.
BUT THERE'S A LOT OF DETAILS
HERE IS THAT WE ARE GOING TO
HAVE TO SKIM OVER, FOR THE
PURPOSE OF GIVING YOU A GOOD
OVERALL SCOPE OF TRIAL DESIGN
HERE. SO THERE'S A HANDFUL OF
CONTACT THE RANDOMIZATION YOU
CAN DO FOR YOUR STUDY.
YOU CAN HAVE A SIMPLE 1:1, THE
MOST BASIC INVESTIGATION. WE
CAN HAVE WEIGHTED RANDOMIZATION
FOR WE ARE RANDOMIZING MORE
PEOPLE THAN OTHERS, 1:2, OR
THREE GROUPS, THREE TREATMENTS;
WE CAN HAVE A 1:1:1
RANDOMIZATION.
WE CAN HAVE LOG RANDOMIZATION
AND ADAPTIVE RANDOMIZATION. ALL
OF THE THINGS THAT CAN HAPPEN
IN THE RANDOMIZATION PROCESS.
IN GENERAL RANDOMIZATION IS
CONNECTED BUT HE MUCH LIKE HOW
YOU WOULD EXPECT. SO IF IN
YOUR STUDY, YOU KNOW YOU NEED
50 PEOPLE FOR YOUR STUDY. AND
THERE ARE TWO GROUPS IN YOU'RE
DOING 50-50 RANDOMIZATION,
ESSENTIALLY WHAT YOUR STEAM
CONCENTRATION WILL DO OR
WHOEVER IS TASKED TO GENERATE
THE RANDOMIZATION LIST IS TO
GENERATE A PROBABILITY LIST OF
50% FOR EACH GROUP OF THE
LENGTH OF YOUR TRIAL SO YOU
WILL END UP WITH SOMETHING LIKE
IN AB, AAB, ABABB, ETC, ENDING
WITH A RANDOMIZED GROUP OR
GREATER IF YOU WOULD ALLOW FOR
DROPOUTS AND THINGS LIKE THAT.
AS YOU RANDOMIZE PEOPLE YOU
FOLLOW THIS LIST AND ADMINISTER
THE TREATMENT ACCORDINGLY FOR
EACH NEW LIEN ENROLLED PATIENT.
THE OTHER TYPES A RANDOMIZATION
ARE BASICALLY ALTERATIONS OF
THAT BASIC THEME, REALLY IT IS
NOT THAT MUCH MORE COMPLICATED.
AGAIN YOUR STATISTICIAN CAN
HELP YOU WITH THE STUFF.
IN CASES WHERE YOU HAVE THIS
WEIGHTED RANDOMIZATION OR IF
YOU WANT MORE PEOPLE
PREFERENTIALLY IN YOUR
TREATMENT GROUP OR IN YOUR
CONTROL GROUP OR A 2:1
RANDOMIZATION YOU ARE JUST
CHANGING THE PROBABILITY HERE.
YOUR TREATMENT LIST WILL HAVE
2:1 RANDOMIZATION AND 56% IN
YOUR TREATMENT GROUP AND 33% IN
THE CONTROL GROUP.
IF YOU HAVE THREE GROUPS, NOW
YOU HAVE 33, 33, 33%. AND AGAIN
ABC, RANDOMIZING THE WHOLE
LIST.
WHERE IT GETS A TINY BIT MORE
COMPLICATED IS WHEN WE TALK
ABOUT BLOCK RANDOMIZATION. OR
BLOCK BEHAVIOR AND
RANDOMIZATION AND STRATIFIED
RANDOMIZATION FOR BLOCK
RANDOMIZATION THE SHUFFLING OF
GROUP LABELS HAPPENS WITHIN A
SPECIFIC BLOCK SIZE OF
PATIENTS. SO AS WE CAN SEE
HERE AT THE TOP OF THIS
EXAMPLE, IN THE FIRST BLOCK OF
FOUR PATIENTS WE HAVE THREE
PEOPLE RANDOMIZED FOR A, ONE TO
B. IF WE CARE ABOUT
MAINTAINING THE BALANCE OF
RANDOMIZED INDIVIDUALS TO EACH
TREATMENT, AS THE TRIAL
PROCEEDS, IF WE THINK THAT
MAYBE THERE'S GOING TO BE AN
EARLY STOPPING. OR PERHAPS
THERE IS SOME OTHER REASON WHY
WE WANT TO MAINTAIN BALANCE,
OVER THE COURSE OF THE TRIAL AS
YOU RANDOMIZE PEOPLE, THEN WE
CAN CONSTRAIN THE
RANDOMIZATION. SUCH THAT
WITHIN EACH BLOCK OF FOUR
THERE'S IN THIS CASE IF YOU
TREATMENT, TWO AND TWO WITHIN
EACH BLOCK OF FOUR.
SO THE LIST CAN STILL RUN. WE
WOULD STILL ADMINISTER THE
FIRST PATIENT A, BBA, THEN WE
WOULD ADMINISTER A, BAB, AND SO
FORTH. SO YOU WOULD HAVE THESE
CHECK POINTS AT EACH OF THESE
ENDS OF THE FOUR BLOCKS TO
ENSURE THAT YOU HAVE THIS
BALANCE AS YOU TREAT.
FOR STRATIFIED RANDOMIZATION,
AGAIN THE SAME IDEA OF
GENERATING A RANDOMIZATION LIST
IS THE SAME CONCEPT. BUT WE
USE STRATIFIED RANDOMIZATION IN
CASES WHERE WE THINK THERE
MIGHT BE AN INFLUENCE OF SOME
KIND OF VARIABLE. OR WE WANT
TO MAKE SURE THERE IS AN EQUAL
NUMBER OF PEOPLE WITH CERTAIN
CHARACTERISTICS IN EACH OF THE
TREATMENT GROUPS.
FOR EXAMPLE IN YOUR TRIAL, YOU
THINK THAT SEX AND AGE IS
HIGHLY RELATED TO HOW A PERSON
WILL RESPOND TO TREATMENT, THAT
WE CREATE THESE STRATIFICATION
LEVELS. WHERE WE WOULD THEN
BREAK APART INDIVIDUALS BY SEX
AND AGE, AND WE GENERATE A
RANDOMIZATION LIST FOR EACH
GROUP AND FOR EXAMPLE MALES,
>50 YEARS OLD, AND THEN FOR
YOUNG MALES WE HAVE THE BALANCE
OF STRATIFICATION BALANCE IN
EACH OF THE STRATA. AND
HONESTLY WOULD HAVE TWO OTHER
STRATIFICATION LEVELS, COULD BE
FEMALE, YOUNG AND OLD IN THIS
EXAMPLE.
AND AGAIN THIS ENSURES THAT WE
ARE MAINTAINING AN EQUAL NUMBER
OF TREATED PEOPLE WITH EACH OF
THE LEVELS OF INTEREST.
AND AGAIN, WE CAN HAVE ADAPTIVE
RANDOMIZATION. I AM NOT GOING
TO GO INTO A LOT OF DETAILS
HERE. BUT WE CAN RANDOMIZE
PEOPLE TO TREATMENTS THAT ARE
DOING BETTER IN THE COURSE OF
THE TRIAL OR ALTER THE
RANDOMIZATION DURING THE TRIAL
BASED ON SOME TREATMENT DESIGN.
IT SHOULD STILL BE
PRESPECIFIED.
AND I WANT TO STEP THROUGH SOME
COMMON DESIGNS, JUST TO GIVE
YOU A SENSE OF THE DIFFERENT
FLAVORS OF CLINICAL TRIALS THAT
YOU CAN HAVE. AND AGAIN, THE
SCAN TO BE A VERY LARGE
DECISION TO MAKE IN YOUR DESIGN
PROCESS. AND I AM TRYING TO
JUST PRESENT THIS IN A SIMPLE
WAY, SOME OF THESE OBVIOUSLY
FOR PAROL DESIGNS FOR EXAMPLE
YOU CAN HAVE MORE THAN TWO ARMS
HERE, ETC.
SO FOR APPAREL DESIGN, YOU HAVE
YOUR INDIVIDUALS, YOU RANDOMIZE
TO ONE OF TWO OR MORE GROUPS.
AND YOU FOLLOW THEM
CONCURRENTLY OVER TIME. AND
AGAIN, THE MAIN GIST OF THIS
HERE IS THAT THEY ARE RECEIVING
TREATMENT AT THE SAME TIME
POINT AND UNDER THAT TREATMENT
COURSE, THERE MAY BE CERTAIN
MEASUREMENTS FOLLOWING OR NOT
FOLLOWING THE SAME ONE EITHER
ACTIVE TREATMENT OR PLACEBO.
WHATEVER YOU OTHER CHOICE OF
CONTROL IS, NOTED SIMPLY BY A
MEDICINE ALTHOUGH THIS CAN BE
WHATEVER THE INVESTIGATIONAL
PRODUCT YOU HAVE.
THIS IS GOING TO BE LIKE THE
MOST SIMPLE TYPE OF DESIGN YOU
CAN THINK OF WHEN TALKING ABOUT
RANDOMIZED CONTROLLED TRIAL
YOU CAN ALSO HAVE A CROSSOVER
DESIGN WHERE PEOPLE ARE
ESSENTIALLY RANDOMIZED TO AN
ORDER OF ALL DRUGS USUALLY IN
THE TRIAL. SO THEY MIGHT BE
RANDOMIZED TO RECEIVE TREATMENT
A FIRST AND THEN TREATMENT B.
OR RANDOMIZED TO RECEIVE
TREATMENT B FIRST AND THEN
TREATMENT A. THERE ARE A LOT
OF CONSIDERATIONS FOR CROSSOVER
DESIGNS. WASHOUT PERIODS. HOW
LONG WE WAIT BEFORE
ADMINISTERING THE SECOND DRUG.
IS THERE A CARRYOVER EFFECT
THAT WE NEED TO BE CONCERNED
ABOUT? DROPOUTS. FOLLOWING UP
WITH PEOPLE FOR THIS TO BE TOO
LONG. IN THE SECOND PORTION OF
THE CROSSOVER. THIS IS NOT
ANOTHER UNCOMMON DESIGN I WOULD
SAY, OF CROSSOVER TRIAL.
IF DONE PROPERLY IF RANDOMIZED
WITH SUBJECT DATA, TO MAKING
SURE THERE IS NO CARRYOVER OR
WASHOUT DURING TREATMENT.
ALSO YOU HAVE N-OF-1 STUDIES,
RELATIVELY UNHEARD OF. MAYBE
YOU HAVE A VERY RARE, ULTRA
RARE DISEASE. IT CAN BE
DIFFICULT TO DESIGN A FULL
TRIAL. OR THERE IS SOME
SPECIFIC REASON WHY YOU WANT TO
LOOK AT A SPECIFIC PATIENT. YOU
COULD RANDOMIZE, YOU COULD
FOLLOW ONE INDIVIDUAL UNTREATED
AND RANDOMIZE THEM TO ONE OR
MORE TREATMENT THE NOTED HERE
BUT YOU HAVE SOME FLEXIBILITY
IN THE DESIGN TO DO A DEEP
INVESTIGATION ON ONE SPECIFIC
PERSON. THERE'S A LOT OF
LITERATURE ON THE SPECIFIC
DESIGN. BUT THIS IS ANOTHER
TYPE OF DESIGN THAT CAN COME UP.
WE ALSO HAVE STEPPED WEDGE
DESIGNS, WHERE PEOPLE
RANDOMIZED TO THE TIME OF
STAGGER OF THE DRUG. IN THIS
CASE EVERYBODY WILL RECEIVE THE
DRUG, OR THE TREATMENT OF
INTEREST, WHICH IS GOOD FOR
SOME MEDICAL REASONS OR SOME
LOGISTICAL REASONS. MAYBE WE
CAN'T ROLL OUR TREATMENT TO
EVERYBODY AT THE SAME TIME.
SO EVERYBODY IS ABSURD FOR SOME
BASELINE AMOUNT OF TIME. AT
LEAST SOME AMOUNT OF TIME, AND
THEN THEY ARE ROLLED INTO
TREATMENT OVER TIME AND THEN
FOLLOWED FOR THE REST OF THE
TRIAL.
WE CAN ALSO HAVE FACTORIAL
DESIGNS, RANDOMIZED TO
COMBINATIONS OF TREATMENT
CONCURRENTLY. MAYBE BECAUSE THE
CASE WE ARE INVESTIGATING,
PAIRS OF PLACEBOS -- THIS IS
ANOTHER NOT UNCOMMON TYPE OF
DESIGN. THIS CAN BE VERY
EFFICIENT IF YOU'RE TRYING TO
LEARN THAN ONE DRUG FOR
TREATMENT.
WE ALSO HAVE MATCHED PAIRS
DESIGN. IF WE HAVE VERY GOOD
EVIDENCE OR VERY SPECIFIC
FRAMEWORK WHERE WE HAVE NATURAL
PAIRING IN OUR DATA, WE CAN
RANDOMIZE WITHIN PAIRS OF
PEOPLE TO TREATMENT OR CONTROL.
AND THAT ANALYTICALLY, WE CAN
COMPARE BEHAVIOR WITHIN THESE
PAIRS. THE MOST OF HIS EXAMPLE
WILL BE LIKE A JOINT STUDY FOR
EXAMPLE WHAT WE HAVE BUILT IN
PAIRS, OR OTHER TYPES OF
GENETIC STUDIES WHERE YOU CAN
RANDOMIZE THOSE PAIRS OF PEOPLE
WITH A MORE GENETIC PROFILE TO
GENETIC TREATMENTS. ANOTHER
FRAMEWORK.
WE CAN HAVE MORE ADVANCED
DESIGNS. GOING INTO THE WEEDS
HERE A LITTLE BIT. SEAMLESS II
OR III DESIGN WHERE WE CAN DROP
TREATMENT AFTER SOME PERIOD OF
TIME. MOVING INTO A FOUR LOOK
AT PHASE 3 EFFICACY WE ARE
DETERMINING FROM THE ANALYSIS
THAT THERE IS A SPECIFIC
TREATMENT THAT IS NOT BEING AS
BENEFICIAL WE CAN ROLL INTO A
MORE RIGOROUS LOOK AT FEWER
DRUGS.
AND OTHER TYPES OF ADAPTIVE
DESIGNS, INCLUDING INTERNAL
PILOTING. IT IS KIND OF
ADAPTIVE, THE SAME FLAVOR.
AFTER SOME PERIOD OF TIME WE
MIGHT DO SOME KIND OF RANDOMIZE
PROCESS OR OTHER WAYS OF
COLLECTING PATIENTS, WHETHER
PART OF THE PILOT OR ROLLING
INTO A STUDY. AND MAKING SURE
THAT THE PROCESS FOR THE STUDY
IS WORKING PROPERLY. AGAIN THIS
IS MORE ADVANCED.
SO THERE'S A LOT OF FACTORS TO
CONSIDER IN DESIGN SELECTION.
THE NUMBER OF TREATMENTS THAT
YOU HAVE. THE STUDY POOL. WHAT
PEOPLE WILL TOLERATE AND THE
TIMEFRAME DURATION OF THE STUDY
THAT YOU CAN AFFORD TO CONDUCT.
CARRYOVER EFFECTS LIKE I SAID.
DRUGS WILL TAKE SLOW ACROSS THE
DESIGN FOR EXAMPLE.
PATIENT EXPERIENCE OR ETHICAL
CONCERNS. SOME OF THE DESIGNS
ARE GOING TO BE MORE THAN
OTHERS, OR CERTAIN PATIENT
GROUPS THAN OTHERS.
THE VARIABILITY OF THE SUBJECT
POOL IS ALSO GOING TO BE A
COMMENT CONSIDERATION FOR
DESIGN HERE.
AND FOR THE LAST PIECE OF THE
LECTURE, I WANT TO TALK ABOUT
STATISTICAL ANALYSES BROADLY
AND THE ROLE OF THE
STATISTICIAN IN THIS PROCESS.
SO YOU CAN GET A SENSE FROM THE
PREVIOUS PART OF THE LECTURE
THAT THERE'S A LOT OF THINGS
THAT GO INTO THE ANALYSIS THAT
WE ARE NOT REALLY GOING TO GET
INTO DETAIL HERE. BUT THAT YOU
WOULD NEED TO LEAN ON SOMEBODY
TO HELP WITH DECISIONS ABOUT
EVEN THINGS THAT WE DIDN'T TALK
ABOUT IN DESIGN. SUPERIORITY,
EQUIVALENT OR NONINFERIORITY
QUESTIONS COMPARED TO THE USUAL
SUPERIORITY QUESTIONS.
MATCH DATA CONSIDERATIONS FOR
THAT. SAMPLE SIZE CALCULATION.
RANDOMIZED CALCULATIONS WHICH
YOU UNDERSTAND A LITTLE BIT
BETTER BY NOW HOPEFULLY. AND
STATISTICAL ANALYSIS PLAN AND
HOW YOU PRESENT THE GOALS.
AND I THINK IT CAN BE KIND OF A
MISCONCEPTION, THAT
STATISTICIANS ARE ONLY INVOLVED
KIND OF FOR PROTOCOL WRITING
POWER CALCULATIONS AND HELPING
WITH THE ANALYSIS OF DATA, AND
DISSEMINATION. HELPING YOU
WRITE YOUR PAPER AT THE END.
BUT REALLY THIS IS PART OF A
MUCH FULLER PICTURE OF GOAL
RESEARCH MAP. THIS IS A NICE
FIGURE THAT I USE TO TRY TO
SHOW THIS A LITTLE BETTER. YOU
CAN IMAGINE THE STUDY
CONCEPTION ALTHOUGH IT TO
ARCHIVING OF DATA. ETHICS
REVIEWS. RECRUITMENT AND
CONSENTING. AN ITERATIVE
PROCESSES HERE.
I WANTED TO TAKE A COUPLE
MINUTES TO HIGHLIGHT ALL THE
WAYS THAT STATISTICIANS CAN
HELP DURING THE COURSE OF STUDY.
AND, BE A KEY PART OF YOUR
STUDY TEAM.
FIRST WOULD BE STUDY DESIGN.
THEY CAN HELP WITH A LOT OF THE
THINGS I JUST MENTIONED. CHOICE
OF OUTCOME MEASURES BASED ON
YOUR STUDY GOALS. CHOICE OF
CONTROL GROUP, TIMING OF
MEASUREMENTS, WHETHER WE WANT
REPEATED MEASURES OR THE TIMING
THAT YOU WANT YOUR VISIT TO BE.
SOMETIMES CAN BE HELPFUL WITH
THOSE THINGS.
WHAT YOUR PRIOR DATA LOOKS
LIKE. DO YOU HAVE ANY PILOT
DATA? ANY DATA IN THE
LITERATURE THAT CAN HELP YOU TO
DESIGN OR POWER YOU STUDY? AND
THE CHOICE OF DESIGN WHETHER WE
CAN DO A CROSSOVER DESIGN.
WHETHER WE WANTED TO RANDOMNESS
OR JUST A COHORT STUDY, ETC.
WE CAN HELP WITH ALL THOSE
SORTS OF QUESTIONS AS WELL.
STATISTICIANS CAN SERVE AS A
PEER REVIEW PROCESS. WE CAN
HELP VET IDEAS AND PROVIDE
FEEDBACK AND TALK ABOUT
DISABILITY.
IN THIS DIAGRAM, THERE IS A
PROTOCOL SECTION HERE. THIS
OCCURS BEFORE PROTOCOL BUT
STATISTICIANS ALSO REVIEW
PROTOCOLS IN FULL AS PART OF
THE SCIENTIFIC REVIEW AT NINDS.
FOR PREPARING STUDY
OPTIMIZATION, WE CAN EVEN HELP
WITH CONSIDERATIONS FOR DATA
MANAGEMENT. WE SEE DATA ALL
THE TIME. OFTEN THERE'S
MANAGERS ON YOUR TEAM TO HELP
YOU. BUT WE CAN ALSO PROVIDE
INSIGHTS AS FAR AS DATA
STORAGE, AND FORMATTING AS
WELL. THAT CAN BE VERY
HELPFUL.
IN THE PROTOCOL WRITING
PROCESS, WE CAN HELP DO THAT
WRITING, DEVELOP STATISTICAL
ANALYSIS PLAN THAT IS DETAILED
ENOUGH FOR GOOD, RIGOROUS
STUDY. WE CAN HELP CLARIFY OR
WRITE OUTCOME MEASURES AND
ENDPOINTS. AND OBVIOUSLY DO THE
SAMPLE SIZE AND CALCULATION AS
PART OF THE PROTOCOL WRITING.
AND YOU KNOW, CONSENTING
OBVIOUSLY, WE DO NOT DO AS MUCH
OF THAT BUT THERE IS THIS BIG
ITERATIVE PIECE IN THE MIDDLE
THAT HAPPENS CONCURRENTLY. MOST
OF THE TIME IN RECRUITMENT.
WHICH IS PROTOCOL AMENDMENTS,
MANAGEMENT AND MONITORING, AND
THIS HAPPENS ALL THE TIME AS
YOUR STUDY IS ONGOING AND WE
CAN HELP WITH A LOT OF THAT
TOO. AND MAYBE THERE INTERIM
THINGS, OR DATA SUMMARIES OR
DATA QUALITY CHECKING,
ESPECIALLY IF BLINDED, AND WE
CAN HELP IN ANY WAY WITHOUT. WE
CAN HELP WITH ALL OF THESE
THINGS AS WELL.
AND OBVIOUSLY, CONDUCT THE
ANALYSIS ON LOCKED DATA
ACCORDING TO THE STATISTICAL
ANALYSIS PLAN DEVELOPED.
PRODUCING FINAL REPORTS AND
ALSO SPECIFICALLY REPORTING TO
CT.GOV, IS ALSO SOMETHING WE
CAN HELP WITH WHICH YOU ARE
MANDATED TO DO.
AND WE CAN ASSIST WITH
RESPONSES TO REVIEWERS, IN THE
PUBLICATION PROCESS, AND
IDEALLY AS A COLLABORATOR. BUT
IF YOU EVER COME TO A
STATISTICAL QUESTIONS ABOUT
COMMENTS YOU RECEIVE ON YOUR
STUDY IN THE REVIEW PROCESS WE
ARE ALSO ABLE TO HELP WITH ALL
THAT. AND EVEN WITH ARCHIVING.
WE CAN HELP DEVELOP THAT FINAL
CLEAN DATA SET, INCLUDING THE
FINAL DATA CLEANING AND
ACCOMPANYING DATA DICTIONARIES.
ALL OF THAT HELPS TO MAKE THIS
A CLEAN, CLOSED PROCESS.
AND I WOULD SAY, HAND-IN-HAND
DATA SHARING TO JOURNALS WHICH
IS BECOMING MORE COMMON.
THIS IS A COMMENT FROM A
STATISTICIAN. YOU PROBABLY HAVE
HEARD THIS BEFORE. A QUOTE FROM
R.A. FISHER CONSIDERED THE
FATHER OF MOTHER STATISTICS.
"TO CALL IN A STATISTICIAN
AFTER THE EXPERIMENT IS DONE
MAY BE NO MORE THAN ASKING HIM
TO PERFORM A POSTMORTEM
EXAMINATION-- HE MAY BE ABLE TO
SAY WHAT THE EXPERIMENT DIED
OF."
MAYBE IT IS A LITTLE BIT MORBID
BUT THE TRUTH IS WE ARE ONLY AS
HELPFUL AS WE ARE ALLOWED TO
BE. AS THE COLLABORATORS. WE
REALLY DO NEED TO BE INVOLVED
IN AS MUCH OF THE STUDY
DEVELOPMENT IS GOOD DESIGN OR
WRITING AS POSSIBLE. MAKING
SURE WE CAN HELP YOU WITH THAT
AS POSSIBLE, AND MAKE YOUR
TRIAL SUCCESSFUL.
SO IN SUMMARY, THERE'S A LOT OF
DECISIONS TO BE MADE IN TRIAL
DESIGN. THERE ARE MANY PIECES
OF INFORMATION THAT YOU NEED TO
PROPERLY PLAN AND DESIGN IN A
TRIAL.
WHAT PHASE ARE WE LOOKING AT
ANSWER QUESTIONS? DO WE NEED A
TRIAL AT ALL? IT IS ETHICALLY
OKAY FOR OUR PATIENTS TO
CONDUCT THE TRIAL? ARE WE
TAKING ALL THE MEASURES
POSSIBLE TO REDUCE BIAS AND
IMPROVE RIGOR AND
GENERALIZABILITY WHILE
PROTECTING THE PATIENT?
AND AGAIN ALL THESE DECISIONS
OF CONTROL GROUP. DO WE NEED
MORE THAN ONE GROUP HERE?
ENDPOINT DEFINITION. THE
PRIMARY MEASURE OF INTEREST IN
HOW WE ARE GOING TO DEFINE IT.
HOW MANY GROUPS ARE GOING TO BE
BLINDED OR MASKED IN THIS
INVESTIGATION? AND HOW CAN WE
DO THIS IN THE BEST WAY AS
POSSIBLE AND CONSIDERATIONS ARE
RANDOMIZATION AND HOW WE CAN
CONDUCT THAT AND MAKE SURE WE
ARE BALANCING OUR MAIN GROUPS
IN A RANDOM WAY.
AND CREATING A STUDY DESIGN
THAT IS SUFFICIENT TO ANSWER
THE STUDY QUESTIONS WHILE BEING
EFFICIENT AND APPROPRIATE FOR
THE DISEASE AND SUBJECT
POPULATION.
AND IN ALL OF THIS, TO WRAP UP,
THE STUDY TEAM IS CRUCIAL. THE
STUDY TEAM GOES FURTHER THAN
JUST CLINICAL INVESTIGATORS.
AND A LOT OF WHO WE ARE AS
STATISTICIANS IS PART OF THAT
STUDY TEAM INCLUDING DATA
MANAGERS, QUALITY ASSURANCE,
REGULATORY, PHARMACY, PARTICLE
WRITING, MEDICAL RESOURCES,
SUPPORTING DSMB AND OTHER
SCIENTIFIC REVIEW PROCESSES. IT
IS A HUGE TEAM TO HELP MAKE
THESE DECISIONS TO MAKE SURE WE
HAVE THE BEST OUTCOME POSSIBLE
FOR YOUR TRIAL.
THERE'S A COUPLE MINUTES LEFT.
I CAN OPEN UP FOR QUESTIONS
PEOPLE WANT TO PUT IN THE CHAT
OR UNMUTE. I AM HAPPY TO
ANSWER.
THE RECORDINGS WILL BE
AVAILABLE. AND THE SLIDES WILL
LIKELY BE DISSEMINATED AT SOME
POINT. YOU CAN KEEP AN EYE OUT
FOR THE.
I DON'T SEE ANY QUESTIONS
COMING THROUGH. THANK YOU ALL
FOR JOINING TODAY. PLEASE COME
BACK AND JOIN US NEXT WEEK FOR
THE CONTINUATION OF OUR
STATISTICAL LECTURE SERIES
HERE. PLEASE REACH OUT IF YOU
HAVE ANY QUESTIONS.
HOW CAN WE GET HELP FOR POWER
ANALYSIS?
YEAH. WHICH ARE TO YOUR
STATISTICIAN, IF YOU NEED THAT
INFORMATION LET ME KNOW. OUR
NINDS STATISTICIANS-- I DON'T
KNOW WHAT GROUP YOUR PART OF
BUT IF YOU ARE HERE AT NINDS,
WE ARE GLAD TO HELP.
THANK YOU ALL.
>> [END]