2014 EUGM - Blinded Adaptations, Permutations Tests and T Tests
Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm
Transcript of Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm
A P ti A P ti A Perspective oA Perspective oEnvironment for AEnvironment for A
TriTriRobert T. ORobert T. O
Senior StatistSenior Statist
Office of TranslationalOffice of Translational
For presentation at the 2nd Annual East UMA ; October 12, 2012
th C t th C t on the Current on the Current Adaptive Clinical Adaptive Clinical ppials ials ’Neill, PhD’Neill, PhD
tical Advisortical Advisor
l Sciences, CDER, FDAl Sciences, CDER, FDA
ser Group Meeting, Cambridge,
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Outline oOutline oOutline oOutline o
How did the adaptive dHow did the adaptive dh did it d l ithh did it d l ithhow did it develop withhow did it develop withenvironmentenvironment
P i d idiP i d idi Promoting and guidingPromoting and guiding
Some concerns and currSome concerns and curr
What have we learnedWhat have we learned
Where are we goingWhere are we going Where are we goingWhere are we going
of the talkof the talkof the talkof the talk
design initiative begin and design initiative begin and hi th l t hi th l t hin the regulatory hin the regulatory
i i i i g innovation g innovation
rent climaterent climate
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http://wwww.fda.gov/oc/initiatives/criticalpath/
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Main mMain mMain mMain m
Failure rate of phase 3 confirFailure rate of phase 3 confir
Few industry case studFew industry case stud
Desire to streamline clinicalDesire to streamline clinical
Desire to take advantage of nDesire to take advantage of nare not impacting success ratare not impacting success rat
Concern for a non sustainabConcern for a non sustainab Concern for a non sustainabConcern for a non sustainab
This is a problem for multipThis is a problem for multipacademics, regulators, patienacademics, regulators, patien
regulatory science is nregulatory science is nrecognized as a disciplrecognized as a discipl
messagesmessagesmessagesmessages
rmatory trialsrmatory trials
dies diagnosing the causesdies diagnosing the causes
trials trials
new science and discoveries that new science and discoveries that tes for new treatmentstes for new treatments
ble model for drug developmentble model for drug developmentble model for drug developmentble model for drug development
ple stakeholders (industry, ple stakeholders (industry, nts) nts)
not well understood or not well understood or lineline
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The PhRMAThe PhRMAdiscussion discussion discussion discussion
A WG with A WG with (JBS 2006) (JBS 2006) (JBS 2006) (JBS 2006)
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Impact of PDUImpact of PDUFDA negotiated andFDA negotiated and
on Adapton Adapt
FA IV (Sept. 2007)FA IV (Sept. 2007)d promised a guidance d promised a guidance tive Designstive Designs
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Two RegulatoTwo RegulatoIssued (20Issued (20Issued (20Issued (20
ory Guidances ory Guidances 006 2010)006 2010)006, 2010)006, 2010)
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Philosophy of FPhilosophy of FPhilosophy of FPhilosophy of F
Understandable to a wiUnderstandable to a wiclinicians and statisticiaclinicians and statisticiaclinicians and statisticiaclinicians and statisticia
Cautionary but encouraCautionary but encourastudies and for confirmstudies and for confirm
ddwarrantedwarranted
Terminology and definiTerminology and definiSeamless Phase 2 /PhaseSeamless Phase 2 /PhaseSeamless Phase 2 /PhaseSeamless Phase 2 /Phaseexploration with confirmexploration with confirm
We are still learning, exWe are still learning, exl dl d
ggevolving , as is methodoevolving , as is methodo
FDA Guidance FDA Guidance FDA Guidance FDA Guidance
de audience, including de audience, including ans and othersans and othersans, and othersans, and others
age use for exploratory age use for exploratory matory studies, if and when matory studies, if and when
itions are important: itions are important: e 3 terminology confuses e 3 terminology confuses e 3 terminology confuses e 3 terminology confuses mationmation
xamples are increasing and xamples are increasing and ll
p gp gologyology
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Definition andDefinition andd id iadaptiveadaptive(FDA Gu(FDA Gu
For the purposes of this guFor the purposes of this guclinical study is defined as clinical study is defined as
ti l l d d ti l l d d prospectively planned and sprospectively planned and spotential for modification opotential for modification oaspects of the study design aspects of the study design
l i f d t f bjl i f d t f bjanalysis of data from subjecanalysis of data from subjecof the accumulating study dof the accumulating study dprospectively planned poinprospectively planned poinb f d i b f d i f ll blif ll blibe performed in a be performed in a fully blinfully blinblinded mannerblinded manner, and may, at, and may, atoccur with or without formoccur with or without formt ti ( d i i t l ) t ti ( d i i t l ) testing (eg. decision tools). testing (eg. decision tools).
d concept of an d concept of an d i d ie designe design
uidance)uidance)idance, an adaptive design idance, an adaptive design a study that includes a a study that includes a
ifi d difi tiifi d difi ti specified modificationspecified modification or or of one or more specified of one or more specified and hypotheses, and hypotheses, based on based on t i th t dt i th t d A l A l cts in the studycts in the study. Analyses . Analyses
data are often performed at data are often performed at nts within the study, may nts within the study, may
d d i d d i nded manner or in a nonnded manner or in a non--t an interim time point, t an interim time point,
mal statistical hypothesis mal statistical hypothesis
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Some ClarSome Clar(FDA G(FDA G(FDA Gu(FDA Gu
hh “ i ”“ i ” hhThe The term “prospective”term “prospective” hereherewas planned (and details spewas planned (and details speexamined in an unblinded foexamined in an unblinded foinvolved in planning for theinvolved in planning for theinvolved in planning for theinvolved in planning for theplans that are introduced or plans that are introduced or has commenced if confidenchas commenced if confidencthe personnel involved is unthe personnel involved is unthe personnel involved is unthe personnel involved is unand documented when the mand documented when the mproposed. The documentatioproposed. The documentatiounequivocal assurance of bliunequivocal assurance of bli
l hil d i l hil d i personnel while a study is onpersonnel while a study is onto discuss with FDA. to discuss with FDA. ChangChangoccurring after an interim anoccurring after an interim andata and that were not prospdata and that were not prospdata and that were not prospdata and that were not prospwithin the scope of this guidwithin the scope of this guid
rificationsrificationsid )id )uidance)uidance)
h h d ih h d ie means that the adaptation e means that the adaptation ecified) before data were ecified) before data were orm by any personnel orm by any personnel
e revision This can include e revision This can include e revision. This can include e revision. This can include finalized after the study finalized after the study
ce in the blinded state of ce in the blinded state of nequivocally maintained nequivocally maintained nequivocally maintained nequivocally maintained modification plan is modification plan is on that can support on that can support inding for the necessary inding for the necessary
i b i i b i ngoing may be important ngoing may be important ges in study design ges in study design nalysis of unblinded nalysis of unblinded study study pectively planned are not pectively planned are not pectively planned are not pectively planned are not dance. dance.
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Some ClarSome Clar(FDA G(FDA G(FDA Gu(FDA Gu
R i i d dR i i d dRevisions made or proposedRevisions made or proposedanalysisanalysis raise major concernraise major concernpotential introduction of biapotential introduction of biad fi d d f ll i ld fi d d f ll i ldefined and carefully impledefined and carefully impleirresolvable uncertainty in tirresolvable uncertainty in tIn contrast, In contrast, revisions based revisions based
f d t ( t f d t ( t of data (e.g., aggregate evenof data (e.g., aggregate evenrates, baseline characteristicrates, baseline characteristicbias to the study or into subbias to the study or into subth l C t ith l C t ithe same personnel. Certainthe same personnel. Certainsuch as sample size revisionsuch as sample size revisionor variance, are advisable pror variance, are advisable pr
b i l l b i l lcan be prospectively plannecan be prospectively planne
rificationsrificationsid )id )uidance)uidance)
d ft bli d d i t id ft bli d d i t id after an unblinded interimd after an unblinded interimns about study integrity (i.e., ns about study integrity (i.e., as) and need to be prospectively as) and need to be prospectively
t d t id i ki t d t id i ki emented to avoid risking emented to avoid risking the interpretation of study results. the interpretation of study results. on blinded interim evaluations on blinded interim evaluationst t i di ti ti t t i di ti ti t rates, variance, discontinuation t rates, variance, discontinuation
cs, etc.) usually do not introduce cs, etc.) usually do not introduce bsequent study revisions made by bsequent study revisions made by
bli d d bli d d d t b d h d t b d h n blindedn blinded--data based changes, data based changes, ns based on aggregate event rates ns based on aggregate event rates rocedures for most studies, and rocedures for most studies, and d d ed. ed.
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ConfirmatoryConfirmatoryExploratorExploratorExploratorExplorator
Confirmatory studieConfirmatory studied t d lld t d lladequate and welladequate and well--cc
phase clinical studiephase clinical studiehypotheseshypotheseshypotheseshypotheses
Exploratory studies Exploratory studies primary basis for effprimary basis for effprimary basis for effprimary basis for effwell designed to addwell designed to addexplore dose, populaexplore dose, populaconditions, PD endpconditions, PD endp
y studies and y studies and ry studiesry studiesry studiesry studies
es : otherwise known as es : otherwise known as t ll d ll l t t ll d ll l t controlled, usually later controlled, usually later
es that have prees that have pre--stated stated
: not intended as : not intended as ficacy evaluations yet ficacy evaluations yet ficacy evaluations yet ficacy evaluations yet dress dose selection or dress dose selection or ations, optimal study ations, optimal study points, markers, etc.points, markers, etc.
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I t f th d fI t f th d fImpact of the drafImpact of the draf
Alot of comments and specific Alot of comments and specific
Generally well receivedGenerally well received
S i l i ‘l S i l i ‘l Some terminology issues: ‘less Some terminology issues: ‘less with their actual usewith their actual use
Set out FDA’s expectations andSet out FDA’s expectations and
Communication and expCommunication and expFDA, investigators, NIH FDA, investigators, NIH
CDER is receiving protocols forCDER is receiving protocols formedical areasmedical areasmedical areasmedical areas
Internal education of both cliniInternal education of both clini
Discussions of the operational Discussions of the operational
ft id t d tft id t d tft guidance to dateft guidance to date
suggestions for editssuggestions for edits
ll d d’ l i ll d d’ l i well understood’ vs. less experience well understood’ vs. less experience
d a framework to move forwardd a framework to move forward
perience is needed, among industry, perience is needed, among industry, and others and others
r adaptive designs across many r adaptive designs across many
icians and statisticiansicians and statisticians
modelmodel
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The intersection oThe intersection ob i hb i hbayesian approachesbayesian approaches
We are not there yet, buWe are not there yet, buin progressin progressin progressin progress
The NIH/FDA ADThe NIH/FDA AD
F th di iF th di i Further discussionFurther discussiondemonstrate familydemonstrate familycontrol for multiplcontrol for multipldesignsdesignsdesignsdesigns
Promotion to all when oPromotion to all when oissues issues –– a potential to raa potential to ra
ddpp
contribute to disappoincontribute to disappoin
of frequentist and of frequentist and t d ti d i t d ti d is to adaptive designss to adaptive designs
ut interesting initiatives are ut interesting initiatives are
APTAPT--IT projectIT project
i l ti t i l ti t n on simulations to n on simulations to y wise strong type 1 y wise strong type 1 le hypotheses in K stage le hypotheses in K stage
only a few understand the only a few understand the aise expectations and aise expectations and
l dl dpp
ntments ntments –– it can be solvedit can be solved
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The Bayesian / FrequThe Bayesian / FrequEnrichmentEnrichmentEnrichmentEnrichment
uentist Intersectionuentist Intersectiont strategiest strategiest strategiest strategies
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ADAPT‐IT ‐ ObjeADAPT IT Obje
• “To illustrate and exploreTo illustrate and explore clinical trial designs to impdrugs and medical devicesdrugs and medical devicesmethods to characterize aopinions and concerns ofopinions, and concerns of and after the developmen
ectiveective
how best to use adaptivehow best to use adaptive prove the evaluation of s and to use mixeds and to use mixed and understand the beliefs, f key stakeholders duringf key stakeholders during nt process.”
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ADAPT‐IT ‐ ObjeADAPT IT Obje
• “To illustrate and exploreTo illustrate and explore clinical trial designs to impdrugs and medical devicesdrugs and medical devicesmethods to characterize aopinions and concerns ofopinions, and concerns of and after the developmen
ectiveective
how best to use adaptivehow best to use adaptive prove the evaluation of s and to use mixeds and to use mixed and understand the beliefs, f key stakeholders duringf key stakeholders during nt process.”
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UNIQUE PUBLIC/PRIVACOLLABORATION
NETT—Neurological Emergnetwork
‐NINDS funded clinical t
B C lt tBerry Consultants‐Statistical Consulting com
innovative/adaptive designsinnovative/adaptive designs
ATE
gencies Treatment Trials
trials network (NS056975)
mpany specializing in (Bayesian)(Bayesian)
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Specific TaskSpecific Task• Design four, five clinical g ,trials– Status Epilepticus (Refractory)(Refractory)
– Glycemic control in stroke– Spinal cord traumap– Post cardiac arrest hypothermiaProgesterone for ischemic– Progesterone for ischemic stroke
ksks• Learn about processp
– Surveys– Focus Groups– Observation– Key Stakeholder Interviews– Thematic analysisThematic analysis
Ed t• Educate– Clinicians– Statisticians
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Statisticians
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ADAPT‐IT ProcADAPT IT Proc• Investigators and statisDi li i l blFTF ‐ 1 • Discuss clinical problem
• Berry Consultants presCTC
y p• Clinical & data teams p
Si l ti t dPerf WG
• Simulations presented • Several iterations
FTF – 2
• Near final design prese• Work out final details f
cesscesssticians meet
d i l d im and potential designs
ent concept pprovides feedback
ith f db kwith feedback
entationfor grant / IND submission
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Wh t i FDA’ i tWh t i FDA’ i tWhat is FDA’s interWhat is FDA’s inter
P d i l i iP d i l i i Promote and stimulate innovationPromote and stimulate innovation
Contribute feedback to a novel projectContribute feedback to a novel project
Involve multiple centers (CDRH, CBERInvolve multiple centers (CDRH, CBERmultiple disciplines (clinical and statismultiple disciplines (clinical and statismultiple disciplines (clinical and statismultiple disciplines (clinical and statis
Expand the experience base (actual examExpand the experience base (actual exam
Operationally, disciplines, consOperationally, disciplines, cons
Most of FDA’s experience is witMost of FDA’s experience is witnetwork, funding streams, studynetwork, funding streams, study
These clinical studies are dealing with These clinical studies are dealing with solutions to date solutions to date –– ie. Study failures ie. Study failures -- itityycontribution to refining the issues, studcontribution to refining the issues, stud
The project has an evaluation of the proThe project has an evaluation of the pro
t i ADAPTt i ADAPT ITITrest in ADAPTrest in ADAPT--ITIT
R, CDER ) in the collaboration and R, CDER ) in the collaboration and tical) in the experiencetical) in the experiencetical) in the experiencetical) in the experience
mples) with adaptive designsmples) with adaptive designs
stituencies (NIH, academics, industry)stituencies (NIH, academics, industry)
th the industry and not the NIH th the industry and not the NIH y sectionsy sections
complex issues that have not had good complex issues that have not had good t is an opportunity to determine if new t is an opportunity to determine if new pp ypp ydy designs, questions, etc.dy designs, questions, etc.
ocess and an assessment of participantsocess and an assessment of participants
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A lot of movingA lot of movingd i d i EEdesigns designs –– ExEx
ConfirmConfirm
Response or outcome adaptive rResponse or outcome adaptive rprognostic covariates vs. both aprognostic covariates vs. both a
Longitudinal modeling of interLongitudinal modeling of interoutcomes to aid in random allocoutcomes to aid in random alloc
Assumed models and evaAssumed models and evaof early date to later outcof early date to later outc
Type 1 error control for multiplType 1 error control for multiplof simulation vs closed form tesof simulation vs closed form tes
Dose response estimation vs. piDose response estimation vs. pione study or two studies in seqone study or two studies in seq
Currently, no sample size reCurrently, no sample size re--estest
g parts to these g parts to these l t l t xploratory or xploratory or
matorymatory
randomization vs. balancing on randomization vs. balancing on and the proper analysis of suchand the proper analysis of such
rmediate outcome and final clinical rmediate outcome and final clinical cation or in recruitment strategiescation or in recruitment strategies
aluation of strength of association aluation of strength of association ggcomecome
le hypotheses le hypotheses –– not that easy not that easy –– role role stingsting
icking the right dose or doses icking the right dose or doses –– in in quencequence
timationtimation
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Enrichment Enrichment strategies strategies –– thethe
with adaptivwith adaptivwith adaptivwith adaptiv
A guidance on enricA guidance on enricsoon be out for commsoon be out for commsoon be out for commsoon be out for commcommitment from Pcommitment from P
designs and designs and eir relationship eir relationship ve approachesve approachesve approachesve approaches
hment designs will hment designs will ment ment –– another another ment ment another another DUFA IVDUFA IV
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Genomics, biomGenomics, biomsubsets and tarsubsets and tarsubsets and tarsubsets and tar
markers, patient markers, patient rgeted therapyrgeted therapyrgeted therapyrgeted therapy
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Nested sub-populatiop p ons
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What are someWhat are someconcerns aconcerns aconcerns aconcerns a
Trust in the firewallTrust in the firewallimplementing the adimplementing the adunblindingunblinding
The new role for datThe new role for datcommittees, if they tcommittees, if they tyyresponsibilityresponsibility
e of the current e of the current and issuesand issuesand issuesand issues
l process for l process for daptations that require daptations that require
ta monitoring ta monitoring take on this take on this
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Early reportingEarly reportingEarly reportingEarly reportingunblinding, preservunblinding, preservcritical for adaptivecritical for adaptivecritical for adaptivecritical for adaptive
g of trial results g of trial results g of trial results, g of trial results, ving trial integrity ving trial integrity ––e designs to succeede designs to succeede designs to succeede designs to succeed
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May 7May 7May 7May 77 20127 20127, 20127, 2012
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Is the Data MonitIs the Data Monitd l id l imodel appropriatemodel appropriate
adaptive adaptive
IndependenceIndependence
FirewallsFirewalls
Al ith Al ith Algorithms vs more Algorithms vs more choiceschoices
Concern for back calConcern for back calsize resize re--estimation anestimation an
Who represents the sWho represents the s
toring Committee toring Committee f i l if i l ie for implementing e for implementing
designs ?designs ?
fl ibilit i d i i fl ibilit i d i i flexibility in decision flexibility in decision
lculation in sample lculation in sample nd inducing biasnd inducing bias
sponsor, if at allsponsor, if at all
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A BA B P d t f tP d t f tA ByA By--Product of tProduct of t
Better up front planning andBetter up front planning andclinical trials, fixed or adapticlinical trials, fixed or adapticlinical trials, fixed or adapticlinical trials, fixed or adapti
Consideration of routine useConsideration of routine useadvance how trial assumptioadvance how trial assumptiounexpected features will impunexpected features will impunexpected features will impunexpected features will imp
My concern !My concern !
Not enough time to doNot enough time to do Not enough time to doNot enough time to dofast fast –– this is a return tothis is a return to
th AD i iti tith AD i iti tithe AD initiativethe AD initiative
d design choices for all late phase d design choices for all late phase ive ive –– the choice is not obviousthe choice is not obviousive ive the choice is not obviousthe choice is not obvious
e of simulations to play out in e of simulations to play out in ons as well as unknown or ons as well as unknown or pact results pact results NOT THAT EASYNOT THAT EASYpact results pact results –– NOT THAT EASYNOT THAT EASY
o the planning o the planning –– desire to move too desire to move too o the planning o the planning –– desire to move too desire to move too o failure in my mindo failure in my mind
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AdaptiveAdaptiveHave stimulated a Have stimulated a modeling and simumodeling and simu
among clinical tamong clinical tgg
Designs for confirmDesigns for confirm
Designs for exploratDesigns for explorat Designs for exploratDesigns for explorat
Designs to accommoDesigns to accommo
Software availabilitySoftware availability
e designse designs renewed interest in renewed interest inulation, particularly ulation, particularly trial statisticianstrial statisticians
mationmation
tiontiontiontion
odate bothodate both
y ?y ?
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Models caModels caModels caModels ca
Mechanistic: assuming Mechanistic: assuming
Disease progression basDisease progression basfollowfollow--up data: clinical up data: clinical d d i i l d l fi i l d l fdata data -- empirical model fempirical model f
Models for the study deModels for the study de
MultiMulti--center, adapcenter, adap
Stochastic probabilisticStochastic probabilistic Stochastic, probabilisticStochastic, probabilistic
an includean includean includean include
one knows enough one knows enough
sed upon longitudinal sed upon longitudinal trials or observational trials or observational fi ifi ifittingfitting
esign itselfesign itself
tive, group sequentialtive, group sequential
c sources of variabilityc sources of variabilityc, sources of variabilityc, sources of variability
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SimulSimulMany options aMany options aMany options aMany options aUsed for planniUsed for planni
To evaluate what you obTo evaluate what you obsuspected suspected -- sensitivity asensitivity asuspected suspected sensitivity asensitivity a
To evaluate what you hTo evaluate what you hdata approaches data approaches -- fill infill in
i h i bi h i bpoints where it was obspoints where it was obs
To predict what you didTo predict what you didapproaches with properapproaches with properapproaches with properapproaches with properuncertainty associated wuncertainty associated wprediction itselfprediction itself
l fl f To evaluate performancTo evaluate performancbias, achieved dose levebias, achieved dose leve
lationslationsand applicationsand applicationsand applicationsand applicationsing and analysising and analysis
bserved, but where bias is bserved, but where bias is analysisanalysisanalysisanalysis
have not observed have not observed -- missing missing n data between design n data between design
ddservedserved
d not observe d not observe -- prediction prediction r accounting for stochastic r accounting for stochastic r accounting for stochastic r accounting for stochastic with model selection and with model selection and
ce characteristics; power, ce characteristics; power, elsels
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The current eThe current efor protocofor protocofor protocofor protoco
Simulate the performance chaSimulate the performance chadesigns , fixed or adaptive, befordesigns , fixed or adaptive, beforexercise to engage the entire deveexercise to engage the entire deve
made and the expectations suchmade and the expectations suchmade and the expectations suchmade and the expectations sucheveryone understand variability, everyone understand variability, uncertainties involved uncertainties involved –– that shouthat shou
environmentenvironmentol planningol planningol planningol planning
aracteristics of candidate study aracteristics of candidate study re they are carried out and use the re they are carried out and use the lopment team in the choices to be lopment team in the choices to be h choices present h choices present it will help it will help h choices present h choices present –– it will help it will help sources of heterogeneity, and the sources of heterogeneity, and the uld reduce failure rates hopefullyuld reduce failure rates hopefully
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Interactions with FDAInteractions with FDAof an adaptiveof an adaptivepp
possibly dupossibly du
Early and Middle PerioEarly and Middle Perio
Late stages of drug deveLate stages of drug deve
Special Protocol AssessSpecial Protocol Assesspp
FDA does not wish to bFDA does not wish to bdesign decisions, as witdesign decisions, as witdecisionsdecisions
However, it may be timHowever, it may be timi t i ht di t i ht dinspects, oversights, audinspects, oversights, audcompliance with SOP’s compliance with SOP’s
A during the planning A during the planning e design study and e design study and g yg yuring its conducturing its conduct
d of Drug developmentd of Drug development
elopmentelopment
mentsments
be involved in any adaptive be involved in any adaptive th not being aware of DMC th not being aware of DMC
me to consider how one me to consider how one dit d dit d dits, and assures dits, and assures for firewalls for firewalls
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Wh t d thWh t d thWhat do othWhat do oth
A lot of literature coming ouA lot of literature coming oublinded access to interim datblinded access to interim dat
Others suggest new ways to Others suggest new ways to designsdesigns
V l t i i t i l t V l t i i t i l t Value to up sizing a trial to mValue to up sizing a trial to mzone’zone’
Interesting to see and hear NInteresting to see and hear Nresponse and/or reactions response and/or reactions nnresponse and/or reactions response and/or reactions –– nnthisthis
Also interesting in ADAPTAlso interesting in ADAPT--IIinteractions and iterative feeinteractions and iterative feeinteractions and iterative feeinteractions and iterative feeexperienceexperience
h thi k ?h thi k ?hers think ?hers think ?
ut ut –– some do not even agree that some do not even agree that ta protects type 1 errorta protects type 1 errorp ypp yp
analyze response adaptive analyze response adaptive
i t i i t i th ‘ i i th ‘ i i maintain power maintain power –– the ‘promising the ‘promising
NIH network statisticians NIH network statisticians not clear where they are with not clear where they are with not clear where they are with not clear where they are with
IT to observe the clinical team IT to observe the clinical team edback edback –– part of the learning part of the learning edback edback –– part of the learning part of the learning
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So what have wSo what have wthe last 5 ythe last 5 ythe last 5 ythe last 5 y
There has been an extensive literatuThere has been an extensive literatu
Regulators have helped focus the pRegulators have helped focus the p Regulators have helped focus the pRegulators have helped focus the pfuture of these designs (Europe andfuture of these designs (Europe and
A lot of education remains A lot of education remains –– but it ibut it i
Several companies now specializinSeveral companies now specializin p pp p
FDA feedback and constructive advFDA feedback and constructive advare viewed and usedare viewed and used
Methodology is not the issue Methodology is not the issue –– impimp
Over promotion; naïve unblOver promotion; naïve unbl
Continued need for communicationContinued need for communication
we learned over we learned over years or soyears or soyears or soyears or so
ure developed on AD’s with good ideas ure developed on AD’s with good ideas
purpose utility and framework for the purpose utility and framework for the purpose, utility and framework for the purpose, utility and framework for the d US)d US)
is happening; conferences, ADAPTis happening; conferences, ADAPT--ITIT
ng in advice and designng in advice and designg gg g
vice is very important to how the designs vice is very important to how the designs
plementation isplementation is
linding can be a problemlinding can be a problem
n among disciplines and experiencen among disciplines and experience
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6 | Horizontal | Short | Landscape | Yes | Landscape