Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm

A P tiA P tiA Perspective oA Perspective o
Environment for AEnvironment for A
TriTri
Robert T. ORobert T. O
Senior StatistSenior Statist
Office of TranslationalOffice of Translational
For presentation at the 2nd Annual East U
MA ; October 12, 2012
th C tth C ton the Currenton the Current
Adaptive ClinicalAdaptive Clinicalpp
ialsials
’Neill, PhD’Neill, PhD
tical Advisortical Advisor
l Sciences, CDER, FDAl Sciences, CDER, FDA
ser Group Meeting, Cambridge,
1
6 | Horizontal | Short | Landscape | Yes | Landscape

Outline oOutline oOutline oOutline o
 How did the adaptive dHow did the adaptive d
h did it d l ithh did it d l ithhow did it develop withhow did it develop with
environmentenvironment
 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 anddesign initiative begin and
hi th l thi th l thin the regulatoryhin the regulatory
i ii ig innovationg innovation
rent climaterent climate
2

http://wwww.fda.gov/oc/initiatives/criticalpath/
3

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 n
are 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 multip
academics, regulators, patienacademics, regulators, patien
 regulatory science is nregulatory science is n
recognized as a disciplrecognized as a discipl
messagesmessagesmessagesmessages
rmatory trialsrmatory trials
dies diagnosing the causesdies diagnosing the causes
trialstrials
new science and discoveries thatnew 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 ornot well understood or
lineline
4

5

6

The PhRMAThe PhRMA
discussiondiscussiondiscussiondiscussion
A WG withA WG with
(JBS 2006)(JBS 2006)(JBS 2006)(JBS 2006)
7

Impact of PDUImpact of PDU
FDA negotiated andFDA negotiated and
on Adapton Adapt
FA IV (Sept. 2007)FA IV (Sept. 2007)
d promised a guidanced promised a guidance
tive Designstive Designs
8

9

10

11

Two RegulatoTwo Regulato
Issued (20Issued (20Issued (20Issued (20
ory Guidancesory Guidances
006 2010)006 2010)006, 2010)006, 2010)
12

Philosophy of FPhilosophy of FPhilosophy of FPhilosophy of F
 Understandable to a wiUnderstandable to a wi
clinicians and statisticiaclinicians and statisticiaclinicians and statisticiaclinicians and statisticia
 Cautionary but encouraCautionary but encoura
studies and for confirmstudies and for confirm
ddwarrantedwarranted
 Terminology and definiTerminology and defini
Seamless Phase 2 /PhaseSeamless Phase 2 /PhaseSeamless Phase 2 /PhaseSeamless Phase 2 /Phase
exploration with confirmexploration with confirm
 We are still learning, exWe are still learning, ex
l dl d
gg
evolving , as is methodoevolving , as is methodo
FDA GuidanceFDA GuidanceFDA GuidanceFDA Guidance
de audience, includingde audience, including
ans and othersans and othersans, and othersans, and others
age use for exploratoryage use for exploratory
matory studies, if and whenmatory studies, if and when
itions are important:itions are important:
e 3 terminology confusese 3 terminology confusese 3 terminology confusese 3 terminology confuses
mationmation
xamples are increasing andxamples are increasing and
ll
p gp g
ologyology
13

Definition andDefinition and
d id iadaptiveadaptive
(FDA Gu(FDA Gu
For the purposes of this guFor the purposes of this gu
clinical study is defined asclinical study is defined as
ti l l d dti l l d dprospectively planned and sprospectively planned and s
potential for modification opotential for modification o
aspects of the study designaspects of the study design
l i f d t f bjl i f d t f bjanalysis of data from subjecanalysis of data from subjec
of the accumulating study dof the accumulating study d
prospectively planned poinprospectively planned poin
b f d ib f d i f ll blif ll blibe performed in abe performed in a fully blinfully blin
blinded mannerblinded manner, and may, at, and may, at
occur with or without formoccur with or without form
t ti ( d i i t l )t ti ( d i i t l )testing (eg. decision tools).testing (eg. decision tools).
d concept of and concept of an
d id ie designe design
uidance)uidance)
idance, an adaptive designidance, an adaptive design
a study that includes aa study that includes a
ifi d difi tiifi d difi tispecified modificationspecified modification oror
of one or more specifiedof one or more specified
and hypotheses,and hypotheses, based onbased on
t i th t dt i th t d A lA lcts in the studycts in the study. Analyses. Analyses
data are often performed atdata are often performed at
nts within the study, maynts within the study, may
d d id d inded manner or in a nonnded manner or in a non--
t an interim time point,t an interim time point,
mal statistical hypothesismal statistical hypothesis
14

Some ClarSome Clar
(FDA G(FDA G(FDA Gu(FDA Gu
hh “ i ”“ i ” hhTheThe term “prospective”term “prospective” herehere
was planned (and details spewas planned (and details spe
examined in an unblinded foexamined in an unblinded fo
involved in planning for theinvolved in planning for theinvolved in planning for theinvolved in planning for the
plans that are introduced orplans that are introduced or
has commenced if confidenchas commenced if confidenc
the personnel involved is unthe personnel involved is unthe personnel involved is unthe personnel involved is un
and documented when the mand documented when the m
proposed. The documentatioproposed. The documentatio
unequivocal assurance of bliunequivocal assurance of bli
l hil d il hil d ipersonnel while a study is onpersonnel while a study is on
to discuss with FDA.to discuss with FDA. ChangChang
occurring after an interim anoccurring after an interim an
data and that were not prospdata and that were not prospdata and that were not prospdata and that were not prosp
within the scope of this guidwithin the scope of this guid
rificationsrifications
id )id )uidance)uidance)
h h d ih h d ie means that the adaptatione means that the adaptation
ecified) before data wereecified) before data were
orm by any personnelorm by any personnel
e revision This can includee revision This can includee revision. This can includee revision. This can include
finalized after the studyfinalized after the study
ce in the blinded state ofce in the blinded state of
nequivocally maintainednequivocally maintainednequivocally maintainednequivocally maintained
modification plan ismodification plan is
on that can supporton that can support
inding for the necessaryinding for the necessary
i b ii b ingoing may be importantngoing may be important
ges in study designges in study design
nalysis of unblindednalysis of unblinded studystudy
pectively planned are notpectively planned are notpectively planned are notpectively planned are not
dance.dance.
15

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 proposed
analysisanalysis raise major concernraise major concern
potential introduction of biapotential introduction of bia
d fi d d f ll i ld fi d d f ll i ldefined and carefully impledefined and carefully imple
irresolvable uncertainty in tirresolvable uncertainty in t
In contrast,In contrast, revisions basedrevisions based
f d t ( tf d t ( tof data (e.g., aggregate evenof data (e.g., aggregate even
rates, baseline characteristicrates, baseline characteristic
bias to the study or into subbias to the study or into sub
th l C t ith l C t ithe same personnel. Certainthe same personnel. Certain
such as sample size revisionsuch as sample size revision
or variance, are advisable pror variance, are advisable pr
b i l lb i l lcan be prospectively plannecan be prospectively planne
rificationsrifications
id )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 interim
ns about study integrity (i.e.,ns about study integrity (i.e.,
as) and need to be prospectivelyas) and need to be prospectively
t d t id i kit d t id i kiemented to avoid riskingemented to avoid risking
the interpretation of study results.the interpretation of study results.
on blinded interim evaluationson blinded interim evaluations
t t i di ti tit t i di ti tit rates, variance, discontinuationt rates, variance, discontinuation
cs, etc.) usually do not introducecs, etc.) usually do not introduce
bsequent study revisions made bybsequent study revisions made by
bli d dbli d d d t b d hd t b d hn blindedn blinded--data based changes,data based changes,
ns based on aggregate event ratesns based on aggregate event rates
rocedures for most studies, androcedures for most studies, and
dded.ed.
16

ConfirmatoryConfirmatory
ExploratorExploratorExploratorExplorator
 Confirmatory studieConfirmatory studie
d t d lld t d lladequate and welladequate and well--cc
phase clinical studiephase clinical studie
hypotheseshypotheseshypotheseshypotheses
 Exploratory studiesExploratory studies
primary basis for effprimary basis for effprimary basis for effprimary basis for eff
well designed to addwell designed to add
explore dose, populaexplore dose, popula
conditions, PD endpconditions, PD endp
y studies andy studies and
ry studiesry studiesry studiesry studies
es : otherwise known ases : otherwise known as
t ll d ll l tt ll d ll l tcontrolled, usually latercontrolled, usually later
es that have prees that have pre--statedstated
: not intended as: not intended as
ficacy evaluations yetficacy evaluations yetficacy evaluations yetficacy evaluations yet
dress dose selection ordress dose selection or
ations, optimal studyations, optimal study
points, markers, etc.points, markers, etc.
17

I t f th d fI t f th d fImpact of the drafImpact of the draf
 Alot of comments and specificAlot of comments and specific
 Generally well receivedGenerally well received
 S i l i ‘lS i l i ‘l Some terminology issues: ‘lessSome 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 exp
FDA, investigators, NIHFDA, investigators, NIH
 CDER is receiving protocols forCDER is receiving protocols for
medical areasmedical areasmedical areasmedical areas
 Internal education of both cliniInternal education of both clini
 Discussions of the operationalDiscussions 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 ill d d’ l iwell understood’ vs. less experiencewell 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 othersand others
r adaptive designs across manyr adaptive designs across many
icians and statisticiansicians and statisticians
modelmodel
18

The intersection oThe intersection o
b i hb i hbayesian approachesbayesian approaches
 We are not there yet, buWe are not there yet, bu
in progressin progressin progressin progress
 The NIH/FDA ADThe NIH/FDA AD
 F th di iF th di i Further discussionFurther discussion
demonstrate familydemonstrate family
control for multiplcontrol for multipl
designsdesignsdesignsdesigns
 Promotion to all when oPromotion to all when o
issuesissues –– a potential to raa potential to ra
dd
pp
contribute to disappoincontribute to disappoin
of frequentist andof frequentist and
t d ti d it d ti d is to adaptive designss to adaptive designs
ut interesting initiatives areut interesting initiatives are
APTAPT--IT projectIT project
i l ti ti l ti tn on simulations ton on simulations to
y wise strong type 1y wise strong type 1
le hypotheses in K stagele hypotheses in K stage
only a few understand theonly a few understand the
aise expectations andaise expectations and
l dl d
pp
ntmentsntments –– it can be solvedit can be solved
19

The Bayesian / FrequThe Bayesian / Frequ
EnrichmentEnrichmentEnrichmentEnrichment
uentist Intersectionuentist Intersection
t strategiest strategiest strategiest strategies
20

ADAPT‐IT ‐ ObjeADAPT IT Obje
• “To illustrate and exploreTo illustrate and explore
clinical trial designs to imp
drugs and medical devicesdrugs and medical devices
methods to characterize a
opinions 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.”
21
21

ADAPT‐IT ‐ ObjeADAPT IT Obje
• “To illustrate and exploreTo illustrate and explore
clinical trial designs to imp
drugs and medical devicesdrugs and medical devices
methods to characterize a
opinions 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.”
22
22

UNIQUE PUBLIC/PRIVA
COLLABORATION
NETT—Neurological Emerg
network
‐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)
23
23

Specific TaskSpecific Task
• Design four, five clinical g ,
trials
– Status Epilepticus
(Refractory)(Refractory)
– Glycemic control in stroke
– Spinal cord traumap
– Post cardiac arrest
hypothermia
Progesterone 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
24
Statisticians
24

ADAPT‐IT ProcADAPT IT Proc
• Investigators and statis
Di li i l blFTF ‐ 1 • Discuss clinical problem
• Berry Consultants pres
CTC
y p
• Clinical & data teams p
Si l ti t d
Perf WG
• Simulations presented
• Several iterations
FTF – 2
• Near final design prese
• Work out final details f
cesscess
sticians meet
d i l d im and potential designs
ent concept p
provides feedback
ith f db kwith feedback
entation
for grant / IND submission
25
25

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, CBER
multiple 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 wit
network, funding streams, studynetwork, funding streams, study
 These clinical studies are dealing withThese clinical studies are dealing with
solutions to datesolutions to date –– ie. Study failuresie. Study failures -- itityy
contribution 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 andR, 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 NIHth the industry and not the NIH
y sectionsy sections
complex issues that have not had goodcomplex issues that have not had good
t is an opportunity to determine if newt is an opportunity to determine if newpp ypp y
dy designs, questions, etc.dy designs, questions, etc.
ocess and an assessment of participantsocess and an assessment of participants
26

A lot of movingA lot of moving
d id i EEdesignsdesigns –– ExEx
ConfirmConfirm
 Response or outcome adaptive rResponse or outcome adaptive r
prognostic covariates vs. both aprognostic covariates vs. both a
 Longitudinal modeling of interLongitudinal modeling of inter
outcomes to aid in random allocoutcomes to aid in random alloc
 Assumed models and evaAssumed models and eva
of early date to later outcof early date to later outc
 Type 1 error control for multiplType 1 error control for multipl
of simulation vs closed form tesof simulation vs closed form tes
 Dose response estimation vs. piDose response estimation vs. pi
one 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 theseg parts to these
l tl txploratory orxploratory or
matorymatory
randomization vs. balancing onrandomization vs. balancing on
and the proper analysis of suchand the proper analysis of such
rmediate outcome and final clinicalrmediate outcome and final clinical
cation or in recruitment strategiescation or in recruitment strategies
aluation of strength of associationaluation of strength of associationgg
comecome
le hypothesesle hypotheses –– not that easynot that easy –– rolerole
stingsting
icking the right dose or dosesicking the right dose or doses –– inin
quencequence
timationtimation
27

EnrichmentEnrichment
strategiesstrategies –– thethe
with adaptivwith adaptivwith adaptivwith adaptiv
 A guidance on enricA guidance on enric
soon be out for commsoon be out for commsoon be out for commsoon be out for comm
commitment from Pcommitment from P
designs anddesigns and
eir relationshipeir relationship
ve approachesve approachesve approachesve approaches
hment designs willhment designs will
mentment –– anotheranothermentment anotheranother
DUFA IVDUFA IV
28

29

Genomics, biomGenomics, biom
subsets and tarsubsets and tarsubsets and tarsubsets and tar
markers, patientmarkers, patient
rgeted therapyrgeted therapyrgeted therapyrgeted therapy
30

Nested sub-populatiop p ons
31

32

What are someWhat are some
concerns aconcerns aconcerns aconcerns a
 Trust in the firewallTrust in the firewall
implementing the adimplementing the ad
unblindingunblinding
 The new role for datThe new role for dat
committees, if they tcommittees, if they tyy
responsibilityresponsibility
e of the currente of the current
and issuesand issuesand issuesand issues
l process forl process for
daptations that requiredaptations that require
ta monitoringta monitoring
take on thistake on this
33

Early reportingEarly reportingEarly reportingEarly reporting
unblinding, preservunblinding, preserv
critical for adaptivecritical for adaptivecritical for adaptivecritical for adaptive
g of trial resultsg of trial resultsg of trial results,g of trial results,
ving trial integrityving trial integrity ––
e designs to succeede designs to succeede designs to succeede designs to succeed
34

35

May 7May 7May 7May 77 20127 20127, 20127, 2012
36

37

38

Is the Data MonitIs the Data Monit
d l id l imodel appropriatemodel appropriate
adaptiveadaptive
 IndependenceIndependence
 FirewallsFirewalls
 Al ithAl ith Algorithms vs moreAlgorithms vs more
choiceschoices
 Concern for back calConcern for back cal
size resize re--estimation anestimation an
 Who represents the sWho represents the s
toring Committeetoring Committee
f i l if i l ie for implementinge for implementing
designs ?designs ?
fl ibilit i d i ifl ibilit i d i iflexibility in decisionflexibility in decision
lculation in samplelculation in sample
nd inducing biasnd inducing bias
sponsor, if at allsponsor, if at all
39

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 and
clinical trials, fixed or adapticlinical trials, fixed or adapticlinical trials, fixed or adapticlinical trials, fixed or adapti
 Consideration of routine useConsideration of routine use
advance how trial assumptioadvance how trial assumptio
unexpected 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 do
fastfast –– 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 phased design choices for all late phase
iveive –– the choice is not obviousthe choice is not obviousiveive the choice is not obviousthe choice is not obvious
e of simulations to play out ine of simulations to play out in
ons as well as unknown orons as well as unknown or
pact resultspact results NOT THAT EASYNOT THAT EASYpact resultspact results –– NOT THAT EASYNOT THAT EASY
o the planningo the planning –– desire to move toodesire to move tooo the planningo the planning –– desire to move toodesire to move too
o failure in my mindo failure in my mind
40

AdaptiveAdaptive
Have stimulated aHave 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 inrenewed interest in
ulation, particularlyulation, particularly
trial statisticianstrial statisticians
mationmation
tiontiontiontion
odate bothodate both
y ?y ?
41

Models caModels caModels caModels ca
 Mechanistic: assumingMechanistic: assuming
 Disease progression basDisease progression bas
followfollow--up data: clinicalup data: clinical
dd i i l d l fi i l d l fdatadata -- 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 enoughone knows enough
sed upon longitudinalsed upon longitudinal
trials or observationaltrials 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
42

SimulSimul
Many options aMany options aMany options aMany options a
Used for planniUsed for planni
 To evaluate what you obTo evaluate what you ob
suspectedsuspected -- sensitivity asensitivity asuspectedsuspected sensitivity asensitivity a
 To evaluate what you hTo evaluate what you h
data approachesdata 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 did
approaches with properapproaches with properapproaches with properapproaches with proper
uncertainty associated wuncertainty associated w
prediction itselfprediction itself
 l fl f To evaluate performancTo evaluate performanc
bias, achieved dose levebias, achieved dose leve
lationslations
and applicationsand applicationsand applicationsand applications
ing and analysising and analysis
bserved, but where bias isbserved, but where bias is
analysisanalysisanalysisanalysis
have not observedhave not observed -- missingmissing
n data between designn data between design
ddservedserved
d not observed not observe -- predictionprediction
r accounting for stochasticr accounting for stochasticr accounting for stochasticr accounting for stochastic
with model selection andwith model selection and
ce characteristics; power,ce characteristics; power,
elsels
43

The current eThe current e
for protocofor protocofor protocofor protoco
Simulate the performance chaSimulate the performance cha
designs , fixed or adaptive, befordesigns , fixed or adaptive, befor
exercise 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 such
everyone understand variability,everyone understand variability,
uncertainties involveduncertainties involved –– that shouthat shou
environmentenvironment
ol planningol planningol planningol planning
aracteristics of candidate studyaracteristics of candidate study
re they are carried out and use there they are carried out and use the
lopment team in the choices to belopment team in the choices to be
h choices presenth choices present it will helpit will helph choices presenth choices present –– it will helpit will help
sources of heterogeneity, and thesources of heterogeneity, and the
uld reduce failure rates hopefullyuld reduce failure rates hopefully
44

45

46

47

48

49

Interactions with FDAInteractions with FDA
of 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 b
design decisions, as witdesign decisions, as wit
decisionsdecisions
 However, it may be timHowever, it may be tim
i t i ht di t i ht dinspects, oversights, audinspects, oversights, aud
compliance with SOP’scompliance with SOP’s
A during the planningA during the planning
e design study ande design study andg yg y
uring its conducturing its conduct
d of Drug developmentd of Drug development
elopmentelopment
mentsments
be involved in any adaptivebe involved in any adaptive
th not being aware of DMCth not being aware of DMC
me to consider how oneme to consider how one
dit ddit ddits, and assuresdits, and assures
for firewallsfor firewalls
50

Wh t d thWh t d thWhat do othWhat do oth
 A lot of literature coming ouA lot of literature coming ou
blinded access to interim datblinded access to interim dat
 Others suggest new ways toOthers suggest new ways to
designsdesigns
 V l t i i t i l tV l t i i t i l t Value to up sizing a trial to mValue to up sizing a trial to m
zone’zone’
 Interesting to see and hear NInteresting to see and hear N
response and/or reactionsresponse and/or reactions nnresponse and/or reactionsresponse and/or reactions –– nn
thisthis
 Also interesting in ADAPTAlso interesting in ADAPT--II
interactions and iterative feeinteractions and iterative feeinteractions and iterative feeinteractions and iterative fee
experienceexperience
h thi k ?h thi k ?hers think ?hers think ?
utut –– some do not even agree thatsome do not even agree that
ta protects type 1 errorta protects type 1 errorp ypp yp
analyze response adaptiveanalyze response adaptive
i t ii t i th ‘ i ith ‘ i imaintain powermaintain power –– the ‘promisingthe ‘promising
NIH network statisticiansNIH network statisticians
not clear where they are withnot clear where they are withnot clear where they are withnot clear where they are with
IT to observe the clinical teamIT to observe the clinical team
edbackedback –– part of the learningpart of the learningedbackedback –– part of the learningpart of the learning
51

So what have wSo what have w
the 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 p
future of these designs (Europe andfuture of these designs (Europe and
 A lot of education remainsA 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 adv
are viewed and usedare viewed and used
 Methodology is not the issueMethodology is not the issue –– impimp
 Over promotion; naïve unblOver promotion; naïve unbl
 Continued need for communicationContinued need for communication
we learned overwe learned over
years or soyears or soyears or soyears or so
ure developed on AD’s with good ideasure developed on AD’s with good ideas
purpose utility and framework for thepurpose utility and framework for thepurpose, utility and framework for thepurpose, 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 designsvice 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
52

Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm

Recomendados

Recomendados

Mais conteúdo relacionado

Semelhante a Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm

Semelhante a Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm (20)

Mais de Cytel USA

Mais de Cytel USA (20)

Eugm 2012 oneill - perspective on the current environment for adaptive clinical trials - 2012 eugm