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,

1

6 | Horizontal | Short | Landscape | Yes | Landscape

mike

Typewriter

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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5


6


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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9


10


11


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.”

21

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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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48


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

Documents

horizontal short landscape

drug developmentble

adaptive d h

ooutline ooutline ooutline

nregulatory science

main mmain mmain mmain

discoveries thatnew

patien regulatory science