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

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

  1. 1. 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
  2. 2. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  3. 3. http://wwww.fda.gov/oc/initiatives/criticalpath/ 3 6 | Horizontal | Short | Landscape | Yes | Landscape
  4. 4. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  5. 5. 5 6 | Horizontal | Short | Landscape | Yes | Landscape
  6. 6. 6 6 | Horizontal | Short | Landscape | Yes | Landscape
  7. 7. The PhRMAThe PhRMA discussiondiscussiondiscussiondiscussion A WG withA WG with (JBS 2006)(JBS 2006)(JBS 2006)(JBS 2006) 7 6 | Horizontal | Short | Landscape | Yes | Landscape
  8. 8. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  9. 9. 9 6 | Horizontal | Short | Landscape | Yes | Landscape
  10. 10. 10 6 | Horizontal | Short | Landscape | Yes | Landscape
  11. 11. 11 6 | Horizontal | Short | Landscape | Yes | Landscape
  12. 12. Two RegulatoTwo Regulato Issued (20Issued (20Issued (20Issued (20 ory Guidancesory Guidances 006 2010)006 2010)006, 2010)006, 2010) 12 6 | Horizontal | Short | Landscape | Yes | Landscape
  13. 13. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  14. 14. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  15. 15. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  16. 16. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  17. 17. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  18. 18. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  19. 19. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  20. 20. The Bayesian / FrequThe Bayesian / Frequ EnrichmentEnrichmentEnrichmentEnrichment uentist Intersectionuentist Intersection t strategiest strategiest strategiest strategies 20 6 | Horizontal | Short | Landscape | Yes | Landscape
  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.” 21 21 6 | Horizontal | Short | Landscape | Yes | Landscape
  22. 22. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  23. 23. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  24. 24. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  25. 25. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  26. 26. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  27. 27. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  28. 28. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  29. 29. 29 6 | Horizontal | Short | Landscape | Yes | Landscape
  30. 30. Genomics, biomGenomics, biom subsets and tarsubsets and tarsubsets and tarsubsets and tar markers, patientmarkers, patient rgeted therapyrgeted therapyrgeted therapyrgeted therapy 30 6 | Horizontal | Short | Landscape | Yes | Landscape
  31. 31. Nested sub-populatiop p ons 31 6 | Horizontal | Short | Landscape | Yes | Landscape
  32. 32. 32 6 | Horizontal | Short | Landscape | Yes | Landscape
  33. 33. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  34. 34. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  35. 35. 35 6 | Horizontal | Short | Landscape | Yes | Landscape
  36. 36. May 7May 7May 7May 77 20127 20127, 20127, 2012 36 6 | Horizontal | Short | Landscape | Yes | Landscape
  37. 37. 37 6 | Horizontal | Short | Landscape | Yes | Landscape
  38. 38. 38 6 | Horizontal | Short | Landscape | Yes | Landscape
  39. 39. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  40. 40. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  41. 41. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  42. 42. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  43. 43. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  44. 44. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  45. 45. 45 6 | Horizontal | Short | Landscape | Yes | Landscape
  46. 46. 46 6 | Horizontal | Short | Landscape | Yes | Landscape
  47. 47. 47 6 | Horizontal | Short | Landscape | Yes | Landscape
  48. 48. 48 6 | Horizontal | Short | Landscape | Yes | Landscape
  49. 49. 49 6 | Horizontal | Short | Landscape | Yes | Landscape
  50. 50. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  51. 51. 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 6 | Horizontal | Short | Landscape | Yes | Landscape
  52. 52. 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 6 | Horizontal | Short | Landscape | Yes | Landscape

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