08.30 Registration & Coffee

08.50 Chairman’s Opening RemarksAlex Sverdlov, Director, Statistical Scientist, Novartis

THERAPEUTIC POTENTIAL OF ADAPTIVE DESIGNS

OPENING ADDRESS09.00 Statistical and design considerations in personalised medicine

• Identifyinggenetic,genomicandclinicalcharacteristicstopredict patient susceptibility

• Biomarkersandthechallengesintheirusefordiagnostics• Selectingappropriatedesignstodeterminebiomarker

performance, reliability and regulatory acceptance• Casestudiesforbiomarkerdriventrials Sandeep Menon, Vice President and Head of Early Clinical Development, Pfizer

SPOTLIGHT SESSION09.40 Adaptive designs in multiple sclerosis clinical trials

• MSSocietyinitiativetoestablishplatformtrial• Thepracticalitiesofsettingupplatformtrials• MethodologicalchallengesinMStrialdesign• EthicalandpatientperspectiveonadaptivedesignsEmma Gray, Head of Clinical Trials, MS Society

10.20 Morning Coffee

10.50 Adaptive signature designs for cancer vaccines• Mage-A3:adouble-blind,randomised,placebo-controlled,

phase 3 trial• Thepracticalandoperationalconsiderationsof

immunotherapeutic adaptive designs• Futilityforsubgroupanalysesinadaptivesignaturedesign• Thefutureofadaptivedesignsforcancervaccines Andrea Callegaro, Senior Manager, Biostatistician, GSK Vaccines

DEEP DIVE11.30 TheEuropeanPreventionofAlzheimer’s

Disease platform trial• EPADisapublic-privatepartnershiprunning

two connected trials:- A longitudinal cohort study identifying subjects with

biomarker evidence of early Alzheimer’s- An adaptive platform trial for Proof-of-concept testing of newpreventivetreatments,recruitingfromthefirsttrial

• Advantagesanddisadvantagesoftestingdrugsinthissetup compared to classical one-drug trials

Philip Hougaard, Vice President Biometrics, H.Lundbeck

12.10 Networking Lunch

REGULATORY OUTLOOK OF ADAPTIVE DESIGNS

KEYNOTE ADDRESS13.10 An industry outlook on adaptive designs in clinical trials

• Innovationsofadaptivedesignsinclinicaltrials• Howhastheuseofadaptivedesignsinclinicaltrials

developed?• ViewsonthedraftFDAguidanceonadaptivedesigns• HeadsofMedicinesAgencies:ClinicalTrialsFacilitation

Group practical implicationsChristine Fletcher, Executive Director Biostatistics, Amgen

13.50 The evolution of adaptiveness• RecentupdatesinEuropeanguidance• TheMAPPsengagementprocess• Criticalquestionstobeasked• Adaptiveapproachestobringingdrugstothemarket Solange Corriol-Rohou, Senior Director Regulatory Affairs and Policy, EU, AstraZeneca

14.30 Afternoon Tea

15.00 A regulatory perspective of adaptive design trials• InitialClinicalTrialAuthorisation(CTA):pointstoconsider• Regulatorypointstoconsiderforsubmissionswith

substantial amendments• SafetyconsiderationsBeatrice Panico, Medical Assessor, MHRA

15.40 Using Estimand Framework in Adaptive Designs: The implication of ICH E9 R(1) • ICHE9(R1)andadaptiveclinicaltrials• Usingestimandframeworkinadaptiveclinicaltrials• DesignchallengesthatICHE9(R1)mightbringtoadaptive

designs• ImpactofICHE9(R1)ontheanalysisofadaptiveclinicaltrials Macaulay Okwuokenye, Associate Director Biostatistics, Syros Pharmaceuticals Inc

16.20 Chairman’s Closing Remarks and Close of Day One

Adaptive Designs in Clinical Trials Day One | Monday 1st April 2019

LETTER FROM THE CHAIRS:

Dear participants,

It is eleven years since the start of SMi’s series of conferences on Adaptive Designs in Clinical Trials and twenty years since I started working on adaptive trials. There are now multiple threads that continue to drive the development of adaptive designs, their acceptance and their use. These threads include the radical “Platform Trial” design, the impact of advances in digital technology, the increased potential of personalized medicine and the attitude of regulators.

With so many evolving themes it is hard, even for an avid practitioner of adaptive designs, to stay current across all of them which is why conferences such as this are so useful. With a diverse program and experienced speakers the conference presents a vibrant and up to date cross-section of current practice in adaptive clinical trial design.

As the chairs of this event, we look forward to personally welcoming you to this must-attend conference in London this April.

Tom Parke, Alex Sverdlov,Director, Director, of Software Solutions Statistical Scientist, Berry Consulting Novartis

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08.30 Registration & Coffee

08.50 Chairman’s Opening Remarks

Tom Parke, Director of Software Solutions, Berry Consulting

CLINICAL APPROACHES OF ADAPTIVE DESIGNS

OPENING ADDRESS

09.00 Digital therapeutics: an integral component of digital

innovation in drug development

• Thepotentialforreducingcurrentcostsofmedicalcare

• Theunmetmedicalneedsaddressedbydigitaltherapeutics

• Emergingpathwaystoregulatoryapproval

• Howinnovativebusinessmodelsareenablingfurther

growth in digital therapeutics

Alex Sverdlov, Director Statistical Scientist, Novartis

09.40 Applying adaptive designs in industry

• OverviewofadaptivedesignsatBI

• Jointescalationmodelsinoncologydosefinding

• EarlyphasebasketdesignsandGoNoGodecisionmaking

• Blindedsamplesizereassessment–isthereafuture?

Frank Fleischer, Expert Statistician Methodology,

Boehringer-Ingelheim

10.20 Morning Coffee

10.50 Extrapolation in clinical trials and beyond

• Basicsofextrapolation:whenisitapplicable-andwhennot

• Extrapolationfromadultstochildren:“adaptive”borrowing

• Bridgingstudies

• Beyondindividualstudies:extrapolationviamixturemodels

for meta-analysis

Simon Wandel, Associate Director, Statistical Methodology and

Consulting, Novartis

11.30 Continuous Decision Making within a Clinical Trial

• OverviewofDecisionMakinginEarlyclinicaldevelopmentat

AstraZeneca

• Incorporatingcontinuousdecisionmakingintotheframework

• Standardizingtools/figurestoconveytheinformation

• Statisticalrisksandconsiderationsinadoptingthisapproach

Paul Frewer, Early Clinical Development, AstraZeneca

12.10 Networking Lunch

STATISTICAL APPROACHES OF ADAPTIVE DESIGNS

SPOTLIGHT SESSION13.10 Forward looking response-adaptive designs

• Thebenefitsofforwardlookingresponse-adaptiverandomisation in adaptive designs

• Trialsforrarediseasesandfindingtreatmentsthatwork subgroups

• Type1errorinflationduetoanunknowntimetrendover the course of the trial

SofiaVillar,Senior Statistician, MRC Biostatistics Unit

PANEL DISCUSSION13.50 Bayesian vs. frequentist designs incorporating

multiple treatment arms• Response-adaptiverandomisation• Triangulartests• Droppingpoorly-performingarmsinmulti-arm

multi-stage designs• FlexibilityinBayesianvs.frequentistdesignsModerated by: Michael Proschan, Mathematical Statistician, National Institute of Allergy and Infectious Diseases, USAPanellists:KasparRufibach,Principal Statistical Scientist, RocheAlex Sverdlov, Director, Statistical Scientist, NovartisSofiaVillar,Senior Statistician, MRC Biostatistics Unit

14.30 Planning a phase 3 trial with time-to-event endpoint• TheMIRROSphase3trial• Futilityinterimanalysisusingamechanisticsimulationmodel• Samplesizeplanning• Explorationofoperatingcharacteristicsofthefutilityinterim

analysisKasparRufibach,Principal Statistical Scientist, Roche

15.10 Afternoon Tea

15.40 Definingdecisionrulesbasedonsimulateddevelopmentprograms• Go/nogodecisionafterphase2andfutilityanalysisinphase

3 trials based on estimated probability of success• Probabilityofsuccessisestimatedusingsimulationstaking

into account observed association between short-term andlong-term endpoint from phase 2

• Simulationofcompletephase2and3developmentprogramallowstodefineappropriatedecisionboundaries

Heiko Goette, Biostatistician, Merck KGaA

16.20 Chairman’s Closing Remarks and Close of Day Two

Adaptive Designs in Clinical Trials Day Two | Tuesday 2nd April 2019

Register online at www.adaptivedesigns.co.uk

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The FDA – a new guidance on adaptive designs

Workshop Leader: Tom Parke, Director of Software Solutions, Berry Consulting

HALF-DAY POST-CONFERENCE WORKSHOP AWednesday 3rd April 2019

08.30 – 12.30Holiday Inn Kensington Forum, London, UK

Overview of the workshop:ThenewFDAdraftguidanceonAdaptiveTrialsisasignificantchange from the 2010 version of the draft guidance. This workshop will look at the changes and what it means for submitting proposals for adaptive trials to the FDA.

The workshop will cover:• Howtosubmitadaptivedesignstoregulators• Whatthecontentsofthedocumentsshouldbe• Whatsimulationdetailsneedtobesubmitted• Whatproblemstoexpect• Howtosubmitsimulationresults• Howtosubmitsimulationsoftware

Why you should attend?• Attendthisworkshopifyouwouldliketounderstand:• HowthenewguidancereflectschangesattheFDA• HowtojustifytheuseofanadaptivedesigntotheFDA• Howtodocumentanadaptivedesign• How to organise, perform, and report the clinical trial

simulations necessary to support an adaptive design• Howtoreporttheresultsofanadaptivedesign

Programme08.30 Registration and Coffee09.00 Opening remarks and introductions09.10 A look at the draft guidance in detail

• Changestothedetailedprinciples• Classesofadaptivedesigns• Operationaldetailsandconsiderations• Regulatoryinteractionandsubmissionguidance

09.50 Describing and justifying a proposal to perform an adaptive trial• Statisticalefficiency• Ethicalconsiderations• Operationalconsiderations• Broaderquestionsthetrialmightaddress• Stakeholderflexibility

10.30 Morning Coffee11.00 Trial simulation necessary to support

a complex trial design• Howtosimulatetrials• Theartofsimulatingclinicaltrials–choosing

scenarios & choosing operating characteristics• Avoidingdoingtoomuch• Showingtype-1errorcontrol

11.40 Submitting the results of an adaptive trial• Analysisofresultsandanalysiscode• Interimanalysesandresults• Interimcommunications

12.20 Closing remarks12.30 End of workshop

About the workshop leaderTom Parke is Director of Software Solutions for Berry Consultants. Tom joined Berry Consultants in 2016 having previously worked at Tessella, a UK scientific softwarecompany where he first met and worked with Don Berry.In 1998 Tom managed the development and running of a softwaresystemtosupportPfizer’sASTINStroketrial–agroundbreaking response adaptive randomization dose ranging trial designed by Don Berry and Peter Mueller. Following that he managed multiple projects to support different aspects of many adaptive clinical trials, mostly designed by Berry Consultants, and projects to develop clinical trial simulators, first with Pfizer, then Wyeth, andfinally with Eli Lilly to develop FACTS. Latterly, as well asmanaging the continuing development of FACTS, Tom has researched the estimation of expected Net Present Value of development programs leading to the development of the QUOTES software package.Tom originally graduated with joint First Class Honors in Maths and Computer Science from Bristol University, and enjoyed two decades in the software industry (inmos, ImperialSoftware Technology and then Praxis - which became part ofDeloittes)before stumblingupon thewonderfulworldofadaptive clinical trials.

Berry ConsultantsBerry Consultants is a statistical consulting company specializing in the Bayesian approach to medical statistics, an approach that is radically changing the way research is done throughout the medical industry in both device and drug development.

Berry Consultants employs world renowned experts in Bayesian statistics and strives to set the standard for innovative clinical trial design and analysis in the statistical and medical communities.

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Design and analysis of clinical trials evaluating novel digital technologies

Workshop Leader: Alex Sverldlov, Director, Statistical Scientist, Novartis

YevgenRyeznik, PhD, Uppsala University

HALF-DAY POST-CONFERENCE WORKSHOP BWednesday 3rd April 2019

13.30 – 17.30Holiday Inn Kensington Forum, London, UK

Overview of the workshopDigital technologies (such as wearable devices, smartphoneapps) are increasingly used in clinical research anddevelopment. Despite numerous pilot clinical studies evaluating merits of digital technologies, there is still little knowledge on how to properly design and run such studies, and how to analyse the collected experimental data. The current course will cover several important statistical aspects of clinical trials evaluating digital technologies.

Why you should attend?Attend this workshop if you would like to understand:• Potentialchallengesandbenefitsofutilizingdigital

technologies in clinical research• Whattrialdesignsareavailableforevaluatingdigital

technologies• Howtoanalyzedatageneratedbydigitaltechnologies• Currentregulatorypathwaystotheapprovalofdigital

therapeutics

Programme

13.30 Registration and Coffee

14.00 Opening remarks and introductions

14.10 Innovative designs for developing mobile health interventions•Micro-randomizedtrials•MOSTandSMARTdesigns•Choiceofsamplesize•Dataanalysisaspects

14.50 Digital biomarkers as screening/diagnostic tools•Challengesandopportunities•Classificationproblems• Buildingpredictorsofclinicaloutcomes

15.30 Afternoon Tea

16.00 Digital therapeutics•Addressingunmetmedicalneed• Emergingbusinessmodels• Clinicaltrialstodevelopdigitalhealth

interventions

16.40 Current regulatory landscape for digital health technologies• Pathwaystoregulatoryapprovalofadevice• Existingregulatoryguidelines• Examplesofsuccessfulapprovals

17.20 Closing Remarks

17.30 End of Workshop

About the workshop leadersAlex Sverdlov has worked as a statistical scientist in biopharmaceutical industry since 2007. He has been involved in active research on adaptive designs for clinical trials to improveefficiencyofdrugdevelopment.Heeditedabook“Modern Adaptive Randomized Clinical Trials: Statistical and Practical Aspects” which was published by CRC Press in 2015. Alex’s most recent work involves design of proof-of-endpoint clinical trials evaluating digital technologies in neuroscience.

Since 2014, Yevgen Ryeznik is a Ph.D. student in Uppsala University, Uppsala. Before that, he had a 2-year experience of working as a SAS programmer and clinical data analyst in the Ukrainian department of Quartesian LLC, a CRO located inPrinceton,NJ.Forthelasttenyears,hehasbeenactivelyinvolved in research on optimal designs and adaptive randomization for clinical trials, mainly, trials with time-to-event outcomes. Yevgen’s most recent research interests are digital therapeutics and mobile health, and applications of deep learning for biopharmaceutics.

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