PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING (PART I)

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5/5/2017PHASE I/II CLINICAL TRIALDESIGN AND DOSEFINDING (PART I)(CHAPTER 1, 7)1NAITEE TING, BOEHRINGER-INGELHEIMDRUG DEVELOPMENT PROCESSDrug DiscoveryNon-clinical DevelopmentClinical Development2 Phase I Clinical pharmacology (PK/PD, MTD) Phase II Drug efficacy/safety, dose ranging Phase III Long-term, large scale, confirmatory Phase IV Post-market1

5/5/2017PHASE I CLINICAL TRIALS – NONLIFE-THREATENING DISEASESHealthy normal volunteersPrimarily for PK propertiesHelp recommend dosing frequencyEstimate maximally tolerated dose (MTD)3Dose escalation design or crossover designs are popular inPhase ICONCERNS IN DEVELOPING DRUGSFOR LIFE-THREATENING DISEASESMay not be ethical to use placebo controlMay not be ethical to recruit normal healthy volunteers4Open label, single arm, dose escalation study designs2

5/5/2017DOSE-FINDING IN ONCOLOGYCancer patients in Phase INot ethical for placebo controlDose limiting toxicity (DLT)P[toxicity at MTD] 5Where is the target probability of toxicityDOSE-FINDING IN ONCOLOGYTRADITIONAL 3 3 DESIGNThe most widely used design in oncologySubjects are assigned in groups of 3If only 3 subjects on the current dose, then6 no toxicity - 3 on next higher dose one toxicity - add 3 on the same dose two or more toxicity - MTD is exceeded3

5/5/2017DOSE-FINDING IN ONCOLOGYTRADITIONAL 3 3 DESIGNIf 6 patients on the same dose, then:7 If at most one toxicity - 3 on next higher dose If two or more toxicities - MTD exceededThe estimated MTD is the highest dose level with observedtoxicity rate less than 0.33.PHASE II CLINICAL TRIALSFirst Phase II is Proof of Concept (PoC)Followed by dose-ranging trialsObjective is to propose dose(s) for Phase III designMoving doses down to MinED8If dose-range is not found in Phase II, it will be too expensivein later Phases4

5/5/2017PROOF OF CONCEPT (POC)STUDY Typically two treatment groups Parallel design Placebo controlled Use a dose at MTD or close to MTD Short term, clinical efficacy endpoint (surrogate markersmay be used at times)9 Moderate sample sizeSAMPLE SIZE FOR A POC DESIGNPeople come to statistician asking for sample sizeThis is the opportunity for a statistician to contribute to thestudy designAssuming is positiveAssuming variance 110N is calculated given and 5

5/5/2017PROOF OF CONCEPTHypothesis testingPrimary endpoint is clinical efficacyPre-specified two-sided alpha could be 0.05Power may be greater than 80%11Go/No Go decisionPROPOSE A TOOL TO HELP WITHCOMMUNICATIONSA communication tool is proposed to help the team membersin understanding the risksDiscussions should happen before breaking blindAfter the design is finalized12Clear Go/No Go criteria can be documented6

135/5/2017STATISTICAL HYPOTHESISH0: T P vs H1: T Pis tested at Type I error 0z ( z z )The distance between z and reflect the absolute value of z 14Hence z z 7

5/5/201715DECISION PROCESS16DECISION PROCESS8

5/5/2017DOSE RANGING STUDY Parallel dose groups Placebo controlled Duration of treatment limited by animal tox coverage Many doses of test drug17 Objective is to explore a range of efficacious dosesMINIMUM EFFECTIVE DOSE(MINED)Imagine the difficulty in a PoC studyIt was MTD in PoCFrom a dose ranging design, there are multiple test dosesWhen each dose is compared with placebo, there is a PoCdiscussion18Which dose is efficacious? And the minimal dose?9

5/5/2017WHAT IS DOSE RANGE?Suppose study A is designed with placebo, 20 mg, 40 mg,and 80 mgStudy B with placebo, 0.1 mg, 1 mg, and 10 mg19Which design has a wider range?WHAT IS DOSE RANGE?Dose range for a given study is defined as the high dosedivided by the low dose in the designDesign A has a dose range of 420Design B has a dose range of 10010

5/5/2017CONCERNS IN DOSE RANGINGSTUDIES Number of doses to be tested Need an active control? Dose spacing Choice of endpoints21 Length of studyWHY POC AND DOSE RANGINGSEPARATE? Not sure if test drug works Formulation (dose strength) limitations Extrapolation from PD endpoints to clinical efficacyendpoints Investment/cost22 Possible ethical concerns11

5/5/2017IMPACT OF POC DECISIONSDrug formulationOrdering large quantity of raw materials?Long term toxicity studies?Clear Go/No Go decision very critical23Avoid inconclusivenessRISKS OF INCONCLUSIVENESSClinical trial process: design - conduct - unblind - results ? Decision ?To go? Or not to go? is the questionThis decision has to be madeDelay in this decision impact formulation,order of raw materials, and tox studies24Inconclusiveness happens between studyresults and decision12

5/5/2017RISKS OF INCONCLUSIVENESSAfter results are ready, there is very little a statistician can doThe critical time for statisticians to help the team is at thedesign stageClearly communicate the Type I and II risks2625Define Go/No Go criteria13

5/5/20172827INDIVIDUAL DOSE RESPONSEAND POPULATION DOSERESPONSE14

295/5/2017DRUG LABEL (PACKAGE INSERT) Summary Information of the Drug Agreed with Regulatory Agencies Target Product Profile Competitors on Market30 Easy for Physicians to prescribe15

5/5/2017PLANNING PROCESSForward: Accumulating informationBackward: Planning Based on apter 1WHAT ARE THE ISSUES IN DOSEFINDING? Individual versus global responses What are you looking for? What range of doses should we consider? How many doses to be tested? What are we measuring?32 The differences in exploration and confirmation16

5/5/2017INDIVIDUAL VERSUS GLOBALRESPONSES In most of drugs, we need to recommend a few fixed doses For wide Therapeutic Index (TI), it is possible to use onedose33 Dose response relationship vs concentration responserelationshipPHARMACOKINETICS (PK),PHARMACODYNAMICS (PD) PK, PD, PK/PD34 PK: body act on drug PD: drug act on body Concentration response uses PK, but should we considerPD?17

5/5/2017DETERMINING DOSINGFREQUENCY When determining dosing frequency, the35pharmacodynamics of a compound shouldbe considered as critical as thepharmacokinetics In contrast to the pharmacokinetic half-life,the pharmacodynamic half-life will be dosedependent Will a control release formulation beneeded?QD Feasible if high levels arewell tolerated, otherwisewill need to default toBID dosing or change shapeof curve with CR.12h24hQ day dosing at 2x doseBid Dosing at 1x doseMinimal effective levelby PD marker36Drug ConcentrationDETERMINING DOSINGFREQUENCY18

5/5/2017IS THERE A DOSE TANCE OF 8Placebo19

5/5/2017ACTIVE aceboACTIVE lacebo20

5/5/2017ACTIVE CONTROL Active control is not strictly necessary It serves as a useful control in case thetest drug “doesn’t work” or works poorly Active control “worked” or not? An active comparator may also be criticalif there is an effective competitor on themarket41 How appropriate are Phase II comparisons? Statistically valid vs “looks similar”?DRUG ASTUDY 1 - WHAT’S NEXT?0Placebo80 mg120 mg160 mg-5-10Series1-15-2042-2521

5/5/2017DRUG ASTUDY 2 - WHAT’S NEXT?0-5Placebo 40 mg80 mg120 mg-10Series1-15-2043-25DRUG AAfter study 2, the Phase III study started with dose 120 mgAt end of Phase II meeting, FDA questioned about dose44We designed the third dose finding study to look at doses 2.5mg, 10 mg and 40 mg22

5/5/2017DRUG A - STUDY 30Placebo2.5 mg10 mg40 mg-5-10Series1-15-2045-25DRUG ARedesigned Phase III studies with 20 mg and 40 mgIt took 3 studies to find the efficacy dose responseThe large scale study with 120 mg cannot be used forregistration46Filing was delayed by many years23

475/5/2017MULTIPLE-ARM DOSE-RESPONSETRIALMonotonic dose-response relationship is very common inpractice.Two groups are not sufficient to characterize the nonlinearnature of dose-response.48Multiple-arm trial is specially informative for drug with a widetherapeutic window.24

5/5/2017WHAT RANGE OF DOSES SHOULD WECONSIDER In early Phase II, not much information available (preclinical, PK, MTD) We know 0 (Placebo), we know MTD Exploring an Adequate Dose Range49 Selecting Doses for Early Dose-ranging StudiesWHAT RANGE OF DOSES SHOULD WECONSIDER Examine a wide dose range in early development and follow thisstudy with a narrower dose range study Use pharmacological response or biological markers from animal50studies and phase I studies to guide the selection in dose range forthe early studies Although not always attainable in early studies, a goal should be totry and define the Maximally Tolerated Dose (MTD), the MaximallyEffective Dose (MaxED), and the Minimum Effective Dose (MinED)25

5/5/2017HOW MANY DOSES TO BE TESTED Can we set all possible doses to test Do we include control groups If so, which controls51 Spacing between dosesLIMITED NUMBER OF FIXEDDOSES Multiple center designs Formulation considerations Placebo and maximally tolerable dose (MTD) Incorporate active control?52 Concerns in interpreting titration dose26

5/5/2017TREATMENT BY CENTERINTERACTIONPlacebo LowMedium High6768Center 21101Center 3423253Center 1LIMITED NUMBER OF FIXEDDOSES Too few doses may not cover a wide range Can we study all possible doses? Under fixed total sample size, too many doses left very fewsubjects per dose54 Based on intensive simulation, it is recommended to use 4to 5 doses, plus placebo27

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5/5/2017BINARY DOSE SPACING For 2 test doses, one above 1/2, one below Continue with this fashion to the lower end Any cut for 1/p, where p 2 Non-parametric, model independent59 Applies to titration design, sequential design, activecontrol, early or late PhaseBINARY DOSE SPACING Assume MTD known and non-decreasing relationship Intuitive and with wide applications Model independent60 A general recommendation, not one size fits all30

5/5/2017DRUG B: EXPLORATORYSTUDY – PRIMARY ENDPOINTWeek0-1012-2Placebo-3-450 mg-5250 mg61-6DRUG B: EXPLORATORYSTUDY – SECONDARYENDPOINT5050 MG250 MGPlacebo3020100-4-3-2-101234Negative Indicates Improvement62Percent4031

5/5/2017DRUG B: DESIGNCONSIDERATIONSThe safety profile indicates the high dose could be too highSecondary endpoints are used to help design the next studyUse of MCP-Mod63Consider a linear modelDRUG B: DOSE RANGINGSTUDY DESIGNLength of study restricted by toxicity coveragePlacebo controlledIncluding an active control64Proposed 5 test doses – 2.5 mg, 5 mg, 12.5 mg, 25 mg and 75mg32

5/5/2017DRUG BSTUDY ies1-3-465-5WHAT ARE WE MEASURING PD marker, clinical endpoint (hard, soft) or safety Efficacy can’t be observed from normal volunteer Early Phase or late phase Time after baseline (short, long)66 Multiple endpoints33

5/5/2017MULTIPLE Y DESIGN – ANALYSISPLAN – STUDY REPORTSample size calculationPrimary and secondary endpointsEfficacy and safetyOther analyses of interestStatistical Analysis Plan (SAP) – more details68Clinical Study Report (CSR)34

5/5/2017DESIGN CONSIDERATIONSA stepwise approachConfirmatory – go/no go decisionAfter confirmation, then explore –Secondary endpointsMultiple treatment comparisonsDose response modelingSafety analysesSubset analyses69 DESIGN CONSIDERATIONSClinical question – Clinical objectives – Study designAre these objectives clear enough?Are they sequential?Which part is confirmatory?70What are the exploratory objectives?35

5/5/2017EFFICACY VS SAFETYIn most studies, sample size calculation is based on efficacy,or PKSafety data are observed after study read outEfficacy or PK is for confirmatory purposes71Safety is exploratory36

5/5/2017PHASE I/II CLINICAL TRIALDESIGN AND DOSEFINDING (PART II)QIQI se I dose escalation design1:45-2:45Phase II dose finding study: Hypothesis Testing2:45-3:00Break3:00-3:45Modeling of dose response, including Emax model.3:45‐4:00Optimal Design.37

5/5/2017PHASE I DOSEESCALATION STUDY3 3, BLRM AND EWOC(CHAPTER 3, 4, 5)OBJECTIVE FOR PHASE I DOSEFINDING0.60.20.4Toxicity0.0response0.81.0Phase I0MRSD204060dose80MTD/MFD/PAD10038

5/5/2017PHASE I DOSE FINDING STUDYPrimary objective(s): Estimate the maximum tolerable dose (MTD) ormaximum feasible dose (MFD) For a compound with limited toxicity, a dosebased on PAD may be used For oncology, to define the recommendedphase 2 dose (RP2D)PHASE I: TERMINOLOGYMRSD: Maximum recommended starting doseNOAELs: No-observed adverse effect levelsHED: Human equivalent doseMTD: Maximal tolerable doseMFD: Maximal feasible dosePAD: Pharmacologically active dose39

5/5/2017DOSE SELECTION FOR FIHCAVEATS FORPHARMACOLOGICALLY ACTIVE DOSE PAD may not be possible Knowledge of animal models of disease or mechanism ofaction (MoA) Target site and receptors may be absent or modified PAD may not be reliable Extrapolation from animal to human Route of administration often different PD effect vs clinical effect PAD often helpful in guiding the dose escalation, but overconfidence may lead to inconclusive results in phase II.40

5/5/2017PD MARKER OR CLINICAL ENDPOINTPHASE I DESIGNIN HEALTHY VOLUNTEERSRD: Single rising studyMRD: Multiple rising study41

5/5/2017TRADITIONALLY IN ONCOLOGY DF Generally assumed toxicity is a prerequisite for optimal antitumoractivity for cytotoxic agents (Wooley and Schein, 1979) Monotonicity for efficacy Dose limiting toxicity (DLT) usually defined based on CTCAE (National Cancer InstituteCommon Terminology Criteria for Adverse Events), e.g. astreatment related nonhematological toxicity Grade 3, ortreatment related hematological toxicity Grade 4. RP2D are often close to MTD ( ), whereSELECTION OF DOSE FORONCOLOGY Too low a starting dose or slow escalation is a concern Murine LD10: Dose with approximately 10% mortality mice 1/10 or 2/10 of murine equivalent of LD10 (milligrams perm2) as starting dose Based on estimated MTD Modified Fibonacci is often used: (x, 2x, 3x, 5x, 7x, 9x, 12x, and 16x) or Increase of (100, 65, 50, 40, and 30% thereafter)42

5/5/2017PHASE I DESIGN FOR ONCOLOGY Nonparametric Methods (Rule-based design) E.g. 3 3, A B Design, Accelerated titration Parametric method (Model-based design) E.g. Continual Reassessment method (CRM) (O’Quigley et al.,Biometrics, 1990, 1996)Bayesian Logistics regression model (BLRM)Escalation with over dose control (EWOC) Hybrid design mTPI (Yuan Ji et al 2010)ILLUSTRATION OF 3 3 DESIGN43

5/5/20173 3 DESIGNMTD: highest dose with 0 or 1DLT out of 6 patientsProblem: Not flexible target rate of toxicitycohort sizeorder of doselevel of accuracy before stoppingIncorporating other data, e.g. biomarker, PK, efficacy Memory-less (using data only from most recent cohort Insufficient operation characteristics: Reiner et al. 1999; Lin et al. 2001BLRM (BAYESIAN LOGISTICREGRESSION MODEL)Two-parameter model, dose as continuous variable : probability of having a DLT in the first cycle at dose : reference dose: intercept, odds of a DLT at d*: slope, steepness of curveNeuenschwander et al (2008), Statist.Med. 27: 2420-243944

5/5/2017PLOTSESCALATION:INTERESTINTERVALS OFIntervals of interest:underdose : 16%target dose: [16%-33%)overdose :33%45

5/5/2017ESCALATION WITH OVERDOSECONTROL (EWOC)The overdose risk willthen be calculated foreach dose andescalation will bepermitted to all doses forwhich this probability islower than a boundary(e.g. 25% )ESCALATIONOverdose control: Probability for overdosing should beless than 25%Escalation maximal 100% compared to already testedlevels (e.g. Modified Fibonacci ) In-between dose levels are possibleThe MTD may be considered found, e.g. if the posteriorprobability of the true DLT rate in the target interval isabove 50% or at least 12 patients overall have beentreated at this dose46

5/5/2017DECISION – COMBINATION OF CLINICAL ANDSTATISTICAL EXPERTISEPriorinformationStudy data:DLTinformation(e.g. 0/3)Additionalstudy data:PK, AE,labs, Bayesian model:Dose recommendationDoseescalationdecisionData safety board:Clinical expertiseESCALATIONProbability ofovertoxicityProbability oftarget toxicityProbability ofundertoxicity47

5/5/2017FINAL ANALYSISRecommended Phase II DoseAt the end of the trial, run model for doseconfirmation using all patient (including anexpansion cohort)Sensitivity analysisRun the model using a new DLT definitionBLRM – Combination trials / MotivationCombinations May lead to synergistic efficacy May help to overcome resistance mechanismsBut:Potential for interaction and in-/decreased safety riskProtective:The toxic effect ofthe drugcombination is lessthan that obtainedif the drugs actindependently inthe body.No interaction:The toxic effect ofthe drugcombination isequal to thatobtained if thedrugs actindependently inthe body.Synergism:The toxic effect ofthe drugcombination isgreaterthan that obtainedif the drugs actindependently inthe body.48

5/5/2017SOFTWARE EAST: ESCALATE ADDPLAN DF R package: e.g. bcrm NextGen-DF (online web tool) http://www.compgenome.org/NGDF/ Various resource online ativephase-i-dose-escalation.htmlHYPOTHESIS TEST INPHASE II DOSEFINDING TRIALS:PARALLEL SETTING(CHAPTER 10, 14)49

5/5/2017OVERVIEW OF DOSE FINDINGPROCESS 0.81.0Phase IPhase II020MED4060MaxED80MTD/MFD100doseOBJECTIVE OF PHASE II DOSEFINDING STUDYProof-of-Concept (PoC) Contrast based test for Proof of Concept (PoCx,PoC) Contrasts based on ranks (OLCT) Model-based contrast (MCPMod) Other contrast testRecomend dose for phase III (Estimation andmodeling)50

5/5/2017A COMBINED POC AND DOSERANGING DESIGNFor illustration purpose, three active dose are used. However,it is generally recommended to have 4-5 doses in a full doseranging study.Four parallel treatment groups Low, medium, and high doses Placebo controlled Contrast test to combine information from multiple doses101 POTENTIAL POC CONTRASTSAH0: H PvsH1: H PCH0: – P – L M H 0 vs H1: – P – L M H 0DH0: – P – L – M 3 H 0 vs H1: – P – L – M 3 H 0EH0: -3 P L M H 0 vs H1: -3 P L M H 0102B H0: -3 P – L M 3 H 0 vs H1: -3 P – L M 3 H 051

5/5/2017FOUNDATION OF CONTRAST TESTPOWER OF A CONTRAST TEST INA DOSE-FINDING STUDYFor normal distributed data104Where ci is the contrast coefficient, fi is the sample size fractionfor the ith group, n is the total sample size(n*fi ni)52

5/5/2017CONTRAST TEST #1: OPTIMALCONTRAST FOR A SINGLE MODEL For given set of means of all treatment groups (µi), and givenallocation ratio (fi) , find contrast coefficient (ci) whichmaximize the power of PoC test. Optimal contrast is independent of total sample size n, but isdependent on allocation ratio. Only the values of response at selected dose groups impactthe power. EXAMPLE1.Mean (0,0,0,0,1), equalallocation:( -0.22, -0.22, -0.22, -0.22, 0.89)2.Mean (0,1,1,1,1), equalallocation:(-0.89, 0.22, 0.22, 0.22, 0.22)3.Mean (0,0,1,1,1), equalallocation(-0.55, -0.55, 0.37, 0.37, 0.37)4.Mean (0,0,0,0,1), allocationratio (2,1,1,1,2):(-0.35, -0.18, -0.18, -0.18, 0.88)53

5/5/2017CONTRAST TEST #2: ORDINALLINEAR CONTRAST TEST (OLCT) Non-parametric, the contrast is based on ranks of differenttreatment groupsDeng and Ting (2016): Sample size allocation in adose-ranging Trial combined with PoC108 In general, not optimal for a specific model. However, it isrobust to most of the monotonic dose-response curves54

5/5/20171:1:1:12:1:1:2MethodLinearStepQuadratic ConvexConcaveA: High vs PBO(‐1,0,0,1)B: OLCT(‐3, ‐1, 1, 3)C: High vs .85.75.75.90.77.39.89.33D: High/Median vs Low/PBO(‐1,‐1,1,1).81.68.85.57

PHASE I/II CLINICAL TRIAL DESIGN AND DOSE FINDING (PART I) (CHAPTER 1, 7) NAITEE TING, BOEHRINGER-INGELHEIM 2 DRUG DEVELOPMENT PROCESS Drug Discovery Non-clinical Development Clinical Development Phase I Clinical pharmacology (PK/PD, MTD) Phase II Drug efficacy/safety, dose ranging Phase III Long-term, large scale, confirmatory

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