Presentation on theme: "Design of Dose Response Clinical Trials"— Presentation transcript:
1Design of Dose Response Clinical Trials Boston Chapter of ASAApril 10, 2006Naitee Ting, Pfizer Global R&D
2Drug Development Process Drug DiscoveryNon-clinical DevelopmentClinical DevelopmentPhase I Clinical pharmacology (PK/PD, MTD)Phase II Drug efficacy/safety, dose rangingPhase III Long-term, large scale, confirmatoryPhase IV Post-market
4Phase I Studies (Drugs developed for non-life-threatening diseases) Healthy normal volunteersSingle doseDouble-blind, placebo controlled, randomized, dose escalationClinical pharmacology – PK/PD, MTDCross-over studies (BA, BE)Answer the question – how often should we dose the patient?
5Phase II Studies (Non-life-threatening diseases) Patients with the disease under studyDose ranging, efficacy dose responseDouble-blind, placebo controlled, randomized, fixed dosesClinical efficacy and safety endpointsExploratory, estimation of efficacy, dose,..Answer the question – how much should we dose the patient?
8Phase III, IV Studies Phase III studies are for registration purposes Confirmatory, hypothesis testingStudy for target dose(s)Phase IV studies are for larger scale safety surveillance, or new indicationChange of labeled dose post market is possible
9Concerns in Developing Drugs for Life-Threatening Diseases May not be ethical to use placebo controlMay not be ethical to recruit normal healthy volunteersOpen label, single arm, dose titration study designs
10Challenges in dose selection Every stage of drug development – from drug discovery to post marketWhat is the right range of dosesIndividual dose response curves vs population curveExposure-response vs dose-responseOther challenges (choice of primary endpoint, multiple comparison, …)
11WHAT ARE THE ISSUES IN DOSE FINDING? Individual versus global responsesWhat are you looking for?What range of doses should we consider?How many doses to be tested?What are we measuring?The differences in exploration and confirmation
13INDIVIDUAL VERSUS GLOBAL RESPONSES In most of drugs, we need to recommend a few fixed dosesFor wide Therapeutic Index (TI), it is possible to use one doseDose response relationship vs concentration response relationship
14PHARMACOKINETICS (PK), PHARMACODYNAMICS (PD) PK, PD, PK/PDPK: body act on drugPD: drug act on bodyConcentration response uses PK, but should we consider PD?
15WHAT ARE YOU LOOKING FOR A single dose or a range of dosesFixed dose or titration dosesAs needed or chronic treatmentHow many doses a day
16DRUG LABEL (Package Insert) Summary Information of the DrugAgreed with Regulatory AgenciesTarget Product ProfileCompetitors on MarketEasy for Physicians to prescribe
17Forward: Accumulating information Backward: Planning Based on LabelPre-clinicalPhaseIPhaseIIPhaseIIIDrugLabel
18DETERMINING DOSING FREQUENCY When determining dosing frequency, the pharmacodynamics of a compound should be considered as critical as the pharmacokineticsIn contrast to the pharmacokinetic half-life, the pharmacodynamic half-life will be dose dependentWill a control release formulation be needed?
19DETERMINING DOSING FREQUENCY QD Feasible if high levels arewell tolerated, otherwisewill need to default toBID dosing or change shapeof curve with CR.Q day dosing at 2x doseBid Dosing at 1x doseMinimal effective levelby PD markerDrug Concentration12h h
20WHAT RANGE OF DOSES SHOULD WE CONSIDER In early Phase II, not much information available (pre-clinical, PK, MTD)We know 0 (Placebo), we know MTDExploring an Adequate Dose RangeSelecting Doses for Early Dose-ranging Studies
24WHAT RANGE OF DOSES SHOULD WE CONSIDER Examine a wide dose range in early development and follow this study with a narrower dose range studyUse pharmacological response or biological markers from animal studies and phase I studies to guide the selection in dose range for the early studiesAlthough not always attainable in early studies, a goal should be to try and define the Maximum Tolerated Dose (MTD), the Maximum Effective Dose (MaxED), and the Minimum Effective Dose (MinED)
29ACTIVE CONTROL Active control is not strictly necessary It serves as a useful control in case the test drug “doesn’t work” or works poorlyActive control “worked” or not?An active comparator may also be critical if there is an effective competitor on the marketHow appropriate are Phase II comparisons?Statistically valid vs “looks similar”?
30HOW MANY DOSES TO BE TESTED Can we set all possible doses to testDo we include control groupsIf so, which controlsSpacing between doses
31LIMITED NUMBER OF FIXED DOSES Multiple center designsFormulation considerationsPlacebo and maximum tolerable dose (MTD)Incorporate active control?Concerns in interpreting titration dose
32TREATMENT BY CENTER INTERACTION PlaceboLowMediumHighCenter 1678Center 21Center 3423
33DOES THE DRUG WORK? Test hypothesis - does the drug work? Null hypothesis (H0) - no difference between test drug and placeboAlternative hypothesis (Ha) - there is a difference
34TYPES OF ERRORS If there is no true difference, but concluded there is => Type I errorIf there is a difference, but concluded there isn’t=> Type II error
35TYPES OF ERRORSRegulatory agencies focus on the control of Type I errorProbability of making a Type I error is not greater than aIn general, a = 0.05; i.e., 1 in 20Avoid inflation of this errorChange method of analysis to fit data will inflate a
36MULTIPLE COMPARISONSFor 20 independent variables (clinical endpoints), one significant at randomFor 20 independent treatment comparisons, one significant at randomFor 20 small studies, one sig. At randomMultiple comparison adjustment
37MULTIPLE COMPARISONSConsider a dose response study with high and low dose against placebo2 comparisons each dose vs placeboBonferroni is to divide a by 2Step-downSpecial contrastsFisher protected LSD
38MULTIPLE COMPARISONS Other types of multiple comparisons compare test drug with placebo and active controlMultiple endpointsSubset analysisVarious statistical methods available to handle these situations
39INTERIM ANALYSISFinal analysis: LPV -> closed database -> break blind -> final analysisAny analysis before final is interimObjectivesclaim efficacystop for no efficacy (for safety, …)help decision making for other studiesother
40INTERIM ANALYSIS Randomized Double-Blind study to control for bias Multiple look at data will inflate aStatistical penaltyinflation of a -> need adjustmentenough efficacy data to help decision?
41CONTROL OF TYPE I ERRORExperiment-wise Type I error is controlled by specifying primary endpoint, primary comparison, primary time point for the primary study populationKeep analysis method as stated in the protocolIf interim analysis is needed, we should pre-specify, and plan for it
42WHAT ARE WE MEASURINGPD marker, clinical endpoint (hard, soft) or safetyEfficacy can’t be observed from normal volunteerEarly Phase or late phaseTime after baseline (short, long)Multiple endpoints