Presentation on theme: "CQ Deng, PhD PPD Development Research Triangle Park, NC 27560"— Presentation transcript:
1CQ Deng, PhD PPD Development Research Triangle Park, NC 27560 Intention-to-Treat and modified Intention-to-Treat Analyses in Clinical TrialsCQ Deng, PhDPPD DevelopmentResearch Triangle Park, NC 27560
2Confusion about Intention-to-Treat? Statistical analyses are based on intention-to-treat basisITT population includes all randomized patients…… who take at least one dose of study drug…… who take at least one dose of study drug and have at least one post-baseline efficacy measurement…… who complete three treatment cyclesITT population includes all patients who take at least one dose of study medication
3Confusion about Intention to Treat? “…The division definition of (modified) intent-to-treat is all patients who are randomized to treatment, and have the infection confirmed by microscopy and culture.The sponsor’s definition of intent-to-treat further limits this to cases with a clinical signs and symptoms score greater than two and requires at least one non-missing post-baseline efficacy assessment…”FDA CDER statistical review of NDA
4What is the Intention-to-Treat analysis? Includes all randomized patients in the groups to which they were randomly assigned, regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal from treatment or deviation from the protocolFisher, LD et al. Intention to treat in clinical trials in Statistical Issues in Drug Research and Development. Edited by Peace KE (1990)
5Intention-to-treat analysis Full analysis set. Analyze once randomized!Analyze as randomized, not as treatedPreserve the initial randomization, keep the baseline comparability among treatment groupsMinimize bias. Prevent the conscious or unconscious attempts to influence the results of the study by excluding the patientsConservative for estimates of the treatment differencePreferred for trials to show a difference between two treatmentsIgnore noncompliance, protocol deviations, withdrawal, and anything that happens after randomization
6Reasons for patients to be excluded from ITT: Further tests after randomization show the patient is ineligible or misdiagnosedThe patient does not receive any of their allocated treatmentThe patient takes the wrong study drugThe patient receives some, but not all their allocated treatmentThe patient is not assessed for the outcome of interest, such as response
7Practical definition of ITT Includes all patients:who were randomizedwho were known to take at least one dose of treatmentwho provided any follow-up data for one or more key efficacy variablesbased on the randomized treatment, not the treatment actually received (if mis-randomization rate is less than 5%)Gillings and Koch (1990) The application of the principle of intention-to-treatto the analysis of clinical trials. Drug Information Journal
8Overuse/Misuse of ITT In non-randomized trial For safety evaluation In non-randomized trialNo randomization, No ITT!For safety evaluationITT analysis may underestimate the incidence rateIn some bioavailability/bioequivalence trialsNo reason to include the subjects who did not take study drugFollow “as treated”, not “as randomized”
9Overuse/misuse of ITT In equivalence/non-inferiority trials In equivalence/non-inferiority trialsAs intention-to-treat analyses tend to dilute an effect between treatment, an ITT analysis in an equivalence trial may make the treatments appear to be more similar than they actually are.For equivalence trials a ‘per protocol analysis’ could be regarded as ‘conservative’ and therefore is often given as much emphasis as an ITT.
10Overuse/misuse of ITT Assuming Safety population = ITT population Assuming Safety population = ITT population“ITT population includes all randomized patients who take at least one dose of study drug”“Safety population includes all randomized patients who take at least one dose of study drug”ITT = Safety population ?In the case of randomization error:NSafety Total = NITT TotalNSafety for each treatment group NITT for each treatment groupAssuming Per-protocol is purely a subset of ITT
11What is the mITT?Modified intention-to-treat (mITT), may also be called quasi ITT, is a subset of the ITT population and allows the exclusion of some randomized subjects in a justified way.
12Some examples of mITT definitions “The mITT population included all patients who were randomized and had a positive culture of (pathogen) at baseline.”“The mITT population included all randomized patients who developed (symptoms) and took at least one dose of study medication.”“The mITT population included any patient who was randomized, took at least one dose of study medication during stabilization period 2 (SP2), maintained a stable dose of 2400 mg/day during SP2, had baseline migraine headache data, and at least 1 day of migraine headache evaluations during SP2.”** Mathew NT et al (2001) Efficacy of Gabapentin in Migraine Prophylaxis. Headache
13modified Intention-to-Treat Not a full analysis set - a subset of ITTAnalyze as randomized, not as treatedMany practical ITT definitions may be called mITTPopular in antimicrobial / anti-infective trialsMultiple mITT populations can be defined for a single study: Clinical mITT, Microbiological mITT
14Situation when mITT is appropriate When the disease diagnosis is not immediately available at randomization or at start of treatmentPatientdevelopingsymptomsRandomizationInitiate thetreatmentSuspectedpatientfor the trialconfirmatory diagnosis results are availableFor the acute disease caused by a bacteria, virus, or fungus, the confirmatorydiagnosis usually takes several days. The randomization and the start of treatmentcannot wait until the confirmatory diagnosis results are available. SARS (Corona virus),Bird Flu (H5N1 subtype of influenza A), Pneumonia…
15Situation when mITT is appropriate When patients initiate the treatmentPatient developssymptomsTakes study medRandomizationDispense drugPatienthas historyof diseasePatient neverdevelops symptomsNo treatmentinitiatedITT population includes all randomized patientsmITT population includes all patients who developed symptoms and tookat least one dose of study medicationExample: Recurrent genital herpes, cold sores (recurrent herpes labialis) trials
16Situation when mITT is appropriate When the period between randomization and start of the medication is long . The longer the period, the more likely the patient will change his/her mindDrug shippedto the siteRandomizationPatient decides notto participate in the trialPatient has no knowledge of which treatment group he/she is in.Whether or not patient takes the study medication is random.There is no merit to say there is any potential bias by excluding those patientswho did not take the study medication.
17Caveat when using mITTExclusion of the patients should be in a justified way, not at willPatient exclusion is not associated with patient characteristicsor clinical outcomeITT (full analysis set) is suggested for sensitivity analysisOther sensitivity analyses may also be employed
18SummaryITTFull analysis set, include all patients who were randomizedAs randomized, not as treatedPrimary analysis population in superiority trialsITT can be overused or misusedmITTA subset of ITT, not a full analysis setPreserve some ITT featuresIn some situations, mITT is more appropriateWhen using mITT, ITT is suggested for sensitivity analysisPopular in antimicrobial / anti-infective trials