CQ Deng, PhD PPD Development Research Triangle Park, NC 27560 Intention-to-Treat and modified Intention-to-Treat Analyses in Clinical Trials CQ Deng, PhD PPD Development Research Triangle Park, NC 27560

Confusion about Intention-to-Treat? Statistical analyses are based on intention-to-treat basis ITT 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 cycles ITT population includes all patients who take at least one dose of study medication   

Confusion 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 20-749

What 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 protocol Fisher, LD et al. Intention to treat in clinical trials in Statistical Issues in Drug Research and Development. Edited by Peace KE (1990)

Intention-to-treat analysis Full analysis set. Analyze once randomized! Analyze as randomized, not as treated Preserve the initial randomization, keep the baseline comparability among treatment groups Minimize bias. Prevent the conscious or unconscious attempts to influence the results of the study by excluding the patients Conservative for estimates of the treatment difference Preferred for trials to show a difference between two treatments Ignore noncompliance, protocol deviations, withdrawal, and anything that happens after randomization

Reasons for patients to be excluded from ITT: Further tests after randomization show the patient is ineligible or misdiagnosed The patient does not receive any of their allocated treatment The patient takes the wrong study drug The patient receives some, but not all their allocated treatment The patient is not assessed for the outcome of interest, such as response

Practical definition of ITT Includes all patients: who were randomized who were known to take at least one dose of treatment who provided any follow-up data for one or more key efficacy variables based 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-treat to the analysis of clinical trials. Drug Information Journal

Overuse/Misuse of ITT In non-randomized trial For safety evaluation    In non-randomized trial No randomization, No ITT! For safety evaluation ITT analysis may underestimate the incidence rate In some bioavailability/bioequivalence trials No reason to include the subjects who did not take study drug Follow “as treated”, not “as randomized”

Overuse/misuse of ITT In equivalence/non-inferiority trials    In equivalence/non-inferiority trials As 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.

Overuse/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 Total NSafety for each treatment group  NITT for each treatment group Assuming Per-protocol is purely a subset of ITT

What 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.   

Some 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   

modified Intention-to-Treat Not a full analysis set - a subset of ITT Analyze as randomized, not as treated Many practical ITT definitions may be called mITT Popular in antimicrobial / anti-infective trials Multiple mITT populations can be defined for a single study: Clinical mITT, Microbiological mITT

Situation when mITT is appropriate    When the disease diagnosis is not immediately available at randomization or at start of treatment Patient developing symptoms Randomization Initiate the treatment Suspected patient for the trial confirmatory diagnosis results are available For the acute disease caused by a bacteria, virus, or fungus, the confirmatory diagnosis usually takes several days. The randomization and the start of treatment cannot wait until the confirmatory diagnosis results are available. SARS (Corona virus), Bird Flu (H5N1 subtype of influenza A), Pneumonia…

Situation when mITT is appropriate    When patients initiate the treatment Patient develops symptoms Takes study med Randomization Dispense drug Patient has history of disease Patient never develops symptoms No treatment initiated ITT population includes all randomized patients mITT population includes all patients who developed symptoms and took at least one dose of study medication Example: Recurrent genital herpes, cold sores (recurrent herpes labialis) trials

Situation 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 mind    Drug shipped to the site Randomization Patient decides not to participate in the trial Patient 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 patients who did not take the study medication.

Caveat when using mITT Exclusion of the patients should be in a justified way, not at will Patient exclusion is not associated with patient characteristics or clinical outcome ITT (full analysis set) is suggested for sensitivity analysis Other sensitivity analyses may also be employed   

Summary ITT Full analysis set, include all patients who were randomized As randomized, not as treated Primary analysis population in superiority trials ITT can be overused or misused mITT A subset of ITT, not a full analysis set Preserve some ITT features In some situations, mITT is more appropriate When using mITT, ITT is suggested for sensitivity analysis Popular in antimicrobial / anti-infective trials