Transcript JSM 2004 Presentation

Intention-to-Treat and modified Intentionto-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
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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:
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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
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
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
“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
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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
Suspected
patient
for the trial
Randomization
Initiate the
treatment
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
Patient
has history
of disease
Randomization
Dispense drug
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
Randomization
Drug shipped
to the site
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