Intention-to-treat concept: A review

Intention-to-treat concept: A review SandeepK Gupta

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Intention-to-treat concept: A review 2011 Perspectives in Clinical Research 10.4103/2229-3485.83221 gupta2011-intention-treat-concept-review gupta2011-intention-treat-concept-review.txt, the project's staged copy 75266a5f8b29470b0f6a7b34e62508ff4098401c cc-by-nc-sa statistics

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them the analysis population of a randomised trial - which subjects are counted when compliance and follow-up fail - and the several incompatible definitions the regulators and the literature give it Quotation withheld because this record is not cleared for redistribution. what the intention-to-treat principle is, what it buys, what it costs, and where the guidelines disagree about applying it Quotation withheld because this record is not cleared for redistribution. assembles the definitions of ITT, per-protocol, modified ITT and the full analysis set side by side with the regulator that issues each, and reports that the modified variant has no consistent definition at all Quotation withheld because this record is not cleared for redistribution. critique Quotation withheld because this record is not cleared for redistribution. one analysis population with four names in circulation, each attached to a different regulator, and a modified variant defined case by case Quotation withheld because this record is not cleared for redistribution. review review Quotation withheld because this record is not cleared for redistribution. THE DEFINITION IS A TRIPLE REFUSAL TO CONDITION ON ANYTHING THAT HAPPENED AFTER RANDOMISATION - `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` Quotation withheld because this record is not cleared for redistribution. and the reason is that the alternative destroys what randomisation bought: `If noncompliant subjects and dropouts are excluded from the final analysis, it might create important prognostic differences among treatment groups` - and subjects `may be noncompliant or may drop out due to their response of treatment` Quotation withheld because this record is not cleared for redistribution. THE COST IS PAID IN THE SAME COIN. `In ITT analysis, estimate of treatment effect is generally CONSERVATIVE because of DILUTION due to noncompliance` - the property that makes it unbiased is the property that makes it small Quotation withheld because this record is not cleared for redistribution. so the criticism is symmetrical: ITT `has been criticized for being too cautious and thus being more susceptible to type II error` Quotation withheld because this record is not cleared for redistribution. AND THE TWO POPULATIONS FAIL IN OPPOSITE DIRECTIONS, WHICH IS WHY THE CHOICE IS NOT NEUTRAL. `ITT tends to make the two treatments look similar, whereas the PP removes patients who do not complete treatment and is more able to reflect treatment differences` Quotation withheld because this record is not cleared for redistribution. THE MODIFIED VARIANT HAS NO STABLE DEFINITION AT ALL - `the definition given to the modified ITT (mITT) in randomized controlled trial has been found to be irregular and arbitrary because there is a lack of consistent guidelines for its application. The mITT analysis allows a subjective approach in entry criteria` Quotation withheld because this record is not cleared for redistribution. and it is not one population but many: `multiple mITT populations can be defined for a single study such as clinical mITT and microbiological mITT` Quotation withheld because this record is not cleared for redistribution. THE SAME OBJECT CARRIES A THIRD NAME FROM A THIRD AUTHORITY - ICH E9 `uses the term FULL ANALYSIS SET to describe the analysis set which is as complete as possible and as close as possible to the ITT ideal` Quotation withheld because this record is not cleared for redistribution. The guidelines do not agree about where the principle applies. `Whereas the importance of the ITT population analysis in superiority designs has been well accepted, however there is no consensus about its role in non-inferiority trials` Quotation withheld because this record is not cleared for redistribution. and the proposed resolution is to require both and hope they agree - `noninferiority should be concluded only if both ITT and PP analyses permit that` - which is a procedure rather than a principle, and the paper notes the conservative effect of PP on such trials `has not been thoroughly explored` Quotation withheld because this record is not cleared for redistribution. the remedy offered for the missing data ITT cannot ignore is itself contested - last observation carried forward, `whereby the LAST AVAILABLE MEASUREMENT for each individual at the time point prior to withdrawal IS RETAINED in the analysis`, presented here without its known bias Quotation withheld because this record is not cleared for redistribution. This is a narrative review for beginners, not a systematic one. No search strategy, no inclusion criteria and no synthesis are reported; the claims about what the literature finds - including the central one about mITT - are carried by citation Quotation withheld because this record is not cleared for redistribution. and the practical advice at the end withdraws the problem rather than solving it: `Anyone who follows these principles intelligently and has a vision to minimize bias should not worry further about 'INTENTION TO TREAT'` Quotation withheld because this record is not cleared for redistribution. intention-to-treat is a statistical concept imported into the conduct and reporting of randomized controlled trials to handle noncompliance and missing outcomes Quotation withheld because this record is not cleared for redistribution. the analysis set is defined by the randomized assignment rather than by the treatment actually received, which is what preserves the randomization Quotation withheld because this record is not cleared for redistribution. randomisation itself - allocating subjects to arms after eligibility is assessed but before the intervention is given eliminates: systematic difference between the groups at baseline; ITT exists to protect this and per-protocol analysis is what spends it · outcome: held Quotation withheld because this record is not cleared for redistribution. requiring full reporting of every deviation from random allocation and every missing response, as CONSORT does eliminates: an ITT label attached to an analysis whose exclusions the reader cannot see; the guideline makes the departures visible rather than forbidding them · outcome: held Quotation withheld because this record is not cleared for redistribution. requiring the ITT and per-protocol analyses to agree before a non-inferiority claim is made eliminates: a conclusion that depends on which population was chosen - the two are known to fail in opposite directions, so agreement between them is informative · outcome: partial Quotation withheld because this record is not cleared for redistribution. intention-to-treat intention-to-treat Quotation withheld because this record is not cleared for redistribution. ITT analysis ITT analysis Quotation withheld because this record is not cleared for redistribution. per-protocol per-protocol Quotation withheld because this record is not cleared for redistribution. modified ITT modified ITT Quotation withheld because this record is not cleared for redistribution. full analysis set full analysis set Quotation withheld because this record is not cleared for redistribution. noncompliance noncompliance Quotation withheld because this record is not cleared for redistribution. prognostic balance prognostic balance Quotation withheld because this record is not cleared for redistribution. type II error type II error Quotation withheld because this record is not cleared for redistribution. sample size sample size Quotation withheld because this record is not cleared for redistribution. last observation carried forward last observation carried forward Quotation withheld because this record is not cleared for redistribution. noninferiority noninferiority Quotation withheld because this record is not cleared for redistribution. superiority trial superiority trial Quotation withheld because this record is not cleared for redistribution. heterogeneity heterogeneity Quotation withheld because this record is not cleared for redistribution. `intention-to-treat` (Fisher et al. 1990) - all randomised patients in their assigned groups, `regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal` Quotation withheld because this record is not cleared for redistribution. `intention-to-treat` (the slogan) - `once randomized, always analyzed` Quotation withheld because this record is not cleared for redistribution. `full analysis set` (ICH E9) - the analysis set `as complete as possible and as close as possible to the ITT ideal` - the same object under a third name Quotation withheld because this record is not cleared for redistribution. `modified ITT` - a subset with exclusions `in a justified way`, whose definition the literature finds `irregular and arbitrary` Quotation withheld because this record is not cleared for redistribution. `ITT` as a whole-trial strategy - `better regarded as a complete trial strategy for design, conduct and analysis rather than as an approach to analysis alone` Quotation withheld because this record is not cleared for redistribution. critiques → the modified ITT population as used in randomised trials, whose definition the paper reports as irregular, arbitrary and lacking consistent guidelines Quotation withheld because this record is not cleared for redistribution. supports → the CONSORT requirement that participants be analysed by the intention-to-treat principle and that deviations be fully reported Quotation withheld because this record is not cleared for redistribution. concedes → that ITT dilutes the treatment effect and is more susceptible to type II error - the arguments against it 'appear valid' Quotation withheld because this record is not cleared for redistribution. ITT analysis —distinct-from→ per-protocol ITT analysis per-protocol the relation itself is separately evidenced · strength of the relation: 0.95 · note: 'ITT tends to…' Not two views of one number - two numbers, and the analyst picks which before seeing either. · the relation stated: ITT keeps the noncompliers and dilutes the difference; per-protocol removes them and shows it - so the choice of population moves the answer, in a direction that is known in advance Quotation withheld because this record is not cleared for redistribution. superiority trial —distinct-from→ noninferiority superiority trial noninferiority the relation itself is separately evidenced · strength of the relation: 0.95 · note: 'WHEREAS the importance…' The same method, the same population, and its authority is a property of the question being asked - which is why 'use ITT' is not an instruction. · the relation stated: ITT's standing depends on what the trial is trying to show: settled as primary in a superiority design, unsettled in a non-inferiority one Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span writes 'non-inferiority', and the ITT role differs between the two designs; distinct-from is loose. Quotation withheld because this record is not cleared for redistribution. THE DEFINITION IS A TRIPLE `regardless of` - all randomised patients in their assigned groups `regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal` THE DEFINITION IS A TRIPLE `regardless of` - all randomised patients in their assigned groups `regardless of their adherence with the entry criteria, regardless of the treatment they actually received, and regardless of subsequent withdrawal` Quotation withheld because this record is not cleared for redistribution. AND IT HAS A SLOGAN THAT IS SHORTER THAN THE DEFINITION - ITT analysis `is usually described as once randomized, always analyzed` AND IT HAS A SLOGAN THAT IS SHORTER THAN THE DEFINITION - ITT analysis `is usually described as once randomized, always analyzed` Quotation withheld because this record is not cleared for redistribution. THE MODIFIED VARIANT'S DEFINITION IS IRREGULAR AND ARBITRARY, AND THE PAPER SAYS SO - `there is a lack of consistent guidelines for its application. The mITT analysis allows a subjective approach in entry criteria, which may lead to confusion, inaccurate results and bias` THE MODIFIED VARIANT'S DEFINITION IS IRREGULAR AND ARBITRARY, AND THE PAPER SAYS SO - `there is a lack of consistent guidelines for its application. The mITT analysis allows a subjective approach in entry criteria, which may lead to confusion, inaccurate results and bias` Quotation withheld because this record is not cleared for redistribution. AND ONE STUDY CAN HOLD SEVERAL OF THEM - `multiple mITT populations can be defined for a single study such as clinical mITT and microbiological mITT` AND ONE STUDY CAN HOLD SEVERAL OF THEM - `multiple mITT populations can be defined for a single study such as clinical mITT and microbiological mITT` Quotation withheld because this record is not cleared for redistribution. ICH E9 calls it the full analysis set: as complete as possible and as close as possible to the ITT ideal ICH E9 calls it the full analysis set: as complete as possible and as close as possible to the ITT ideal Quotation withheld because this record is not cleared for redistribution. ITT tends to make treatments look similar, while per-protocol analysis better reflects treatment differences ITT tends to make treatments look similar, while per-protocol analysis better reflects treatment differences Quotation withheld because this record is not cleared for redistribution. ITS AUTHORITY DEPENDS ON THE QUESTION - settled as primary in superiority designs, and `there is no consensus about its role in non-inferiority trials` ITS AUTHORITY DEPENDS ON THE QUESTION - settled as primary in superiority designs, and `there is no consensus about its role in non-inferiority trials` Quotation withheld because this record is not cleared for redistribution. ITT analysis ITT analysis Quotation withheld because this record is not cleared for redistribution. full analysis set full analysis set Quotation withheld because this record is not cleared for redistribution. modified ITT modified ITT Quotation withheld because this record is not cleared for redistribution. last observation carried forward last observation carried forward Quotation withheld because this record is not cleared for redistribution. complications ITT exists to absorb complications ITT exists to absorb Quotation withheld because this record is not cleared for redistribution. ITT `gives an unbiased estimate of treatment effect` and its estimate `is generally CONSERVATIVE because of DILUTION due to noncompliance`. Both sentences are true and they describe one mechanism - keeping the noncompliers is what preserves the randomisation and what shrinks the difference. A reader who quotes either alone has quoted half of it. a bias and a power loss that are the same property seen twice Quotation withheld because this record is not cleared for redistribution. analysis population analysis population Quotation withheld because this record is not cleared for redistribution.

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