The Origins of Intention To Treat

Posted by minervation on June 28, 2024

Iain Chalmers, Editor Emeritus of the James Lind Library, describes the origins of the intention-to-treat principle as a means of addressing allocation biases in clinical trials.

Read the full story in Chalmers I, Matthews R, Glasziou P, Boutron I, Armitage P† (2023). Analysis of clinical trial by Treatment Allocated or by Treatment Received? Applying ‘the intention-to-treat principle’. JLL Bulletin: Commentaries on the history of treatment evaluation.


During the late 1940s, researchers recognized increasingly that random allocation of participants to treatment comparison groups in controlled trials provided protection against allocation biases.

During the 1950s, researchers went on to recognize that non-random losses of trial participants from initially randomized groups resulted in allocation biases and that these allocation biases could be reduced by
applying a so-called intention to treat principle in designing and analyzing randomized trials.

This article will take you through the background to that recognition and key steps in its implementation.

Over the subsequent 70 years, as Austin Bradford Hill and his son David said, at the end of their treatment of this problem, they concluded there can be no hard and fast rules for, there is no correct answer to all situations.

A Timeline of the Evolution of the Intention to Treat Principle

Half of trials still not observing the ITT principle

Surveys of clinical trials reported in major general medical journals 40 years after the Vienna meeting have shown that only half of the trial reports assessed had observed ‘the intent-to-treat (ITT) principle’  (Hollis and Campbell 1999; Ruiz-Canela et al. 2000).

Hill AB. Principles of medical statistics, 7th edition, pp 258-9.

The Figure below uses a randomized comparison of medical and surgical treatments in which some very ill patients randomized to surgery died before their surgery could be organised. Should these patients be excluded from analysis? As shown in the Figure, doing that would result in an unfair bias against those…Read More

Vienna Conference on Controlled Clinical Trials, 1960

The Vienna conference (Hill 1960; Bird 2014) was not the only gathering considering developments in testing treatments, but it may well have been the first conference in which several speakers had considered how to deal with biased losses from unbiased treatment comparison groups assembled using random allocation, and to have begun…Read More

Mainland D (1952) Intercurrent Events. In: Elementary Medical Statistics: the principles of quantitative medicine.

Its first mention as a methodological principle in a textbook may have been in 1952, in the first edition of Elementary Medical Statistics authored by clinical epidemiologist Donald Mainland. In a section of the book entitled ‘On Planning a Simple Experiment’, a subsection entitled ‘Intercurrent events’ addressed the problem resulting from…Read More

Medical Research Council (1948) Streptomycin treatment of pulmonary tuberculosis: a Medical Research Council investigation.

In the late 1940s, concealed random allocation was used to generate comparison groups in the British Medical Research Council’s celebrated multicentre controlled trial of streptomycin in patients with pulmonary tuberculosis (MRC 1948). In particular, the details of the allocation schedule were concealed from those entering patients into the trial. The…Read More

Medical Research Council 1944, Clinical trial of patulin in the common cold.

During World War 2, the British physician Philip d’Arcy Hart, supported by his wife Ruth and Joan Faulkner, designed, conducted and reported the UK Medical Research Council’s first well controlled multicentre trial.  

Bell JA (1941) Pertussis prophylaxis with two doses of alum-precipitated vaccine.

An early application of the principle was presented by Joseph Bell in his report of a controlled trial of whooping cough vaccine initiated in 1936 in Virginia, USA, with professional support from the Norfolk City Union of King’s Daughters Visiting Nurse Association. Bell provides us with an early and remarkable…Read More

Martini P (1932) Methodenlehre der Therapeutischen Untersuchung [Methodological principles for therapeutic investigations]. Berlin: Springer

During the three years over which I had the good fortune of heading the extensive medical department at St. Hedwig’s Hospital in Berlin, I used every opportunity to look for satisfactory methods for therapeutic investigation. The results presented here are as yet incomplete. Never the less I am publishing them…Read More