Another issue that bothered us in the TTE office in the Lecanemab Early Alzheimer's Disease trial was the use of the modified intention-to-treat population for the efficacy analysis.

Share

Internal validity of clinical trials is the extent to which you trust the methods on which the results are based. There are some simple methodological issues, such as the presence or absence of randomisation, which allows you to understand whether the effect size is dramatically inflated due to differences in the baseline characteristics of the population.

Other essential methods, such as blinding, allocation concealment, and intention to treat, also affect the results. Now, bear with us while we explain one often confusing thing: the intention-to-treat analysis.

In an intention-to-treat analysis, the results are based on those initially assigned to the treatment and not just those who actually took the treatment (often referred to as per-protocol analysis). The intention to treat analysis mainly leads to smaller effect sizes, usually because the denominator is greater than in the per-protocol group. People may stop the treatment; sometimes, they don’t take it as prescribed, and they may be lost to follow-up, but essentially, they should still be counted in the denominator.

The key is that the folk who stopped taking the intervention may have gone on to have the adverse effect of interest; they could have died. You may miss critical adverse effects if you don’t analyse the population. This is precisely what happened in the Vioxx studies, where per-protocol analysis data presented to the FDA underestimated the actual rates of heart attacks.

With surprise and some confusion, we have noticed a dramatic rise in using the ‘modified’ intention to treat analysis.

A 2010 systematic review in the BMJ analysed modified intention-to-treat reporting in randomised controlled trials: at the time, 475 RCTs used a modified intention-to-treat analysis. When the description was examined, 40% reported one type of deviation from the intention-to-treat approach, and 55% reported two or more types.

Is this blindingly obvious, or are we missing something? Modified intention to treat is just a play on words, and in any other language, it is per protocol analysis. Hence, it should be removed from the published literature on clinical trials, as its sole purpose is to confuse readers into missing an inherent bias in the trial methods.

In 2004, CONSORT warned using the term modified intention to treat may lead to confusion and inaccurate results. This is what they say about its use:

‘The term “modified intention-to-treat” is quite widely used to describe an analysis that excludes participants who did not adequately adhere to the protocol, in particular those who did not receive a defined minimum amount of the intervention.(232) An alternative term is “per protocol.” Though a per protocol analysis may be appropriate in some settings, it should be properly labelled as a non-randomised, observational comparison. Any exclusion of patients from the analysis compromises the randomisation and may lead to bias in the results. 

Does it surprise anyone that a 2011 analysis of 367 RCTs published in Trials reported a strong association between trials classified as modified ITT and for-profit agency sponsorship and conflicts of interest?

Peer reviewers and editors need to sort this out or, at the very least, modify something soon. This is beyond the scope of the mainstream media, but avid readers of TTE should look out for the modified intention to treat analysis; it should come with a health warning.

This is the sixth post of the series on the wonder MAB Lecanemab for Early Alzheimer's Disease (AD). We have not been modified (yet).