Science without sense…double nonsense

Píldoras sobre medicina basada en pruebas

The chameleon

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What a fascinating reptile. It’s known by its eyes, with its ability to rotate independently covering the whole angle of the circle. Also known is its long tongue, with which it traps from the distance the bug that it eats without moving from its place. But the most famous of the chameleon’s abilities is that of changing color and blending into the environment when it wants to go unnoticed, which is not surprising because the chameleon is, it must be said, a pretty ugly bug.

But today we’re going to talk about clinical trials. About one type of clinical trial in particular: as a true chameleon of epidemiology, it changes its design as it is being performed to suit the circumstances as they occur. I am talking about adaptive clinical trials.

A clinical trial usually has a fixed design or protocol that we must not change and, when changed, we must explain in detail and justify the reason why we did it. However, in an adaptive clinical trial we defined in advance, prospectively, the possibility of changes in one or more aspects of the study design based on data that are obtained during the trial. We usually plan at what time throughout the study we’ll analyze the available data and results to determine if we perform some of the predetermined changes. Otherwise, any change is a violation of the study protocol that jeopardizes the validity of the results.

There’re many changes we can do. We can change the probabilities of the randomization method, the sample size, and even the characteristics of the follow-up, which can be lengthened or shortened, and modify the visits that were planned in the initial design. But we can go further and change the dose of the tested treatment or the allowed or prohibited concomitants medications, depending on our interests.

We can also change aspects such us the inclusion criteria, outcome variables (especially the components of composite variables), the analytical methods of the study and even to transform a superiority trial to a non-inferiority one, or vice versa.

As we have mentioned a couple of times, these changes must be planned in advance.  We have to define the events that will induce us to make the adaptations of the protocol. For instance, we can plan to increase or decrease the sample size to improve power after enrolling a number of participants, or to include some groups during a predetermined follow-up and, from there, not to implement the intervention with the group in which it is no effective.

The advantages of an adaptive design are obvious. First, flexibility is evident. The other two are more theoretical and are not always met but, a priori, they are more efficient than conventional designs and are more likely to demonstrate the effect of the intervention, if it exists.

Its main drawback is the difficulty of planning a priori all the possibilities of change and the subsequent interpretation of the results. It’s difficult to interpret final results when the course of the trial depends heavily on the intermediate data being obtained. Moreover, this makes it imperative to have a fast and easy access to study data while performing it, which can be difficult in the context of a clinical trial.

And here we end up for today. I insist on the need of the a priori planning of trial protocol and, in the case of adaptive designs, of each adaptive condition. As a matter of fact, nowadays most clinical trials are registered before performing for the recording of their design conditions. Of course, this also facilitates the posterior study publication, even if the results are not favorable, which helps to combat publication bias. But that’s another story…

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