Science without sense…double nonsense

Píldoras sobre medicina basada en pruebas

Steady… ready…

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Don’t!. Not so fast. Before you rush out there you have to be sure that everything is well prepared. It is difficult to conceive that anyone gets to run a marathon without preparing beforehand, without sufficient physical fitness and nutrition. Well, actually it is difficult to conceive what is having to be running nonstop 42 kilometers, so let another credible example.

Imagine that it is bedtime and we are so busted as if we had run a marathon. This situation is already more credible for most. Anyone in their right mind knows that it is advisable to drink water and go through the bathroom before going to bed. Payment for not doing these preparations will be getting up in the middle of the night, stumbling and shivering, to satisfy needs that could have being foreseen and avoided (except prostate imperatives, of course).

Now imagine that we want to conduct a clinical trial. We planned the study, we chose our population, we randomize participants perfectly, and we give to the intervention group our new drug to combat chronic unbearable fildulastrosis that we want to study and wham!! Most of them do not tolerate the drug and withdraw the study early. We will have wasted money and time, and it is difficult to know which of the two the most precious resource is in these times.

Could we have avoided these problem?. Poor tolerance to the drug is a fact that we cannot help but, because there are people who tolerate it, we could have used a little trick: to give the drug at all before randomizing, drawn from the study the intolerant and randomize then only those who can endure the drug until the end of the study. This is what is called using a run-in period, also known as a run-in phase (some call it open-label phase, but I think that this term is not always equivalent to inclusion period).

Overall, during the run-in study participants are observed before being assigned to the study group that corresponds to them to verify that they meet the inclusion criteria for an intervention, or that they are good compliers, tolerate the intervention, etc. Being sure that they meet the prerequisites for inclusion in the study we ensure a more valid and consistent initial observation before random assignment to the group that corresponds.

At other times we can see that intervention is used during the run-in using their response as part of the inclusion criteria, since you can select or exclude individuals based on their response to treatment.

You see how a run-in period can deliver us of the bad compliers, of those with poor health that can give us unpleasant surprises during the trial and of those who cannot tolerate the drug in question, so that we can better focus on determining the efficacy of treatment, since most of the loses during follow-up will be for reasons not related to the intervention.

Anyway, we must take a number of precautions. We must be careful in choosing the initial sample, whose size can be larger than that required without run-in. It is very important the baseline situation of the participants in order to stratify or to make a more efficient statistical analysis. In addition, randomization must be done the latest but as close as possible to the intervention, although it is not uncommon to find studies in which participants were randomized before the run-in period. Finally, to interpret the results of a study with a run-in period, we must take into account the differences between the baseline characteristics of the participants who have been excluded during the period and those who are ultimately assigned to study groups.

But not all is entirely made up of saints. Although to exclude bad-compliers or those with more adverse effects allows us to increase the power of the study and better estimate the effect of the intervention, applicability or generalizability of the results will be compromise because the results come from a more restrictive sample of participants. To say that in a more elegant way, we have to pay for the increased internal validity with a reduction of the external validity of the study.

To end this post, just to say something about something similar to the run-in period. Imagine that we want to test a new proton pump inhibitor in ulcerous patients. As all of them receive some treatment, it may artefact the results of our intervention. The trick here is to tell everyone to stop the medication for a while before randomization and allocation to the branches of the study. But do not confuse this with the run-in period. This is what is known as a washout period. But that is another story…

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