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Randomized Trials Stopped Early for Benefit: Victor Montori, MD, discusses randomized trials that are stopped early for benefit.
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Randomized Trials Stopped Early for Benefit: Victor Montori, MD, discusses randomized trials that are stopped early for benefit.
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Language: EN.
Segment:0 .
>> I'm Joan Stephenson, editor of JAMA's Medical News and Perspectives Section. Today I have the pleasure of speaking with Dr. Victor Montori about stopping randomized trials earlier than planned because there is an apparent benefit. Dr. Montori, why don't you introduce yourself to our listeners? >> Yes. Hi. This is Victor Montori. I'm Professor of Medicine at Mayo Clinic, Director of Healthcare Delivery Research at the Center for Science and Healthcare Delivery, and I work at the Knowledge and Evaluation Unit at Mayo.
>> What are the most common reasons investigators may stop a randomized control trial earlier than planned? >> Well the most common reason is when they find evidence of benefit before they reach the planned end of the study. Other reasons include finding evidence of harm to the participants and finding that they will not end up with an answer at the end of the study because the study's not recruiting or there's really no treatment effect to be found in a [inaudible] look.
>> How are truncated randomized control trials at risk for overestimating treatment effect? >> Perhaps the easiest way to understand this is if you are looking at the data as it accrues in a trial, and you all of a sudden find that there is a difference between treatment arm and control arm, and you decide to stop at that point, you probably are stopping at a point where you're catching the data at a random high. In other words, the data is showing the biggest difference, and that's why you picked it up.
That if you let the data mature as more patients get accrued in the study that you will actually see that the treatment effect really is smaller than what you found when you picked up that blip in the data. So that's probably the most common mechanism by which a trial that stopped early ends up overestimating the treatment effect. >> Could you give an example of how stopping a trial early could potentially harm patients? >> When patients make decisions with their clinicians about whether a treatment is worth taking, they're considering the pros and cons of that treatment.
If one overestimates the benefits, then patients may reasonably consider that those large benefits will outweigh the cost and burdens and side effects of the treatment. If they were to know the real treatment effect, that the real treatment effect is in fact smaller, they may not decide to take the therapy given those [inaudible] therapy potential harm, cost, and burdens. In fact, it is quite possible that when a trial gets stopped early and a treatment is found to be beneficial, that the true effect is no benefit at all.
So you can imagine that if patients are exposed to treatment and in fact they're not beneficial or not as beneficial as advertised that these would not be the treatments that are consistent with patient preferences and goals. >> What areas of study have the most frequent cases of truncated randomized control trials? >> We did a study of randomized trials that we could find in the literature up to 2007. And when we looked at the distribution of these studies, what we found were that the majority of these studies came from the cardiology literature.
But of course, this is an area of [inaudible] medicine where there are many randomized trials. Oncology. So cancer trials and HIV trials correspond to the next most common categories. It turns out that in these categories like cancer, AIDS, and critical care it's very important to find an answer quickly or at least it's been historically important to find an answer quickly. And, as a result, there's been an interest to stop the trials once an apparent answer has become available.
This has led to many of these trials being stopped earlier than planned. >> What characteristics lead investigators to stop trials early for an apparent benefit? >> Well, the most common characteristics that lead to a trial being stopped early have to do with identifying a large treatment effect at an interim analysis. So if there are many interim analyses planned or unplanned, where investigators are picking at the data, this would lead to a higher likelihood of looking and finding a large treatment effect and stopping a clinical trial.
It's important to note that when these trials are stopped early for benefit, they're more likely to overestimate the treatment effect when they get stopped and there are few events accrued up to that point. So the more events accrued, the longer and larger the study, the less likely it is that clinical trials stopped early were overestimating treatment effect. >> What are preplanned stopping rules, and how are they helpful? >> Statisticians have been comfortable about stopping clinical trials earlier than planned for benefit because they set up rules that prevent those trials from being stopped too early.
However, these rules allow for clinical trials to stop earlier than planned when the difference between treatment and control is more extreme than what you could expect by chance. Turns out that differences that are very extreme do happen by chance, and therefore these rules then get triggered and investigators get to look at the data and decide what to do. Unfortunately, what has become obvious to us is that these rules are not helpful to prevent early stopping that ends up overestimating the treatment effect.
And the reason is that the answer usually emerges after multiple studies are conducted, and clinical trials stopped early tend to have a chilling effect on the field where subsequent trials either do not take place or take place after a considerable amount of time, time in which clinicians realize that the benefits are not as good as advertised. >> Is there anything else you would like to tell our listeners about randomized trials that are stopped early because of an apparent benefit? >> I think the fundamental message is that if you read about a clinical trial that advertises a very large treatment effect, as a result the investigators have to stop the trial earlier than planned, that this usually will be associated with tremendous hype about the treatment.
In some cases that hype is appropriate because the treatment obviously is providing great benefit. But in the majority of cases, it is our impression that what we're seeing is an overestimation of the treatment effect. Therefore, clinicians and patients should be very cautious in making decisions fundamentally based on clinical trials that stopped earlier than planned, and they must consider the overall literature on the topic before making an important decision. >> Thank you, Dr. Montori, for your insights into clinical trials that are stopped before the planned end date because of a perceived benefit.
Additional information about this topic is available in Chapter 9.3 of the User's Guide to the Medical Literature. This has been Joan Stephenson of JAMA talking with Dr. Victor Montori about stopping randomized trials early for JAMAevidence.
