randomised controlled trials
Networks, geometry and evidence
Last week at the 19th Cochrane Colloquium in Madrid, Professor John Ioannidis from Stanford University gave a riveting talk about the geometry of the evidence. Among the hundreds of articles he has published, his 2005 paper on Why Most Published Research Findings Are False is the most downloaded technical paper from the journal PLoS Medicine with over 400,000 views. Without question, he is a leader in addressing controversial issues in biomedical research.
In his lecture, he advocated for agenda-wide views of research by using network meta-analysis. Traditional meta-analyses are useful to compare two interventions, or an intervention with placebo. But what happens when there are dozens of randomised controlled trials on many different medications for the same medical condition? For example, there are 68 antidepressant drugs to choose from, how do healthcare professionals determine which one is the most effective? In fact, Ioannidis conveyed it would probably be stupid to depend on a single meta-analysis.
Enter the network. Ioannidis has been leading the development of multiple treatment meta-analysis or network meta-analyses. In its simplistic form, the networks map out all the interventions for a known condition in a lattice or network design. The network displays the number of trials relevant for a certain intervention and illustrates how they connect (or do not connect) to each other. The pattern of the comparisons is called the geometry of the treatment network.
For example, there have been 69 trials for smoking cessation that compared nicotine replacement with no active treatment but zero trials comparing it with the drug varenicline (Champix). To make an informed decision, clinicians need information comparing interventions.
Also, when you look at funding of the clinical trials, you find that head-to-head comparisons of interventions owned by different companies are uncommon. In fact, you find many “auto-loops” showing that the majority industry sponsored trials examine a single intervention owned by the company. Worse still, when two companies sponsor the same trial, it is not due to altruistic cooperation but usually due to co-ownership of the same agents.
Although network meta-analysis offers a wider picture than a traditional meta-analysis, they combine large numbers of trials and comparisons into one academic paper, which Ioannidis pointed out is not good for researchers CV. The current framework encourages narrowly defined systematic reviews and clinical trials which demonstrate effectiveness rather than zooming out to look at the big picture. Networks, although providing a cross-section of a clinical field at one point in time, provide insight into the current evidence base and can identify where connections are missing.
Going back to the above example on smoking cessation, we need trials comparing nicotine replacement with to varenicline (Champix), not another study showing that nicotine replacement compared to placebo is effective. But the problem is that the latter is easy to publish with a large effect size, but the former will probably show no difference and not make BBC headlines.