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Astronomy and Evidence: StaR Gazing for Children's Trials

Peter Gill
Last edited 14th September 2012

On the eve of the 20th anniversary of the United Nations Convention on the Rights of the Child, which recognised the right of all children to "the enjoyment of the highest attainable standard of health", the editor of the Lancet Richard Horton was delivering a plenary address at the first summit of StaR Child Health in Amsterdam in 2009. In his address, he stated the:

“Lack of research, poor research, and poorly reported research are violations of children’s human rights.”

Individuals from various disciplines, including the World Health Organisation, the US Food and Drug Administration, and the European Medicines Agency, gathered together to discuss a topic of shared interest: the paucity and shortcomings of paediatric clinical trials.

The quality, quantity and relevance of data involving children are substantially lower than those involving adults. This problem persists despite knowledge that inadequate testing of medication in children may result in harmful or ineffective drugs being offered or beneficial drugs being withheld.

Indeed a systematic review sponsored by the World Health Organisation found that there were few guidelines relevant to the design, conduct and reporting of research in children. Most guidelines only seem to focus on what should be done, failing to address the important issue of how it should be completed.

The mission of StaR Child Health is to improve the design, conduct and reporting of "research with children through the development and dissemination of evidence-based standards."

How best to achieve this monumental task? The StaR Child Health group is using a "knowledge to action" process that involves using a systematic process to review the current knowledge base, identify gaps, develop guidance and implementation strategies. An ambitious agenda that is gaining tremendous momentum.

Based the results of a systematic review and survey of key stakeholders, they have identified 10 priority issues. Each issue will be systematically addressed by a standard development group that will produce evidence summaries, identify gaps and develop a dissemination strategy. The priority issues include recruitment and informed consent, risk of bias, sample size, age-specific dosage and administration, safety and global health.

But more guidelines and standards will not change the conduct of trials unless they are implemented. StaR Child Health is leading in knowledge translation by involving multiple stakeholders from the beginning and is working with international partners, such as the GRIP Project, a global research network in paediatrics.

For the quality of health care for children across the world to improve, trials must be conducted that address the complexity of child health and provide reliable evidence-based answers. Now we can be confident that we have a bright StaR illuminating the path forward.

Networks, geometry and evidence

Peter Gill
Last edited 27th October 2011

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.

Nothing is as good as Obecalp

Dr Placebo
Last edited 24th October 2011

It’s been tested in more clinical trials than any other drug in history. Even critics admit it is effective for mild pain, mild depression, and other ailments with subjective outcomes. It has fewer side-effects than most alternatives. And now you can buy a bottle containing 50 pills of it for £3.75 ($5.95).

It’s called Obecalp and it comes in cherry flavor.

Here’s the rub: Obecalp is ‘placebo’ spelled backwards. Their website admits: “Obecalp® is a placebo and is not intended to diagnose, treat, cure or prevent any disease, or illness”. It was designed for parents to please (‘placebo’ means ‘to please’) malingering children. But don’t placebos work because people believe they are ‘real’? If so, I’ve removed the fun – and potential benefit – of Obecalp you. Or have I?

A recent study suggests placebos work even if people know they are placebos. There are two plausible explanations for why this might be the case. The first is classical conditioning. Pavlov’s dogs salivated at the mere expectation of food after having associated the sound with imminent food, and your body might react after popping Obecalp after it has learned (over a lifetime) to associate pill popping with symptom reduction.

Another novel explanation comes from evolutionary psychology. Imagine it is the dawn of human evolution. You feel a flu coming on but a sabre-toothed tiger is attacking your clan. If your body evoked the full immune response there would be less energy for fighting the tiger. Your survival therefore depends on ignoring the flu and increasing circulation to the skeletal muscles required for fighting. (In fact, the ‘fight or flight’ response suppresses the immune system.) Thankfully, you and your fellow tribesmen scare the tiger away, and the fight or flight response subsides. Then an authority figure – an elder or shaman – tells you everything is okay. The message from the trusted figure let you know (perhaps subconsciously) that you won’t need to run or fight for a few days. You are free to lie down and let your body’s immune system get to work.

Today tigers, village elders, and shamans are rare, but people with impressive titles like ‘Doctor’ might play the same role. If an authority figure (either in person or in an advertisement) tells you that you are going to be okay, your body (again perhaps subconsciously) might get the message that it is okay to allow the full immune response to kick in.

So even now that you know what it is, Obecalp still may be better than nothing. In the worst case, nothing is as good.

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