The starting point to do a trial well is to identify an important question to address. So much better, if this question emerges from a meta-analysis of the existing evidence as was the case with the ATLAS trial. The Early Breast Cancer Trialists Collaborative Group identified a number of small trials comparing 10 years treatment with tamoxifen with 5 years, but these early trials were too small to reliably assess the effects of longer treatment.
Stories of Trials That Matter
Janet Darbyshire and colleagues from the MRC Clinical Trials Unit in London pioneered the conduct of a series of ground-breaking HIV treatment trials during the 1990s. One of these trials, The Delta trial randomised more than 3,200 patients to treatment with zidovudine (ZDV) alone or ZDV in combination with either didanosine (DDI) or zalcitabine (DDC). One of the questions the trial wanted to answer was whether combination treatment with DDI was superior to DDC.
The authors analysed this in two different ways. The first approach looked at the direct randomised comparison of patients randomised to either DDI or DDC. The second method identified those patients initially randomised to just ZDV and whose treatment was subsequently modified in an open-label fashion to include combination treatment with either DDI or DDC. Death was chosen as the study endpoint with the groups being similar in terms of selected risk factors for clinical progression. This means that the groups “looked” the same giving a false reassurance to be able to reliably investigate the effects of combination treatment across both the randomised and observational analysis.
The analysis clearly showed that in the randomised group ZDV plus DDI showed improved survival compared to ZDV plus DDC, but in the observation group the opposite effect was seen, namely combination treatment with DDC showed improved survival over DDI. Why might this be the case?
One explanation suggested by the authors is that in the observational group patients with a poorer prognosis are more likely to be prescribed DDI over DDC. This selection bias was not identified from the baseline analysis of selected risk factors for progression highlighting again the false reassurance that such results can confer. This highlights once again that only with a proper randomised comparison can selection bias resulting from known and unknown characteristics be reliably eliminated.
You can read the full paper here.
Today is world TB day.
Our colleagues at the MRC Clinical Trials Unit at University College London, including Professors Sarah Meredith and Di Gibb, who are supporters of MoreTrials, are hosting a symposium in London today on the global fight to eradicate TB. It will cover a number of the trials they are currently running to tackle pressing health issues from TB. For example, there are around half a million new cases of multiresistant TB each year. Current treatment takes around two years to complete, with only around half of those treated having a positive outcome. Fortunately, the STREAM trial is testing whether newer shorter treatments lasting 6-9 months might be more effective. You can read more details of all of the CTU’s TB trials here.
What is interesting to note is that randomised trials really started in medicine more than sixty years ago with the MRC trial of streptomycin in 1948. What disease was the trial in? TB.
Every year, millions of people are treated for head injury. A substantial proportion die or are permanently disabled. The theory goes that aside from the direct damage at the time of the injury, the inflammation that follows leads to further problems. Fortunately, corticosteroids can reduce this inflammation so have been used to treat head injury for more than 30 years. This makes perfect sense, right?
This is streptokinase. It was first isolated from bacteria in the 1930s and in the lab was shown to breakdown blood clots (by converting plasminogen to plasmin). When a purified version became available in the 1950s there was great interest to find out if it might increase survival if given after a person had suffered a heart-attack. This resulted in the first randomised trials being undertaken at the end of the 1950s, so what did they show? If streptokinase was given after a person had a heart-attack was survival increased?