What if it’s not Randomized?

Posted on: November 26th, 2021 by admin
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The National Cancer Institute in the USA defines a randomized clinical trial as: “A study in which the participants are divided by chance into separate groups that compare different treatments or other interventions. Using chance to divide people into groups means that the groups will be similar and that the effects of the treatments they receive can be compared more fairly. At the time of the trial, it is not known which treatment is best.” But what happens if the randomization is not properly conducted, and what might the ramifications be for patients?

Forty years ago, a randomized clinical trial was initiated in Canada to answer the question: Does routine screening of women with screen-film mammography (this was before digital X-rays) plus clinical breast examination confer a reduction in mortality compared to usual care for women aged 40 to 49? The results of this Canadian National Breast Screening Study (CNBSS) were first published in 1992, with further follow-up reports in 2000, 2002, and 2014. Each time the answer was always “no”, there wasn’t any benefit conferred by screening.

Although there was criticism of the early CNBSS results, especially by Daniel Kopans from Harvard (seen at left), the 2014 paper in the British Medical Journal re-ignited a media storm between the proponents of mammography and those who believed this screening technique offered little or no benefit for women. Well, a paper authored by Martin Yaffe from Toronto (seen above right) with three other Canadians plus Kopans has just been published in the Journal of Medical Screening. The title says it all: “The randomized trial of mammography screening that was not – a cautionary tale.”

By carefully analysing how the women were recruited, the authors established that clinical breast exams were conducted before allocation to a trial arm and so women with palpable findings were mis-randomized into the mammography arm. The study nurses responsible for allocation probably believed they were helping women with advanced breast cancer.

The figure at right (© Sage) illustrates the impact of subverting the randomization: “The effect of shifting the allocation of women with advanced breast cancers, destined to die, from the usual care arm to the mammography arm of the Canadian National Breast Screening Study. The red arrow indicates that shifting only 10 of these women would cause a mortality reduction benefit of 26% to appear instead as an increased risk of 36%.” The impact of the discredited CNBSS findings has been significant, influencing healthcare policy – for example in Switzerland – and therefore jeopardizing the lives of women who might otherwise have enrolled in a breast screening programme.

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