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Most of my thoughts about clinical trials crystallised during 1971–1976, when I was writing and repeatedly rewriting what became the 69-page British Journal of Cancer paper, which was eventually published in two parts at the end of 1976 and the beginning of 1977. For several years before word processors had been invented, my long-suffering colleague Gale Mead had to deal with a succession of total rewrites, and my heartfelt acknowledgement of her help is made clear in the paper! I had finished a complete draft of the paper in 1975. I felt that what it had to say about randomised evidence was important, so I wanted it taken seriously, and to be published with the endorsement of the Medical Research Council (MRC). However, some on the MRC leukaemia and cancer trial committees did not want it to be published, as it implied (correctly) that the trials they were then doing wouldn’t give reliable answers. They explicitly and unpleasantly blocked the paper, and later managed to get me removed from the relevant committees because of my continuing concerns about their trial methodology and, in particular, the wholly inadequate trial sizes that inevitably followed. At that time, the Oxford Clinical Trial Service Unit carried little weight in the corridors of the MRC, except through Richard Doll. Fortunately, Doll was chair of the MRC leukaemia steering committee, and he suggested to me that if I wrote the paper as a report and submitted it to him as an individual who happened to chair an MRC committee, then nobody else could block it. This is the explanation for the paper’s curious title – Design and analysis of randomized clinical trials requiring prolonged observation of each patient. The other problem was where on earth to try to publish such an enormously long paper. I knew Laszlo Lajtha, then the editor of the British Journal of Cancer, so I telephoned him for advice. He asked me to post it to him for him to read at home over Christmas 1975. He rang me at the end of December to say that he’d read the entire thing and wanted to publish it in the British Journal of Cancer! I was amazed and absolutely delighted, in the way that only young people can be. A publication opportunity as good as that hadn’t even occurred to me as a possibility (or indeed to Richard Doll). Having produced a complete text and received a definite promise of prominent publication, however, I wanted to ensure that I got as many reputable statisticians as possible to endorse it, so I spent most of 1976 collecting the long list of authors – Malcolm Pike, Peter Armitage, Norman Breslow, David Cox, Susannah Howard, Norman Mantel, Klim McPherson, Julian Peto and Peter Smith. In the process, their comments, criticisms and suggestions led to many substantial improvements and clarifications. When the paper finally came out, it engendered both hostility and support. Most trial statisticians and some clinical investigators felt that it expressed what they’d been wanting to get their clinical colleagues to do; but many clinical investigators at that time were still against randomisation. Anyway, it did get noticed, and it engendered favourable editorials in the New England Journal of Medicine, the BMJ and the Lancet. It was also translated into other languages (English had not yet become as dominant as it now is), and it reinforced the efforts of those who wanted to promote better trial methodology. I explained the basis for my views and made recommendations in a paper published in 1978. The British Journal of Cancer paper introduced the logrank statistical methods that we still use in the Early Breast Cancer Trialists Collaborative Group, although, because things are now all done on computers, we now use the exact variance of O-E, as described on pages 38–39 of the paper, rather the simple approximation (O-E)2/E (which is easier only if one is doing calculations by hand). It is perhaps of particular note that Section 30 (pp. 28–29) of Journal of the Royal Society of Medicine; 2019, Vol. 112(2) 78–80

Reflections on the design and analysis of clinical trials and meta-analyses in the 1970s and 1980s