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Control and the therapeutic trial 1918 – 1948 Martin Varnam Edwards Thesis submitted for the degree of Doctor of Medicine, University of London 2004 1 Abstract: Control and the therapeutic trial 1918 – 1948 This thesis examines the rhetoric employed in the debate over the proper means to assess therapeutic efficacy during the first half of the twentieth century. I explore a number of therapeutic investigations including the debate in 1925 over the consumption of raw pancreas as a treatment for diabetes, the MRC’s investigation of ultraviolet light therapy in 1928, the MRC trial of serum therapy in pneumonia during the early 1930s, and the MRC’s wartime influenza vaccination trials during the 1940s. The MRC’s streptomycin trial, published in 1948, provided a model for future work in studies of therapeutic efficacy. Prior to this, therapeutic trials were idiosyncratic affairs and the methodology of a proper clinical trial was neither unified nor codified. But the MRC nevertheless referred consistently to its own trials as ‘controlled’ throughout the first half of the twentieth century. The term ‘controlled’ encompassed an eclectic assortment of methodologies, and conveyed a number of different meanings, sometimes simultaneously. Much of my thesis is devoted to exploring these various meanings and the contexts in which they were used. The unifying characteristic which bound the divers uses of the term ‘controlled,’ was its use as a rhetorical device at a time when the authority to determine the proper means of testing a remedy was very much up for grabs. The MRC, by describing its own therapeutic experiments as ‘controlled,’ was exploiting the powerful rhetorical connotations of the term. Ultimately, the MRC’s ‘controlled trial’ became a construct – prior to 1948 there was no single methodology which could describe it, no published trial which could exemplify it, yet it existed as a rhetorical device which could be used to enhance the authority of a trial performed under the auspices of the MRC. The implications of this insight for current understanding of ‘controlled trials’ are discussed. 2 Contents Acknowledgements Introduction and synopsis of chapters Chapter 1 No word is innocent: The rhetoric of controlled trials prior to 1948 Chapter 2 Good, bad or offal? The rhetoric of control in the evaluation of raw pancreas therapy, 1925 Chapter 3 Bright lights, smoky cities: Light therapy in 1920s Britain Chapter 4 Control and the MRC’s evaluation of serum therapy for pneumonia, 1929 – 1934 Chapter 5 Keeping it controlled: The MRC’s trials of immunisation against influenza Chapter 6 Whose words are they anyway? The contrasting strategies of Almroth Wright and Bradford Hill to attempt to capture the nomenclature of controlled trials Chapter 7 Conclusion: What’s controlled about the controlled trial? Bibliography: Primary sources Bibliography: Secondary sources 3 Acknowledgements I have been able to undertake this thesis thanks only to the encouragement, indulgence, or instruction of a large number of people. Thanks firstly to my supervisor Chris Lawrence for direction and instruction, and being always available, while knowing when to let me simply get on with it. Thanks to everyone at the Wellcome Trust Centre for the History of Medicine at UCL for accepting me as part of their academic and social community. In particular I am grateful to Caroline Essex, Carmen Caballero-Navas and Emese Lafferton for commenting on my work from the perspective of ‘proper’ historians; to Sally Bragg and Sharon Messenger for the help and facilities they provided, and for making everything run so smoothly; and to Gwyn Griffiths and Vera Man for IT support. I am indebted to all the friendly, efficient and ever-helpful staff both at the WTC and the Wellcome Library. I would also like to thank Harry Marks and Desiree Cox for their comments on parts of this manuscript. A modified version of chapter 2 of this thesis has appeared as an article in Annals of Science1 and is included here with permission from the publishers, Taylor and Francis (www.tandf.co.uk/journals.) I am grateful to The Health Foundation for a mid-career award grant which enabled me to carve out protected time pursue these studies on a part-time basis, and to the Starnet primary care research network for encouraging the study of history of medicine within their sphere of activity. I could not have undertaken this work without the support of my colleagues in the Jenner Practice, who have allowed me protected time and have accommodated my various changes to my surgery timetable with good grace. Finally I am eternally grateful to my wife Susan, for putting up with my devotion to the academic and social life of a postgraduate student when I should have been doing a proper job. 1 Edwards M. ‘Good, bad or offal? The evaluation of raw pancreas therapy and the rhetoric of control in the therapeutic trial, 1925,’ Annals of Science 61 (2004), 79 - 98 4 Introduction and synopsis of chapters No word – as my next chapter proclaims – is innocent. Words carry implications, connotations, metaphorical associations, which are inherent and inescapable. And embedded within the phrase ‘randomised controlled trial’ (also in ‘controlled trial,’ the Medical Research Council’s preferred term up to the 1970s) is a word far from innocent; a powerful, dynamic, sexy, authoritative stormtrooper of a word. This is why I have chosen to write this history of rhetoric in the randomised controlled trial (RCT); existing histories of the RCT might be few in number, but some are nevertheless highly effective, as the following chapter will make clear. None, however, have chosen to examine the circumstances in which the term ‘controlled’ was employed in relation to therapeutic trials during the first half of the twentieth century, and the powerful rhetorical associations of the term – which, I shall argue, were exploited by the Medical Research Council (MRC) in its attempts to establish itself as the proper arbiter of therapeutic efficacy through experiment. These arguments are developed in my next chapter, Chapter 1, No word is innocent: The rhetoric of controlled trials prior to 1948. Here I briefly summarise existing histories of therapeutic trials, and the recent trend away from earlier, frequently present-centred and triumphalist, narratives towards more critical analysis of therapeutic assessment within its social and historical context. I describe the variety of techniques to assess therapeutic efficacy which were available to a practitioner in early twentieth-century Britain, and the MRC’s attempts to establish itself, and its own laboratory-orientated philosophy, as the proper channel for such investigation. I examine existing scholarship regarding the place of rhetoric in scientific discourse, and attempt broadly to place the rhetoric of the MRC’s use of the term ‘controlled’ within the context of therapeutic assessment. This theme is examined in more detail in Chapter 2, Good, bad or offal? The rhetoric of control in the evaluation of raw pancreas therapy. In 1925 a debate erupted in the correspondence columns of the British Medical Journal concerning the effectiveness of eating raw pancreas as a treatment for diabetes. Enthusiasts were predominantly general practitioners, who claimed success for the therapy on the basis of their clinical impressions. Their detractors were laboratory-orientated ‘biochemist-physicians,’ who considered that their own experiments demonstrated that raw pancreas therapy was ineffective. The biochemist-physicians consistently dismissed the GPs’ observations as inadequately ‘controlled’. They did not define the meaning of ‘controlled’ in this context, although the physician-biochemists’ ‘properly controlled’ experiments involved careful regulation of their patients’ diet and other environmental factors, and evaluation of the therapy’s success through biochemical, rather than just clinical, criteria. However, I suggest that these factors alone are inadequate to account for the biochemist-physicians’ dismissal of the GPs’ work as ‘uncontrolled’. The biochemist-physicians were deliberately exploiting the powerful rhetorical connotations of the term ‘control’. Ultimately, they implied that only a trial which they themselves had conducted, could be deemed ‘adequately controlled’. I undertake a similar analysis in Chapter 3, Bright lights, smoky cities: light therapy in 1920s Britain. MRC investigators found themselves on the back foot when their investigation of ultraviolet light therapy failed to establish the benefits of the technique for healing leg ulcers, or for improving the health of weedy children. These negative findings attracted incredulity and opposition from medical professionals, whose consensus view almost universally supported the use of light therapy in the treatment of a wide variety of conditions. This was a broader and more public debate than that concerning the use of raw pancreas, and saw MRC members on the defensive against general medical opinion – rather than on the offensive against a treatment favoured by a minority of (relatively low-status) practitioners, as in the raw pancreas debate. Nevertheless, the MRC again adopted the rhetoric of control in defence of its findings, arguing that they were valid because they were the product of ‘controlled’ work. The meaning of ‘controlled’ 5 was, again, not defined, but did not appear to refer solely to the presence of comparison subjects; its further rhetorical functions are discussed. A different issue of control arose when the MRC’s newly-formed Therapeutic Trials Committee (TTC) inherited an ongoing MRC trial investigating the effectiveness of serum treatment for lobar pneumonia. In Chapter 4: Control and the MRC’s evaluation of serum therapy for pneumonia, 1929 – 1934 I examine the serum therapy trial, and the TTC’s criticisms when it assumed responsibility for the trial in 1931. The TTC deemed the trial’s conduct, up to that point, unsatisfactory; the trial was even in danger of becoming an embarrassing source of humiliation for the MRC. The TTC imposed a number of new requirements on its researchers, including a unified plan of activity within the trial in future.