Clinical trials in British medicine 1858 - 1948, with special reference to the development of the randomised controlled trial Benjamin Toth A dissertation submitted to the University of Bristol in accordance with the requirements of the degree of Doctor of Philosophy in the Faculty of Medicine. University of Bristol Department of Social Medicine November 1998 Word count 79,542 1 Abstract This thesis arose from a desire to explore the reasons for two related phenomena: why randomisation wasn’t introduced into clinical trials before the 1940s, and why in 1947 it was. In seeking to answer these questions, this study focuses on the development of clinical trials in Britain from the mid-nineteenth century to the MRC streptomycin trial published in 1948. Control groups and quasi-random allocation and were known to British clinicians in the nineteenth century, well before they became formalised in statistical theory. Chapter two argues that the collective therapeutic enquiries of the 1860s were an attempt to reform the medical profession in the light of the deficiencies of the 1858 Medical Act. Reform in this context was an attempt to create an ‘ideal practitioner’, defined here as one who used a statistical style of knowledge to guide both medical practice and medical etiquette. However, methodological elements such as control groups were largely irrelevant to this enterprise. Collective enquiries were overshadowed by the possibility of an exact knowledge of therapeutic action. Drugs such as diphtheria anti-toxin and Salvarsan, both products of German laboratories, mark the beginning of the modern era of therapeutics. Clinical trials played a secondary role in the development and testing of such drugs. Biological standardisation offered a powerful way for drug companies, research laboratories, and state authorities to promote and regulate the new laboratory based drugs. At the British Medical Research Council, physiological research in a laboratory was regarded as the desirable way to test new drugs. As a result, clinical trials organised by the MRC in the 1930s are historically inconsequential. Nevertheless, they played a role in consolidating the position of the MRC as the leading medical research organisation in Britain at a time when pharmaceutical companies were beginning to produce a range of new therapies. The organisational challenges facing the MRC in the immediate post-war period were changed considerably by the coming of the NHS. Adoption of a more strictly designed form of randomised controlled trial offered the MRC some specific advantages when dealing with a drug such as streptomycin. Using unpublished archival sources, the organisation of the streptomycin trial is reconstructed, and the organisational advantages of an RCT design highlighted. 2 Acknowledgments I am greatly indebted to my supervisor, Professor Stephen Frankel, who has allowed this work to develop at its own pace, and who encouraged me at the outset to look more widely than I otherwise would have. At the Department of Health, Dr Russell Hamilton provided regular friendly motivation as only he can. For any one in the field of medical history, the Wellcome Institute in London is indispensable. My friend and fellow student Alan Yoshioka has been very supportive, and kindly provided me with part of the transcript of his interview with Philip D’Arcy Hart. Also at the Wellcome, Dr Eileen Magnello convened an informal seminar on the history of clinical trials, and shared her work on Karl Pearson. My thanks to the staff at the Public Record Office, especially in the reprographics department, who went to great lengths to help with copying material. Closer to home, I am grateful to the staff of Library of the University of Bristol, especially Debbie Jones and Margaret Burke, who arranged for me to have extended access to archived volumes of the British Medical Journal. Professor John Pickstone and Dr. Mark Jackson at the Wellcome Unit in Manchester enabled me to present work on the Therapeutic Trials Committee at their seminar in 1995. Professor Dennis Lindley kindly talked to me about RA Fisher, randomisation, and 3 Bayesian statistics. Correspondence with Professor Ian Hacking clarified the relationship between his work and that of Michel Foucault. I owe the greatest debt to my family, especially during 1998 when I lived with this thesis as much as with them, and was finished a few days after my dear son Hugo was born. 4 AUTHOR’S DECLARATION I declare that the work in this dissertation was carried out in accordance with the Regulations of the University of Bristol. The work is original except where indicated by special reference in the text and no part of the dissertation has been submitted for any other degree. Any views expressed in the dissertation are those of the author and in no way represent those of the University of Bristol. The dissertation has not been presented to any other University for examination either in the United Kingdom or overseas. SIGNED DATE 20 th November 1998 5 Table of Contents Chapter Section Page Introduction 9 Purpose of this study 9 Plan of this study 12 Methodology 13 Chapter outline 15 What is a randomised controlled trial? 16 ‘The first RCT’ 18 Recent studies of therapeutics and clinical trials 19 The importance of statistics 21 Chapter one Approaches to the history and philosophy of statistics 25 Controversy in the theory and practice of statistics 25 Is a logic of statistical inference possible? 39 How are statistics contingent upon circumstances? 48 Conclusion: statistics as rhetoric 61 Chapter two The British Medical Journal and the creation of 63 statistical medical knowledge in the nineteenth century Introduction 63 Medical reform in mid nineteenth century Britain 65 Medical testimony in court 75 Irregular therapeutics 82 Regular therapeutics 86 The end of therapeutic investigations and the beginning of 121 medical research Summary and conclusion 122 Chapter three Evaluating therapies in the 1930s: the evidence of the 124 MRC Therapeutic Trials Committee Introduction 124 The Medical Research Council 125 The Therapeutic Trials Committee 160 Summary and conclusion 189 Chapter four Austin Bradford Hill and the MRC trial of anti- 192 pneumococcus serum Introduction 192 Serum treatment for lobar pneumonia 193 Austin Bradford Hill 208 Conclusion: the outcome of The Principles of Medical 219 Statistics Chapter five Tuberculin, streptomycin and the first published 221 randomised controlled trial in medicine Introduction 221 Tuberculosis 222 6 The evaluation of tuberculosis therapies 233 The MRC randomised controlled trial of streptomycin 249 Conclusion 279 Chapter six Conclusion 284 Why wasn’t randomisation used before the 1940s? 284 Why was randomisation possible by 1948? 287 Further research 290 Appendix 1 The MRC streptomycin trial paper in the BMJ 292 Appendix 2 Publications on the history and philosophy of statistics 293 1910 – 1989 Appendix 3 Statistical models of hypothesis testing and estimation 303 Appendix 4 The essential oils in the treatment of puerperal fever 329 Appendix 5 William Guy’s lectures on medical statistics, 1860 331 Appendix 6 Substances submitted to the TTC for clinical trial 340 Appendix 7 MRC serum treatment of lobar pneumonia: standard 343 scheme of enquiry Glossary 344 Bibliography 345 7 List of Tables and Figures Page Tables Table 1 Examples of some nineteenth century therapeutic substances 87 Table 2 The meanings of rational and empirical in mid nineteenth 95 century medicine Table 3 Selected tabulated data from the BMJ of 1858 106 Table 4 Therapeutic inquiries initiated by the BMA in 1862 113 Table 5 Schedules for the therapeutic inquiries 120 Table 6 Schedules returned to the Committee 120 Table 7 Initial membership of the TTC 162 Table 8 Principal results from EW Assinder’s comparative trial of anti- 186 syphilitics Table 9 Effects of serum treatment on fatality in Type I pneumonia 203 Table 10 Age distribution in the serum treatment for pneumonia trial 204 Figures Figure 1 Timeline of this study 16 Figure 2 Part of a table of random numbers 42 Figure 3 TTC application schedule 168 Figure 4 Results of streptomycin on experimental tuberculosis in guinea 251 pigs 8 Introduction Purpose of this study Several years ago the present author was among a group of health care researchers discussing the merits of different research methodologies. In the course of discussion it emerged that the first randomised controlled trial (RCT) in medicine was conducted only as recently as the 1940s. The date, if correct, was surprising. The RCT is regarded as the sine qua non of clinical trial design. As a research method it is strikingly economical and powerful in its ability to evaluate therapies. Because of this it now seems, to a great majority of researchers and many clinicians, the intuitive way to evaluate the effectiveness of therapies. Alternative methods, if they exist, are almost unthinkable. Yet only a few generations ago the RCT was unknown to medicine. Stuart Pocock’s brief history in his textbook on clinical trials suggested that the date was correct. 1 According to Pocock the first rigorously organised randomised controlled trial in medicine was that of streptomycin as a treatment for tuberculosis of the lung, conducted under the auspices of the Medical Research Council (MRC), and published in the British Medical Journal in 1948. 2 1 Pocock 1983. Chapter 2. 2 Pocock 1983 p17. The trial, described in more length in chapter 5 of this dissertation, published its report in the BMJ in 1948 (MRC 1948). The report is reproduced in Appendix 1. 9 Several other standard synoptic accounts of the development of the RCT in medical research are available. 3 Many of them refer to the streptomycin trial, although as with any ‘first’ there are other priority claims. A controlled of patulin as a treatment for the common cold was begun before the streptomycin trial and had many of its features.