Helen K. Valier

Clinical Trials and the Reorganization of Medical Research in post-Second World War Britain

The rise of biomedicine is usually associated with the transformation of biological and medical research in the United States following the vast expansion of funding, both private and public, in the years after the Second World War.1 Along with the other authors in this issue, we are interested in describing this phenomenon in national contexts other than the United States. Our discussion of biomedicine in Britain draws upon many of the same themes as our fellow authors and the existing literature on the US—the new role of the state as scientific entrepreneur; the relationship between experimental medicine and clinical services; and the growing institutionalization of associations between laboratory and clinic—to emphasize the clinical trial as a privileged form of therapeutic evaluation in the post-war years. In particular we are keen to stress that the randomized clinical, or controlled, trial (RCT) in Britain developed within a period of increasing centralization of state policy and planning for health services and medical research. The epistemological success of the RCT in demonstrating the value of the anti-tuberculosis drug streptomycin elevated the technique to international prominence in the late 1940s. The 1948 trials of streptomycin conducted by the British Medical Research Council (MRC), along with similar trials in the United States, are usually recognized as the worlds first randomized controlled trials. Indeed, the streptomycin trials, and the trials of PAS and isoniazid that followed in the early 1950s, did combine the statistical technique of randomization, with new organizational techniques, such as the division of specialist labour, and central review and data collection, across multiple sites of study. As Peter Keating and Alberto Cambrosio, Ilana Lowy, and Harry Marks have shown for the US, the success of the co-operative (that is, multi-centre) clinical trial was intimately related to the new role of the federal government, through the National Institutes of Health, in funding such organized biomedical research.2 Similarly, using treatment trials for tuberculosis and lung cancer as our case studies, we show for Britain that the promotion and organization of co-operative trials was fundamentally part of the MRCs new role within the state. We argue that the Council pursued the trials as a means of unifying a research landscape that was characterized by localism and suspicions about MRC plans to remodel clinical research to resemble the basic sciences. We argue further that a controlled trial must be understood both as a tool to produce knowledge persuasive enough to direct best clinical practice, and as a powerful means to discipline research workers in disparate settings.3 Neither process was particularly straightforward. It took years of clinical trials of anti-tuberculosis chemotherapies before sanatorium treatment and bed-rest were entirely given up by British physicians. The MRCs 1955 trials carried out in the Indian city of Madras (Chennai) are generally regarded as conclusively showing domiciliary care to be redundant in the presence of chemotherapeutic intervention; however, we argue that trials influenced but did not change practice overnight. Similarly, the lung cancer trials initiated by the MRC following a conference in 1957 as part of a broader programme of therapy trials for various types of cancer, proved difficult to run. Furthermore, they did not resolve the controversy as intended, not least because procedures and treatment pathways were well established before the trials. Serious historical attention to the organizational details, reception of such RCTs, and resulting changes in practice, is needed if we are not to be blinded by hindsight. Before we turn to the trials, however, we need to discuss the role of the MRC in the history of biomedicine in Britain and the place of the Council within the post-war socialized National Health Service (NHS).

Screening, Patients, and the Politics of Prevention

The year 1979 was a good one for Gerald Murphy’s National Prostatic Cancer Project (NPCP) at Roswell Park. In an article titled Purification of a Human Prostate Specific Antigen, Murphy’s team claimed to have purified and identified a new immunological marker linked to prostate cancer,3 but it was a discovery that a pathologist from the University of Buffalo school of medicine, Richard Ablin, also claimed. Arguments over recognition are, and have long been, a part of doing science. Many researchers in many laboratories do, after all, work on very similar issues so simultaneous discoveries are not uncommon. What made the argument regarding the discovery of prostate specific antigen (or PSA) of particular interest though, is that Ablin’s results were not simultaneous, he had published his data years before and the NPCP team had duly cited it. What’s more, in his book, The Great Prostate Hoax: How Big Medicine Hijacked the PSA Test and Caused a Public Health Disaster (2014), Ablin reports that he had also applied for a grant (which was rejected) from the NPCP during the late 1970s detailing how he would work on extraction and purification procedures linked to his earlier findings, or, in other words, the work that the Roswell group would go on to publish to considerable fanfare.4 As PSA-related patents had been filed by the NCPC, lawyers soon became involved, and the dispute rumbled on for years. Again, a distressing set of circumstances for those involved but not unusual within scientific controversies. What really sets this dispute apart, however, is the extent to which it was retrospectively ignited when one party—Ablin—subsequently became a highly vocal critic of the use (or as he saw it, abuse) of the very substance he had discovered.

Surgery and Specialization

The white heat of the Paris clinics helped in many ways to create a new ‘modern’ style of medicine: one that blended medical and surgical ideas, was research and teaching intensive, and which was, in other words, an early version of the phenomenon that we would now describe as ‘academic medicine’. An important feature of this new trend was the extent to which ‘specialist’ knowledge and practices could be rapidly developed. Take the career of Pierre-Joseph Desault, for instance, a man who began his professional life relatively inauspiciously as a barber-surgeon but who would go on to found famous centres for academic surgery, first at the Charite then at the Hotel Dieu in late eighteenth century Paris.3 At the College of Surgery, Desault oversaw the building of a grand surgical amphitheatre that allowed students to observe and be instructed on live surgeries.4 A similar innovation on the wards, where Desault insisted that surgical students be placed in charge of wards—caring for patients and maintaining records—was an enormously important step, one that opened a new world of practical opportunities for would-be practitioners just as their elevation in status itself symbolized the ascendant status of academic surgery as a whole.

Conclusions: Medicine, Masculinity, and the Problems of the Prostate

The twentieth century decline in the incidence and prevalence of infectious disease has long been recognized by historians as coinciding with a renewed biomedical focus on the ‘disease management’ of the chronically ill. During the 1960s and 1970s the use of ‘risk factors’—clinical indicators, genetic markers, lifestyle choices, and the like—began to increase the frequency and intensity of similar disease management interventions in seemingly healthy populations. During the past forty years the global healthcare industry has engineered hugely profitable markets from healthy ‘patients’, largely by appealing to the value of preventative intervention in the battle against the new diseases of civilization: hypertension, cancer, and diabetes. Robert Aronowitz,2 Ilana Lowy,3 and Charles Rosenberg4 have all documented disturbing trends in disease management directed at the aggressive prevention of anticipated undesirable outcomes. New diagnostic tools and larger programs of more biologically sensitive screening have led to ever greater ‘early detection’ of ‘pre-cancerous’, ‘pre-diabetic’, and ‘pre-hypertensive’ patient populations. As Aronowitz points out, the experiences and patient-pathways of these ‘pre-patient’ patients can become almost indistinguishable from those patients with serious clinical symptoms of disease.5 While the consequences of this elision between statistical risk of disease and actual organic illness can be relatively benign, Aronowitz, Lowy, and Rosenberg highlight at least one dire consequence of this trend: the rising number of healthy but ‘BRCA positive’ women undergoing extremely drastic measures such as prophylactic double mastectomies. In this book I have made similar observations about similarly drastic interventions in men showing prostatic malignancy as a result of biopsies driven by the PSA explosion of the early 1990s.

Sex, Hormones, and Quantification

The revival of microscopy, the development of cell theory, and the emergence of specialization all drastically reshaped medicine during the latter nineteenth century, but so too did the development of another phenomenon I have not yet discussed: the science of physiology. Once again the great medical centres of Europe—London, Paris, Berlin—were at the epicentre of profound transformations in the professional, practical, and intellectual development of medicine and surgery, and nowhere was this more apparent than in the Paris laboratories of Claude Bernard. Bernard’s classic Introduction a la Medecine Experimentale (An Introduction to the Study of Experimental Medicine) was published at the peak of his career in 1865, by which time the Emperor himself, Napoleon III, had promised him a new laboratory suite at the Museum National d’Histoire Naturelle in Paris. Bernard was an aggressive and ambitious experimenter, freed from the necessity of supporting himself through the practise of medicine thanks to the financial support of his wife, Marie Francoise Martin, and the professional support of an early mentor at the Hotel-Dieu, the physician and physiologist, Francois Magendie, who provided Bernard with early access to laboratory equipment. A strict empiricist, Bernard proposed what would become the classic experimental model in science: determination of cause and effect not through correlation but through the control and manipulation of variables. If variables could be altered independently of each other, and reliably caused an observable effect to occur then, and only then, he reasoned, could a causal relationship be established. For Bernard, observation of the sick patient at the bedside, even when supplemented by newer tools, like the stethoscope, limited the science of medicine to a descriptive practice. Similarly, the lesions and diseased organs for so long the focus of attention by morbid anatomists represented the endpoints and not the dynamic process of disease itself. In place of such ‘passivity’ then, he proposed a continuation of Magendie’s interventionist, animal-based (vivisection), approach to the investigation of normal and abnormal physiological function under the most strictly controlled laboratory conditions. In his preface to Medecine Experimentale, Bernard was clear about the relative benefits of these methods of investigation:

Radiotherapy and Evidence in an Age of High Technology

Some remarkable discoveries were made about the fundamental nature of the universe at the turn of the nineteenth century. In 1895, the German physicist Wilhelm Conrad Rontgen, working at the University of Wurzburg, observed a strange fluorescence as he tinkered with cathode ray tubes, a phenomenon he would later describe as ‘x-rays’. Building on this excitingly new and mysterious finding in 1899 two Polish scientists working in Paris—Marie and Pierre Curie—announced to the world the discovery of several compounds that emitted similar radiating energy, including an element they termed ‘radium’ (from the Latin radius or ‘ray’). Within a few years both discoveries were taken up into medical use, particularly in the field of cancer after the Curie’s published evidence demonstrating that ‘radioactivity’ was likely biologically destructive to tumours (as it was to all tissues, as many of the early pioneers in this work found out at the cost of their own health).3

The Problematic Prehistory of Prostate Cancer

In the early summer of 1817, the Professor of Anatomy and Surgery to the Royal College of Surgeons, William Lawrence, presented several cases of ‘Fungus Haematodes’ (including some reported by his colleague, George Langstaff, the attending surgeon for St Giles’ Cripplegate Workhouse). As part of his series, Langstaff recorded a case of extreme urinary blockage arising from, he supposed, a diseased prostate:

Introduction: The Prostate, Cancer, and the Making of Modern Medicine

How can the very old come to define the very new? The ailments that make up a collection of diseases labelled ‘cancer’ are described in ancient manuscripts, depicted in millennia of human artifice and exposed within prehistoric human remains. As a species we have always lived with malignant tumours and wasting death. Nevertheless, there is something undeniably modern about cancer.1 For over a century, the control of cancer has perhaps been the ultimate test of our medical prowess, a yardstick measuring our incremental control over nature and a testament to our unwavering expectation of longer, healthier lives, unhampered by disease and disability. The capricious and intractable nature of cancer has not, by and large, done much to sink our buoyant confidence in scientific progress but it has introduced a paradox, widely felt if not always acknowledged, that all is not well in our scientific age. The history of cancer in the twentieth century is at one and the same time a story of extraordinary optimism for a future mediated and enhanced through technology and a story of human fear and frailty in the confrontation of nature and technology. Charles Rosenberg described his view of this paradox of modern medicine in his book, Our Present Complaint, saying that we have,

Cancer and Clinical Trials

Experiments, as Claude Bernard had shown, manipulate materials and processes in the natural world to determine underlying cause-and-effect relationships. To do this, experimenters seek to change certain known conditions and control for others, an inductive and powerful approach to problem solving. This drive for experimentalism, combined with the search for new therapeutic agents arising in the years before WWII, helped stimulate by mid-century perhaps the key methodological (we might even say ideological) innovation in twentieth century biomedicine, the randomized clinical trial (RCT). Although there are other claimants to the title of the ‘first’ controlled clinical trial, historians generally recognize the MRC’s 1946 study of tuberculosis treated with streptomycin3 as the beginning of the new movement.4 Part of the notoriety attached to the streptomycin trial came because its results were, unlike some earlier efforts, positive and clearly so.5 The original scarcity of the antibiotic had made the division of patients between a treatment group who got the drug and other groups who did not ethically straightforward (a feature of clinical trials that would become increasingly complex as I discuss in the next chapter), and helped to make the results clear and compelling.

Book Review: The cure: a story of cancer and politics from the annals of the cold war.

Part political thriller, part love story, Krementsovs account of a failed and now little remembered cancer therapy is a gripping read. The popular and accessible style of The cure and its considerable meditations on the romantic lives and attractions between the tales chief protagonists, Russian scientists Nina Kliueva and Grigorii Roskin, certainly give the book an appeal beyond an historical audience; none the less, this is good history of medicine. The cure offers a solidly-researched, well-written account of the relationship of medicine and disease to wider social and political events and networks. It is, moreover, a particularly welcome addition to the literature on the history of cancer research and therapy, and more generally to the history of laboratory-based clinical research and its relationship to clinical practice. Accounts of how post-Second World War and Cold War politics affected the development of experimental biology and experimental medicine in the US are quite numerous, but few consider the USSR in any depth. Work on Soviet science has, furthermore, tended to focus on the politics surrounding Sputnik or Lysenkoism; as such the world of Soviet microbiology and medical research cultures described in the pages of The cure is all the more interesting as most know so little of it. The co-constructed nature of science and culture is all too seldom discussed with such texture and nuance. Through his analysis of the lives and work of Kliueva and Roskin, Krementsov weaves the international and national politics of the Cold War with the local politics of a newly established medical research institute and relates all to a wider, somewhat combative, medical research scene. His account of the rise and fall of the pair under Joseph Stalin, followed by their subsequent rise to grace under Nikita Khrushchev, speaks starkly of the ways in which work deemed politically important was brought into the centre of political life in the USSR, and, as such, suffered terribly through the vacillations of policy and the whims of its leaders. As part of the history of cancer research The cure works well too. Although analysis of failed innovation has for several years found a place within the history of medicine, most accounts deal in description and analysis of success and therapeutic transformation; but the history of cancer research is positively littered with failed innovation and unrealized breakthroughs, few of which have been documented by historians. The volume of medical and scientific work on cancer in the post-war era is staggering, so historians wishing to discuss this period would do well to overcome their squeamishness surrounding failure, and begin to find meaningful ways to discuss the nature and characteristics of work in a field where significant breakthroughs held the promise of almost incredible adulation and success (especially given the reputation of cancer as a scourge of the civilized world) but which were, due to the terrible intractability of the illness, very unlikely to be realized. For Krementsov, however, the excitement and frustrations of cancer research merely reflect the bitter-sweet realities of scientific practice and our perceptions of it: “We tend to focus on successes, but spectacular success is a rare event in science. A much larger portion of scientific research never makes it into the public arena, and each rare success is based on—and impossible without—many hundreds of routine experiments and trials that go unnoticed by the public and are often regarded as failures. Yet in a way, the story of these ‘failures’ is often more realistic and ennobling than the rare triumphal tale.”