7 Conclusion: What’s Controlled about the Controlled Trial? Should the gastroenterologist Harold Conn suffer the misfortune to bleed from oesophageal varices,1 he would hope to be included in a randomised controlled trial, enter the trial, and then refuse treatment.2 Thus he would maximise his chance of successful recovery – for simply being selected for a trial is a powerful predictor of a favourable outcome. Subjects entered into a radomised controlled trial (RCT) are likely to be carefully diagnosed, free from other serious diseases, and compliant with their treatment and any strictures it imposes. They will receive meticulous clinical scrutiny from doctors following a careful treatment protocol, and probably also from additional supplementary staff.3 Thus, most RCTs are designed to assess what the British epidemiologist Archie Cochrane designated efficacy – whether a treatment can possibly work, under the idealised conditions of a trial – rather than what he called effectiveness, whether the treatment works in real-life clinical practice. A third question concerns the treatment’s efficiency, or whether its benefits are worth the resources it consumes.4 This work has examined the utilisation, by physicians associated with the MRC, of the powerful rhetorical connotations of the term ‘controlled’ in order to promote their own work in therapeutic assessment prior to the publication of the MRC’s streptomycin trial in 1948. These therapeutic trials were idiosyncratic affairs and the methodology of a proper clinical trial was, at this time, neither unified nor codified. But the MRC nevertheless referred consistently to its own trials as ‘controlled’. The term encompassed an eclectic assortment of methodologies and carried a variety of rhetorical associations. The unifying characteristic which bound the various 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. Ultimately, the MRC’s ‘controlled trial’ became a construct – prior to 1948 there was no single methodology which could define the term, no published trial which could exemplify it, yet the ‘controlled trial’ was exploited as a rhetorical device to enhance the authority of a therapeutic experiment performed under the auspices of the MRC. However, the rhetorical associations of the ‘controlled trial’ did not disappear abruptly with the codifying of RCT methodology in 1948; they remain inherent to 171 Editors Control and the Therapeutic Trial - 9789401204941 Downloaded from Brill.com10/01/2021 01:32:52PM via free access Martin Edwards the discourse on therapeutic efficacy today – where debate still attends the RCT, and more broadly the field of evidence-based medicine (EBM), within which the RCT is embedded. The randomised controlled trial after 1948 The MRC continued to promote its newly-defined controlled trial as the model for therapeutic evaluation and its members were heavily involved in an international conference in Vienna in 1959, staged to promote RCT methodology.5 By 1966, Hedley Atkins, President of the Royal College of Surgeons of England, felt able proudly to proclaim ‘the controlled clinical trial’ as ‘an almost exclusively English contribution to medicine.’6 Scientific evidence now dictated therapeutic decision-making, he claimed: [T]he advocacy of a therapeutic measure depends now, not on the force of personality, the standing in the profession, or the ‘mellifluidity’ of the protagonist, but on more soundly based scientific evidence, and the tool for the forgoing of this evidence is the controlled clinical trial.7 Few present-day advocates of EBM would be likely to quibble with this as a succinct exposition of their philosophy. The trickle of RCTs published in international medical journals expanded steadily throughout the 1950s and 1960s, multiplied dramatically in the 1970s and early-1980s, and reached a peak in the mid-1980s before apparently falling back to levels equivalent to the 1970s over the following decade.8 This decline is probably artefactual, due to increased reporting of RCTs in the recently-burgeoning numbers of specialist journals which were not examined in these surveys; analysis of online databases suggests that actual RCT numbers continue to rise.9 There appears to have been a trend to larger studies, involving more participants, over the past two decades.10 At the same time, the number of published meta-analyses has increased substantially.11 Meta-analysis is a statistical technique whereby the results of a number of RCTs which have all investigated the same therapeutic intervention, are aggregated and analysed en masse, thereby increasing the statistical power of the investigation. It can enable a definitive statistical conclusion to be drawn from disparate RCTs with differing sample sizes, and which might even reach differing individual conclusions; it occupies an important place at the top of the hierarchy of evidence employed by present- day EBM practitioners. Meta-analysis is distinct from systematic review, where reviewers attempt to locate all good-quality trials relating to a therapy and reach a conclusion based upon their assessment of the evidence provided by each individual trial, rather than by statistical analysis of aggregated results – although systematic reviewers might well consider meta-analyses alongside individual trials. Systematic reviews have formed a mainstay of the 172 Editors Control and the Therapeutic Trial - 9789401204941 Downloaded from Brill.com10/01/2021 01:32:52PM via free access Conclusion EBM initiative, particularly in Britain where the influential Cochrane Library includes a database of systematic reviews, and their number has increased substantially over the past couple of decades. A number of influential commentators have examined the factors underlying the rapid rise in the quantity of RCTs, and in the faith placed in them by the medical profession and the public, over the latter half of the twentieth century. Most narratives acknowledge the importance of the thalidomide tragedy. Thalidomide was promoted during the 1950s as a treatment for pregnancy sickness and was responsible for a global epidemic of infants born with deformed or stunted limbs – phocomelia. Although the infant population of the United States escaped almost unaffected due to delays in licensing the drug, the thalidomide debacle nevertheless expedited legislation mandating the American Food and Drug Administration to regulate the drug industry,12 and prompted similar initiatives internationally. Proof of efficacy was for the first time considered intrinsic to establishing a drug’s safety, placing the RCT centre stage in drug regulation. Theodore Porter, in an influential volume, defines two types of objectivity within professional communities – ‘disciplinary objectivity’ and ‘mechanical objectivity’. Disciplinary objectivity arises by consensus from experienced senior members of the community, who employ tacit knowledge – judgement that can only arise from experience and training. Mechanical objectivity is rule-based, frequently employing quantification and numbers, and does not depend on incommunicable wisdom and experience. When an expert community faces a perceived threat, argues Porter, it transfers its legitimacy from disciplinary to mechanical objectivity. Tacit knowledge and expert opinion might still carry some weight within the profession, but its public rhetoric emphasises science and the objectivity implied by numbers. So the Western medical establishment, under threat during the latter twentieth century in many countries from large, frequently state-controlled medical organisations, resorted to placing its trust in numbers and prioritised the controlled trial.13 Harry Marks14 prefers to consider the RCT in the United States as a device employed by academic physicians intent on therapeutic reform, who sought a tool to distinguish effective from ineffective remedies and curb the enthusiasm for excessive prescribing amongst their non-academic colleagues. By forging an alliance with statisticians these practitioners could acquire the tool they needed – the RCT – while giving the statisticians a boost to their hitherto meagre prestige in the medical hierarchy. In a related analysis, Jeanne Daly suggests that the rise in popularity of public health medicine during the 1950s and 1960s led to blurring of the boundaries between clinical medicine, social care. and politics. In danger of being consumed entirely by issues of social justice and poverty and becoming, effectively, social workers, physicians adopted the 173 Editors Control and the Therapeutic Trial - 9789401204941 Downloaded from Brill.com10/01/2021 01:32:52PM via free access Martin Edwards RCT as a research tool which provided scientific credibility to public health work. By adopting only interventions established as effective by an RCT, physicians defined their role more narrowly and excluded murkier areas of activity.15 The RCT in the twenty-first century Harold Conn, who we encountered at the beginning of this chapter, is not alone in his cynical view of the relevance of RCT findings to the wider world. The development and execution of RCTs is a multi-billion pound industry – unsurprising, given the current hegemonic position of the RCT as the gold standard for evaluating therapeutic efficacy. But critics of the RCT have by no means gone away over the past fifty years. Trial methodology has frequently been insufficiently rigorous in the