Control and the therapeutic trial: the influence of insulin

How do we decide whether a drug, or other treatment, actually works? Martin Edwards describes the rhetorical strategy adopted by the Medical Research Council to establish its authority.

Patients’ variations in response to disease and treatment can render it fiendishly difficult to know whether a therapy is benefitting a particular individual. For centuries, the gold standard was the assessment of a wise and experienced clinician but during the first half of the twentieth century, new methodologies arising from the laboratory, hospital and statistical theory challenged this traditional model.

The stakes were high, no less than the moral authority to adjudicate how the therapeutic efficacy should properly be ascertained. Between the wars, the debate in Britain was frequently vitriolic – particularly between the Royal College of Physicians, which prioritised clinical acumen, and the Medical Research Council (MRC) which advocated newer methodologies.

The University of Toronto in 1921 granted British patent rights over insulin to the MRC and thus offered the MRC control, not only over insulin manufacture and supply, but also how to assess its effects and proper usage.

In fact, the MRC’s approach to testing was, as with other drugs at that time, highly eclectic; it sent samples of insulin to trusted clinicians in prestigious hospitals without any protocol or scheme for investigation – the clinicians were simply asked to report their experiences with the drug.

An unanticipated consequence of the MRC’s control of insulin supply was that it was on the receiving end of public clamour for the drug. Heartrending letters to the MRC described young people, typically in their teens or early twenties, dying slowly and horribly from diabetes, and pleaded for supplies of life-saving insulin.

Patients even turned up at the MRC, supported by loved ones. Landsborough Thomson, MRC Council Secretary, recalled the MRC administration being swamped by these requests and unable to fulfil its normal functions.

Reserved for controlled studies

In response, the MRC under the direction of its chairman Walter Morley Fletcher adopted a standard response to such requests, stressing that insulin was a new drug which needed to be reserved for ‘controlled studies’. The meaning of ‘controlled’ was not defined nor did it refer to the presence of a comparison group – none of the MRC insulin trials used one – but rather vaguely implied proper conduct, regulation and scrutiny.

So successful was this rhetorical strategy that the MRC repeated it when restricting supplies of penicillin in the 1930s and streptomycin and influenza vaccine in the 1940s. In each case, it stated that the drug should be reserved for ‘controlled trials’.

Control is a powerful word with implications of authority, power, regulation and order. Without defining it, the MRC appended the word to their own studies in the interwar years, using it as a rhetorical device in the battle for authority to adjudicate therapeutic efficacy.

By the time the MRC’s trial of streptomycin in tuberculosis – reckoned by many trial historians to be the first randomised controlled trial – was published in 1948, the MRC had successfully co-opted the word as applying exclusively to its own studies. It offered the streptomycin trial as an exemplar of how therapeutic trials should be conducted, describing the methodology as ‘the controlled trial’. By then, ‘controlled’ referred technically to the presence of a control group, though the other powerful associations of the word continued to resonate.

We have depended on the ‘controlled trial’ ever since. The MRC’s adoption of the potent word ‘control’ arguably began with insulin. Had it not been for MRC control of British insulin supply, might we simply refer nowadays to a ‘randomised trial’?

This text is an abstract of a talk given to a session of the Apothecaries’ History of Medicine Fellows 8/12/2021 to commemorate the 100th anniversary of the discovery of insulin.

References/further reading:

  1. A Landsborough Thomson, Half a Century of Medical Research vol. 2: The Programme of the Medical Research Council (UK) (London: HMSO 1975) pp 40, 230
  2. Liebenau, ‘The MRC and the Pharmaceutical Industry: The Model of Insulin’, in J, Austoker and L. Bryder (eds), Historical Perspectives on the Role of the MRC (Oxford: Oxford University Press, 1989) 163-80
  3. Edwards, Control and the Therapeutic Trial: Rhetoric and Experimentation in Britain 1918-48 (Amsterdam: Rodopi Publishing, 2007)

Writing medical history for a wider audience

Author Sandra Hempel offers tips to newcomers and a few to more experienced writers

The history of medicine is fertile ground for writers. It offers us a wonderful mix of discoveries, controversies, mysteries and characters, and all of this against a background of life and death. The writer doesn’t have to look far for tales to tell.

And if this sounds more like a list of ingredients for a popular thriller than for a serious, research-based piece of work, I would argue that the two genres have much more in common than might at first appear. Or at least they should if the writer is doing his or her job.

My first two books are both fast-paced narratives, in one case with a quest at its core, and in the other, a murder. However, both involved a huge amount of research among primary sources, as well as dialogues with academics, in order to ensure that both the science and the narratives were informative and correct.

The starting point for any material is always the question: Who are you writing for? Inexperienced authors sometimes write the piece that they want to write, in the style and to the length that they choose, and then submit to an editor or publisher. That rarely works.

Before you invest time and effort, however, look carefully at the publication that you have in mind or at what the book-buying public is currently reading. Check first that the journal or magazine even accepts readers’ contributions – not all do – and then ask if your idea is of interest. Some publications have guidelines on their websites describing the type of material they are looking for and giving helpful details such as word counts.

Physician and medical reformer Thomas Percival from Warrington, Lancs.

Don’t confine yourself to national publications. Try the county magazine and the local paper as well as the history society and community association newsletters. If you can find a subject with a local angle, then you will vastly improve your chances.

Is there a local historical figure who did some interesting work? Was there an outbreak of disease in the past that the doctors struggled to control? What about a trial where the medical evidence played a key role?

Now, of course, the internet offers new outlets such as blogging and self-publishing where you are free to write whatever you want without having to go through an intermediary. Even so, you still have to engage your readers if you hope to reach an audience.

Sandra Hempel is an author, editor and tutor running courses in writing. She has written for a wide range of national newspapers and specialist medical journals including The Lancet. She has published three books on the history of medicine. For more information, contact Sandra at www.sandrahempel.co.uk

 

 

 

Pioneering cardiac surgery in Sheffield

Will Parker describes the work of a pioneer of cardiac surgery, Judson Chesterman.

The first mitral valve replacement is generally credited to Nina Braunwald (1928-1992) in March 1960, the patient surviving for around 4 months. The first Starr-Edwards caged ball valve followed in the same year and the procedure subsequently became widespread. There is good reason, however, to believe that the first operation of this kind was carried out in 1955 at Sheffield’s City General (now Northern General) Hospital by Judson T. Chesterman (1903-1987, Figure 1).

Chesterman studied at Bristol but settled in Sheffield, where his great-grandfather had set up a prominent engineering firm. He developed a practice in cardiothoracic surgery, performing over 100 heart operations a year by the 1950s. However, many cases of heart valve disease, including those resulting from regurgitation (leaking) rather than stenosis (narrowing), remained inoperable and often fatal.

Charles Hufnagel (1916-1989) of Washington D.C. had reported the implantation of an artificial valve for aortic regurgitation in 1954. Chesterman began designing artificial valves, but focussed on the more difficult problem of replacing the mitral valve, the most commonly affected by then-common rheumatic fever.

Initially working with copper prototypes, these evolved into refined Perspex creations. The hospital pathology technician, Clifford Lambourne, turned the valves, consisting of an oval double-flanged ring in which sat a tethered disc, on a huge lathe (Figure 2). Lambourne told the hospital newspaper years later: ‘Turning left a roughish surface and it had to be smooth…My wife and I were keen cinema-goers. We sat in the cinema, watching films, me with a piece of silk cloth in my hands, polishing the pieces…It took about three feature length films to get the valve smooth enough.’

On 22 July 1955, Chesterman implanted the prosthesis into a 34-year-old man with end-stage mitral valve disease. Lacking cardiopulmonary bypass, he cooled the patient, cross-clamped the vena cavae then quickly performed the operation.

Though acutely successful, as Chesterman later wrote: ‘He read the evening paper and was comfortable at night when I last saw him. He was found dead in the night at about 3.30 am.’ The valve had dislocated. Retrieved at post-mortem examination, it still exists. (Figure 3)

Chesterman realised cardiopulmonary bypass would be key to further procedures of this kind. He subsequently visited Walton Lillehei and Richard De Wall in the US, who had developed the pump oxygenator. Chesterman went on to build and use his own machine in Sheffield on 26 February 1957, one of the first outside America to do so. (Figure 4) 

As well as technological contributions, Chesterman’s legacy includes the subsequent flourishing of a cardiothoracic unit in Sheffield, now housed in the Chesterman Wing at the Northern General Hospital. In addition, he had an interest in archaeology and, after retiring from clinical practice, he  founded the University of Sheffield Osteology Laboratory. 

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The patient: from neglected factor to media star

Is the patient a case, a body or a partner with power? Christine Gowing looks at the changing perspective in medical history.

Nursing Times, 22 March 1988,
nursingtimes.net

In 1945 the patient voice was merely a distant echo. That year the medical historian Douglas Guthrie published a paper The Patient: a neglected factor in the history of medicine[1], arguing that the patient’s part in the march of medical progress had long been missing while attention had been devoted to the achievements of science and physicians.

The history of medicine was the history of doctors, or, as Roy Porter put it, ‘a history from above and populated with heroes.’[2]  It was only in the 1960s and 1970s that historians began to look at how wider sociological contexts – social, cultural, professional and economic frameworks – influenced medicine’s history.[3]

But how culpable are we still as medical historians when we push the patient out of the narrative?

The presence of patients throughout history has often been denied, simply due to lack of information about them – and at what point did patients anyway emerge with any significance or autonomy in the doctor-patient encounter?

The historian Edward Shorter blamed the science of healing in the 1940s and 50s for overwhelming the art of healing[4], extending Foucault’s claim that clinical medicine was responsible for depersonalisation and the sidelining of the patient.[5]

The patient contributes

It was psychoanalyst Michael Balint’s work in the 1950s that first recognised and encouraged the emergence of the patient in the medical consultation.[6] Balint’s psychodynamic analysis and his understanding of the patient’s contribution enhanced the consultation as a therapeutic tool. Increasingly accepted, this approach encouraged the involvement of patients in the management of their condition, although in the 1980s, medical ethicist Jay Katz would still argue that the doctor-patient power relationship was impacting patients’ decision-making.[7]

And nurses’ relationship with patients? It may be a surprise to hear that it was only in 1962 that nursing training formally recognised the importance of this relationship by including an element on the topic for the first time in the training syllabus.[8]

But now we find the patient as a media star. Remember the momentous day of the first Covid-19 vaccination (outside of a trial) on 8 December 2020? What a victory for science and medical research, for the extraordinary work of the laboratory teams in developing the vaccine and giving hope to a pandemic-torn world. 

However, the image that we probably recall most vividly on that day – and the one that dominated the media throughout the world – was of the first vaccinated patient, 90-year old Maggie Keenan.  On 9 December 2020, the Daily Express exclaimed:

‘ONE SMALL JAB FOR MAGGIE …ONE GIANT LEAP FOR ALL OF US’

On the same day, the Metro showed an image of nurses providing a guard of honour as she left the vaccination clinic. What we remember in the future when recounting the narrative of Covid-19 – along with the triumph of science and physicians – may be the image of Maggie. 

A named patient placed at centre stage.

Christine Gowing has an MA in the history of medicine with research on 18th and 19th century electrotherapy. She later gained a PhD in the history of the relationship between complementary and alternative medicine (CAM) and biomedicine. The development of the therapeutic alliance in healthcare is a particular interest.


 References

[1] Guthrie, D., A History of Medicine(1945).

[2] Porter, R. (ed), Patients and Practitioners (1985).

[3] Waddington, K., An Introduction to the Social History of Medicine: Europe since 1500 (2011).

[4] Shorter, E., Bedside Manners: the troubled history of doctors and patients (1985).

[5] Foucault, M., The Birth of the Clinic (1989).

[6] Balint, M., The Doctor, his Patient and the Illness (1957).

[7] Katz, J., The Silent World of Doctor and Patient (1984).).

[8] National Archives, Kew, London, General Nursing Council papers, confidential minute, Education and Examination Committee (7 September 1960), DT38/155.

‘Blitz Spirit’ in the Time of Pandemic

Frances Williams looks at the historic concept of ‘Blitz Spirit’ and its evocation during this period of pandemic

Themes of resilience and strength have been drawn from the Second World War and put to use in the current pandemic – including the psychological defence, ‘Blitz spirit’. Yet a risk is run when nostalgia distracts us from important differences between the past and present. They can further skew historical accuracy, too.

Health Secretary Matt Hancock stated in early 2020: ‘Our generation has never been tested like this … Our grandparents were, during the Second World War, when our cities were bombed during the Blitz. Despite the pounding every night, the rationing, the loss of life, they pulled together in one gigantic national effort.’

Working directly with the older generation, palliative care doctor, Rachel Clarke (@doctor_oxford) said they certainly seemed to have taken the ‘Blitz spirit’ to heart, thinking themselves stoic and resilient. Dangerously – and sometimes tragically so – some of over 70s weren’t washing their hands or taking lockdown measures seriously enough, even though the pandemic deaths were mostly among their own age group.

(Photo: Aldwich Tube station 1940, Imperial War Museum)

Historical dispute

The ‘Blitz spirit’ has always been a disputed phenomenon, reflecting contested post-war histories of ‘morale’. Certainly, in the lead-up to war, the government was worried about the likelihood of ‘bomb neurosis’, a form of shell shock that civilian populations might suffer if subjected to prolonged bombing.

A new era of ‘total war’ fed a perception of the vulnerability of citizens to ‘knock out’ blows from the air, that might lead to febrile mental states. A network of specialist hospitals – called ‘neurosis clinics’ – was set up outside UK cities, but ultimately little used.

In his 2012 work, War on Fear: Solly Zuckerman and civilian nerve in the Second World War, Ian Burley cites a visiting commentator from the US who observed the British public’s capacity for ‘pluck’ and such outsider reflections were fed back to the public in the form of propaganda. A prominent psychologist of the day advocated biscuits and nips of whiskey to allay ‘nerves’ during bombing raids, reported by Edward Glover in 1940 in The Psychology of Fear and Courage.

Covid-19 spirit?

In her new book, Blitz Spirit: Voices of Britain Living Through Crisis, Rebecca Brown re-visits the ‘alleged phenomenon’ of the Blitz spirit, delving into diaries from The Mass Observation Archive, daily diaries kept by hundreds of people during the war. These cast fresh insight into our current pandemic, she proposes, because they show the nuance and diversity of everyday feeling.

Many popular descriptions of our of states of mind in lockdown now are anecdotal: a ‘corona coaster’ of high and low moods, sleeplessness and vivid ‘pandemic dreams’.  Speculations centre on how we might arrive at the right level of panic – especially given we get much of our information from internet sources of variable reliability.

Professor Nikolas Rose in Mental Health and Social Change in the Time of Covid-19 points out that the pandemic and the measures taken in response, such as severe restrictions to physical interactions and our daily routines, are discrete and separate. Added to this are widespread uncertainty and distress about the virus, loved ones, education, work and money. Increased anxiety and fear are normal in the circumstances. ‘We need be wary of rushing to frame them in terms of mental health,’ he warns.

As the NHS staff operate on ‘the front line’ of our current battle, it may be that they bear the longer term psychological cost – including diagnoses of PTSD – than the wider ‘civilian’ population on the ‘Home Front’. For now, these are speculations.

In the interim, it is important to consider the ways in which the pandemic is not like a war, and the risk that ‘nostalgic framings’ might distract us from our own mistakes, as says Martha Lincoln in her blog On Memorys Battlefield: The Pandemic as Our Next Forgotten War (2021).

Frances Williams completed her PhD in arts, health and devolution in 2019 and is currently Visiting Researcher at Glyndwr University.

Further reading

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