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Neurological literature: a clinical trial

Posted in Neurological Literature,Special Feature on 2nd Aug 2019

AJ Larner, Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, L9 7LJ, UK.
Correspondence to: Email: a.larner@thewaltoncentre.nhs.uk
To cite: Larner AJ. ACNR 2019;18(4):18-19
Published online: 1/8/19


Clinical trials are an integral part of neurology. Many neurologists will have been involved in their conduct, and all will apply their outcomes to clinical practice. A working knowledge of the methodology of clinical trials is fundamental to their evaluation, and hence a learning objective for neurological trainees.

Sinclair Lewis (1885-1951) was the first American winner of the Nobel Prize for Literature, in 1930, following a series of acclaimed novels published in the 1920s. In one of these, Arrowsmith (1925), the protagonist, Martin Arrowsmith, is a doctor (as was Sinclair Lewis’s father), whose medical career the novel charts, from medical student, to country doctor, to public health official, to research scientist.1  In the latter context, a description of a clinical trial is to be found.

Narrative

Aged 34 (p. 322), and hence, from internal evidence, in about 1917, Martin discovers “the X Principle” which destroys staphylococcus, but the novelty of his finding is short-lived as his scientist mentor Max Gottlieb finds a report from D’Herelle of the same phenomena, described as bacteriophage (p. 327). Martin’s subsequent researches focus on the possibility of curing bubonic plague with phage (p. 337). Aged 37 (p. 384), and hence around 1920, the opportunity arises to put this laboratory discovery into clinical practice.

The scene is the fictional Caribbean island of St Hubert, a “British possession” (p. 355) located in the Lesser Antilles (pp. 352,355) between Barbados and Trinidad (p. 343) where there is an epidemic outbreak of bubonic plague (p. 348).  The plan of Max Gottlieb is “to use the phage with only half [of the] patients and keep the others as controls, under normal hygienic conditions but without the phage” (p. 348), thus permitting “an absolute determination of its value” (p. 348). On departure, he urges Martin: “do not let … your own good kind heart, spoil your experiment” (p. 354).

Martin’s co-worker on the trip, Gustaf Sondelius, wants to give phage to everybody (pp. 349,381) since “in this crisis mere experimentation was heartless” (p. 350) and on principle twice refuses treatment for himself (pp. 352,378), but Martin insists on having “real test cases” (p. 349), perhaps a reflection of his training from Gottlieb as a medical student in the importance of controls (p. 40). Martin’s final plan: in “a district which was comparatively untouched by the plague … one half injected with phage, one half untreated. In the badly afflicted districts, he might give the phage to everyone, and if the disease slackened unusually, that would be a secondary proof” (p. 350).

On St Hubert, both the Governor of the island (pp. 375-6) and the Board of Health (p. 377) object to the plan of “half to get the phage, half to be sternly deprived” (p. 375) despite Martin’s assertion that the “luckless half would receive as much care as at present” (p. 377).

In the village of Carib, where “every third man was down with plague”, Martin “gave phage to the entire village” (p. 379), following which there is an apparent slackening of the epidemic in the village, observations which Martin hopes will prompt the local bureaucracy to “let me try test conditions” (p. 379). Carib village is then burnt in order to kill all the rats, the locals evacuated to a tent village where Martin remains for two days giving them phage (p. 380).

The opportunity for experiment is provided in St Swithin’s Parish, where, unlike Carib, “the plague had only begun to invade” (p. 386). Martin “divided the population into two equal parts. One of them … was injected with plague phage, the other half was left without” (p. 386). “The pest attacked the unphaged half of the parish much more heavily than those who had been treated … These unfortunate cases he treated, giving the phage to alternate cases” (pp. 386-7).

However, following a personal bereavement, Martin damns experimentation and “gave the phage to everyone who asked” other than in St Swithin’s parish where “his experiment was so excellently begun … some remnant of honor [kept] him from distributing the phage universally” (p. 392). Unsurprisingly people from St Swithin’s are seen in the queue for treatment in the main town of St Hubert, Blackwater (p. 393). Eventually Martin “went back to the most rigid observation of his experiment in St Swithin’s … blotted as it now was by the unphaged portion of the parish going in to Blackwater to receive the phage” (p. 394).

Six months after Martin’s arrival, the “plague had almost vanished” (p. 395). Martin is lionised by the populace as “the saviour of all our lives” but one local doctor reflects that “plagues have been known to slacken without phage” (p. 396). Martin knows that he does “not have complete proof of the value of the phage” (p. 397), that “his experiment had so many loopholes” (p. 400). He plans to take his data to a “biometrician” who may, he notes, “rip ’em up. Good! What’s left, I’ll publish” (p. 400).  Raymond Pearl, the biometrician, “pointed out that his agreeable results in first phaging the whole of Carib village must be questioned, because it was possible that when he began, the curve of the disease had already passed its peak” (p. 404). It is evident to Martin’s friend, Terry Wickett, that “you bunged it up badly” (p. 405).

Comment

Arrowsmith has previously attracted attention for its portrayal of contemporary immunology2 and public health,3 and belatedly I discovered a prior commentary related specifically to the details of the clinical trial.4 Whilst literary accounts of neurological illness are often to be found, I have not previously encountered a fictional account of a clinical trial.

It is not difficult to enumerate the many shortcomings in this clinical trial: no ethics, no planning, no involvement of a statistician from the outset, no patient consent, no blinding of any kind, no randomisation, no matching of cases and controls, no clear definition of outcomes, etc. Indeed this might be better termed a “therapeutic experiment” rather than a clinical trial.  Of course, there is no reason why Lewis as author should present the perfect trial, motivated as he was by literary rather than scientific concerns, specifically to illustrate the tension between Martin as clinician-scientist and clinician-humanitarian.5 Although the randomised clinical trial as we know it was not to evolve for several more decades, clinical trials characterised by “fair allocation” schedules had been undertaken at least from the time of James Lind.6

Sinclair Lewis was awarded the Pulitzer Prize for fiction for Arrowsmith, but he declined it, his previous novels (Main Street, Babbitt) having been passed over. In the same year, 1926, the surgeon Harvey Cushing (1869-1939) also won a Pulitzer Prize for his biography of Sir William Osler (1849-1919). According to another Osler biographer, Michael Bliss, “Cushing wrote friends that he had nothing but contempt for the spirit of Lewis’s novel, which had mythologised research and denigrated medical practice. Cushing hoped his Osler biography would be an antidote to Arrowsmith”.7 Cushing’s objection may have been to the “Literary stereotypes that portrayed surgeons as money-grubbers in novels of the early 20th century”:8 his name appears in the novel (p. 85) in a list of surgeons with exceptional surgical technique. He may also perhaps have baulked at a description of one of Martin Arrowsmith’s medical student chums “reading a Sherlock Holmes story which rested on the powerful volume of Osler’s Medicine which he considered himself to be reading” (p. 61; although Holmes’ creator was, of course, medically qualified and the Holmes oeuvre features some interesting medical material9).  Osler is mentioned elsewhere in Arrowsmith: as the “god” (p. 82) of the professor of internal medicine and Dean of Arrowsmith’s medical school who is a “fit disciple of Osler” (p. 127), and his treatment of diphtheria is cited (p. 158).  Lewis had been “fed inside knowledge”10 for the novel by the microbiologist Paul de Kruif (1890-1971), later to gain fame with his book The Microbe Hunters (1926),11 who is acknowledged at the start of the novel.

References

  1. Lewis S. Arrowsmith. New York: Signet Classics [1925] 2008. All page references cited in the text refer to this edition.
  2. Löwy I. Immunology and literature in the early twentieth century: “Arrowsmith” and “The Doctor’s Dilemma”. Med Hist 1988;32:314-332.
  3. Markel H. Reflections on Sinclair Lewis’s Arrowsmith: the great American novel of public health and medicine. Public Health Rep 2001;116:371-375.
  4. Löwy I. Martin Arrowsmith’s clinical trial: scientific precision and heroic medicine. JLL Bulletin: Commentaries on the history of treatment evaluation 2010 (http://www.jameslindlibrary.org/articles/martin-arrowsmiths-clinical-trial-scientific-precision-and-heroic-medicine/)
  5. Fangerau HM. The novel Arrowsmith, Paul de Kruif (1890-1971) and Jacques Loeb (1859-1924): a literary portrait of “medical science”. Med Humanit 2006;32:82-87.
  6. Chalmers I. Comparing like with like: some historical milestones in the evolution of methods to create unbiased comparison groups in therapeutic experiments. Int J Epidemiol 2001;30:1156-1164.
  7. Bliss M. William Osler. A life in medicine. Oxford: Oxford University Press, 1999:483 [index wrongly states 482].
  8. Weisz G. Divide and conquer. A comparative history of medical specialization. Oxford: Oxford University Press, 2006:198.
  9. Larner AJ. “Neurological literature”: Sherlock Holmes and neurology. Adv Clin Neurosci & Rehabil 2011;11(1):20,22.
  10. Williams G. Paralysed with fear. The story of polio. Basingstoke: Palgrave Macmillan, 2015:129.
  11. Summers WC. On the origins of the science in Arrowsmith: Paul de Kruif, Felix d’Herelle, and phage. J Hist Med Allied Sci 1991;46:315-332.
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