The problem with chloroquine. Epistemologists, methodologists, and the (mis)uses of medical history

06/05/2020

Section: Coronavirus and History

Luc Berlivet & Ilana Löwy, CERMES -3, Paris.

Luc Berlivet and Ilana Löwy, researchers at  CERMES -3, Paris.

Even keeping in mind the desirability of wonder-drugs in times of epidemics, the present world craze for chloroquine (a well-known, fairly dated anti-malaria drug), and its variant hydroxycholoquine (used today mainly to treat auto-immune diseases, such as lupus and rheumatoid arthritis) remains puzzling in many ways. One of the main objects of bewilderment is the role played by Pr. Didier Raoult, a French microbiologist and figurehead of Méditerranée Infection (a medical-cum research center based in Marseille) in super-spreading this vogue.

The Amazing Planetary Career of Two Somewhat Modest Drugs

Although he was not the first physician to advocate the use of chloroquine in the treatment of Covid-19 patients — some Chinese experts were promoting it as early as February 2020 — Raoult was instrumental in widening the attention from chloroquine to the somewhat less toxic variant of the former, hydroxycholoquine, and quickly became a prominent if polarizing figure in France, at a time when the number of admissions in intensive care units and the death rate were starting to spike. Whereas chloroquine retained some mighty and vocal champions such as president Trump and president Bolsonaro[1], the pre-publication of a non-randomized clinical trial by Raoult and his collaborators contributed to position the until-then obscure hydroxychloroquine as a more sophisticated, safer, and allegedly effective alternative – according to its authors, patients who had received the molecule were cured in six days[2]. Raoult promptly gained worldwide fame, first through his highly popular You Tube channel (some of his video posts, in French, have been watched over one and a half million times), then, decisively, thanks to the campaigns in favor of chloroquine launched at the same time by celebrities such as James Todaro, Georgy Rigano, Elon Musk (with his 33 million or so followers on Twitter), and a plethora of Fox News hosts.[3]

French biologist Didier Raoult  gained worldwide fame thanks to the campaigns in favor of chloroquine.

Within both international and French medical arenas, however, Raoult’s promotion of hydroxychloroquine was heavily criticized. The fast growing controversy centered mostly on the methodological choices made by the French team: the lack of randomization, and even of a properly constituted control group.[4] On the 3 April, the International Society of Antimicrobial Chemotherapy (ISAC), which had initially fast tracked the publication of the article by Raoult and his collaborators in its house journal, went to the rather extraordinary length of publicly stating that “the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety”.[5] ISAC representatives blamed an unnamed “Associate Editor” for publishing the article without realizing that its authors “had excluded data from patients who were not responding well to treatment”, and firmly maintained that, although one of the authors of the article – Jean-Marc Rolain – was also the editor-in-chief of the journal, he “had no involvement in the peer review of the manuscript”.[6]

Regimes of Proof: “Caring Physicians” Versus “Cold-Blooded Methodologists”

The severe criticisms of hydroxycholoquine treatment cut little ice with Raoult, who swiftly counter attacked with a series of videos, interviews, and an opinion column in France’s most influential newspaper, denouncing the nefarious role of what he called “methodology maniacs” in the bureaucratization of clinical research, and the consecutive forgetfulness of the physician’s first duty: to save lives. [7]

Emotionally detached methodologists vs. clinically oriented medical humanists… At first glance, the controversy seemed to rerun an all-to-familiar theme in the history of medicine, in particular when it comes to the French context, where clinicians long resisted the growing influence of statistics in medicine. One detail, though, proved altogether surprising and interesting, namely Raoult’s insistence that his outstanding medical science stemmed from his command of epistemology and the history of medicine.

At the center of the ongoing controversy on the use of chloroquine to treat Covid-19 is the almost-two-centuries-long discussion on the right way to prove therapeutic effectiveness. Critics of Raoult’s study sustained that, because of the high spontaneous recovery rate of the disease (about 80-85%), only a large-scale randomized trial could provide scientific evidence of clinical efficacy.^[8] This was the rationale for the launch, on 22 March, of a European multi-centric trial called Discovery. Raoult and many of his supporters, for their part, objected to what they saw as a sterile approach promoted by methodology-obsessed purists with an agenda, that could only delay the administration of the much-needed drug to suffering patients. Since the 1820s, when P.C.A. Louis undertook his pioneer comparative evaluation of bloodletting, opponents of clinical trials have championed clinical intuition against statistical protocols, the irreducible idiosyncrasy of each and every medical case against the law of large numbers, etc. In his replies to his detractors, Raoult too drew heavily on this repertoire. [9]

As we explained in a previous text, contrary to what Raoult claimed, the introduction of randomized trials in medicine was not the result of an alliance between statisticians and “methodologists” the pharmaceutical industry, but rather started as a medical reform movement led by clinicians appalled by the negative consequences on patients, especially the more vulnerable ones, of ego battles among senior physicians, and clashes between therapeutic schools of thought. [10] These clinicians, committed to an ideal of equity and social justice, cooperated with statisticians, and adapted to the medical context a method devised by R.A. Fisher, in the interwar period, to neutralize as much as possible conscious and unconscious biases in the evaluation of the effectiveness of human interventions. These original reformist inclinations were later eroded by the routinization of their approach, even before Evidence Based Medicine was abused as a buzzword by health administrators all around the world. However, what the demand by HIV/AIDS activists, in the 1980s, and an increasing number of social movements in the South, to be involved in the, planning, implementation, and evaluation of clinical experiments underlines, somehow paradoxically, is the centrality of modern clinical trials in the collective production of medical knowledge. Even – or especially – during a public health crisis.

What Medical History and Epistemology Are Good For?

Raoult, and other promoters of chloroquine and/or hydrochloroquine explain that these promising treatments are a) cheap and b) harmless, since already used by millions of patients suffering from different conditions: there is therefore nothing to lose trying them out. Facing increasing criticism of his clinical studies, as well as reports that chloroquine and and hydrochloroquine are not as innocuous as he claimed,[11] Raoult developed a second, interesting line of argument. As criticisms of his work were piling up, he attempted to prevail in the controversy by linking the (alleged) superiority of his approach to his command of epistemology and knowledge of medical history. It quickly became a trope of his innumerable public interventions:

“I am an epistemologist, that is a specialist of the science of science. History of infectious diseases teaches us that this method [randomized clinical trials] was practically never used to demonstrate the effectiveness of a new treatment. […] Large scale clinical trials were promoted by the pharmaceutical industry, then everybody confused this approach with science.” [12]

What seems interesting to us, here, is clearly not the claim that randomized clinical trials had little to no impact on the search for treatments against infectious diseases — a bizarre assertion if it ever was, considering the iconic status of the pioneer streptomycin trial of 1946, the trials of antiretroviral drugs in HIV infected patients, and many other randomized trials. But rather his attempt to turn the philosophy of science into an instrument of power, in order to prevail in a medical controversy at the beginning of the 21^st Century. Raoult’s definition of epistemology as “the science of science”, which he repeated in many occasions, seems especially revealing here: as if the philosophy of science was some kind of meta-knowledge that could provide the trained philosopher with an upper hand over the non-initiated. Those who criticized his clinical experiments, Raoult claimed, were simply not familiar with the teaching of Popper, Kuhn and Feyerabend, who had shown that science is never static, and that– consequently – research methods are bound to be outdated sooner or later. This was precisely what had happened to randomized clinical trials: science had moved to a very different place, and the growing strings of unfair attacks leveled at his clinical trials of hydrochloroquine merely revealed a deep epistemological ignorance on the part of his detractors.[13]

As historians of science we hope that our studies not only promote a better comprehension of a bygone past, but also improve our understanding of the present. Some of our colleagues believe that persuading practicing scientists and physicians to pay attention to the history, philosophy, or sociology of science is always a good thing. In principle the spread of historical and epistemological knowledge is indeed a worthy goal, but it is necessary to explain what kind of history of science and epistemology we are talking about, and to pay attention to who uses it, how, when, where, and what for.  Context matters.

[1]Peter Baker, Katie Rogerst, David Enrich and Maggie Haberman, Trump’s Aggressive Advocacy of Malaria Drug for Treating Coronavirus Divides Medical Community, The New York Times, 6 April 2020; Guilherme Henrique. A exaltação da cloroquina por Bolsonaro na TV. Nexo, 09.04.2020. In France, a very successful petition in favour of the administration of chloroquine and hydroxychloroquine in the treatment of Covid-19 was launched by a a former Minister of Health, Philippe Douste-Blazy. Marc Payet, Covid-19 : plus de 80 000 signatures pour le manifeste de Douste-Blazy pour la chloroquine, Le Parisien, 3 April 2020. The president Macron, perhap impressed by popularity of hydrochloroquine traveled to Marseille to visit Raoult’s laboratory. Yves Sciama, Is France’s president fueling the hype over an unproven coronavirus treatment? Science 09.04.2020.

[2] Philippe Gautret, Jean-Christophe Lagier, Philippe Parola et al., Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open label non-randomized clinical trial, International Journal of Antimicrobial Agents – . Received on 16 March 2020, the article was accepted the day later through a fast track, and uploaded online on 20 March 2020.

[3] Julia Wong, Hydroxychloroquine: how an unproven drug became Trump’s coronavirus’miracle cure. The Guardian 07.04.2020. On March 16, Musk tweeted the link to Todaro’s and Gregory Rigano’s document to his nearly 33 milion followers, an especially efficient promotion avenue.

[4] In the original article by Raoult and al. (see above, note 3), the study was described as “a single arm protocol”; the control group was made of patients hospitalised in the Marseille area, who seem to differ significantly from the “hydroxychloroquine group”.

[5] Official Statement from International Society of Antimicrobial Chemotherapy (ISAC).

[6] Trump’s hydroxychloroquine study editor said ‘it was a complete failure, France 24 News, 9 April 2020;

[7] Dider Raoult, Le médecin peut et doit réfléchir comme un médecin, et non pas comme un méthodologiste [Physician can and must think as a physician, not as a methodologist], Le Monde, 26 March 2020.

[8] Marco Cascella; Michael Rajnik; Arturo Cuomo et al, Features, Evaluation and Treatment Coronavirus (COVID-19), NCI Bookshelf, March 2020.

[9] Dider Raoult, Le médecin peut et doit réfléchir comme un médecin. » op.cit ; Raoult’s interview, on site of the Marseille Institute of Institute Méditerranée Infection, 22 April, 2020:

[10] Luc Berlivet et Ilana Löwy, Le professeur Raoult, les maniaques et le parachute. Le Monde, 10.04.2020.

[11] Preliminary reports point to toxicity of chloroquine and hydrochlotoquine e.g., Joseph Magagnoli, Siddharth Narendran, Felipe Pereira et al. Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19, MedRxiv preprint; Mayla Gabriela Silva Borba, Fernando Fonseca Almeida Val,; Vanderson Souza Sampaio et al. Effect of High vs LowDoses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With SARS-CoV-2 Infection.

[12] Didier Raoult, interviewed on Radio Classique, the 1^st of April 2020.

[13] Didier Raoult, interview Radio Classique, 17.04.2020.

How to cite this post:

BERLIVET, Luc: LOWY, Ilana. The problem with chloroquine. Epistemologists, methodologists, and the (mis)uses of medical history. In: Revista História, Ciências, Saúde – Manguinhos (Blog). Publicado em 29 abr. 2020. Acesss [date].

See in Manguinhos:

Berlivet, Luc André. A laboratory for Latin eugenics: the Italian Committee for the Study of Population Problems and the international circulation of eugenic knowledge, 1920s-1940s. Hist. cienc. saude-Manguinhos, Dec 2016, vol.23, suppl.1,

Cancer, women and public health – Researcher Ilana Löwy follows the early history of the pap test, its consequences and controversies.

Zika virus and rubella: similarities and differences – Researcher Ilana Löwy, from the Institut National de la Sante et de la Recherche Médicale Paris, traces a parallel between the current zika epidemics in Brazil and past rubella outbreaks.

Löwy, Ilana. Ludwik Fleck e a presente história das ciências. Hist. cienc. saude-Manguinhos, Out 1994, vol.1, no.1, p.7-18.

Löwy, Ilana and Sanabria, Emilia. A biomedicalização de corpos brasileiros: perspectivas antropológicas. Hist. cienc. saude-Manguinhos, Mar 2016, vol.23, no.1.