You may have heard of the antimalarial agent mefloquine during the Covid-19 pandemic, as scientists suggested repurposing the drug to combat the novel coronavirus. Most drugs are developed for the body of a 27-year-old male Caucasian, and so was this antimalarial. Mefloquine was discovered in the Antimalaria Drug Discovery Program—the biggest program of its kind—launched by the American Army in 1963. Over a period of fifteen years 250,000 antimalarial agents were tested at the Walter Reed Army Institute of Research (WRAIR) in Washington DC. In 1969, researchers discovered WR 142,490, which became known as mefloquine in 1975. While the clinical trials were conducted in malaria-endemic areas, the drug was later marketed by the Basel-based Swiss pharmaceutical company F. Hofmann-La Roche (Roche) as Lariam®.
By now, more than 35 million Western travelers have consumed the drug or its generic equivalent. While the neuropsychiatric side effects have attracted a great deal of media attention in the Anglo-Saxon world, African health experts’ clinical trials and their knowledge production on the drug have not. To remedy this in a small way, this blog post opens a small window into a larger project on Zambian experts’ contributions to medical science, particularly concerning malaria treatments, and the way these contributions have been overlooked.
How Roche Came to Produce Lariam®
In the 1970s, Roche was the leading pharmaceutical company in the world due to the revenues it received from sales of the tranquilizers Librium and Valium. Since 1968, it had conducted research in malaria chemotherapy. After the Plasmodium falciparum parasite developed resistance to chloroquine, Roche was interested in finding the urgently needed “magic bullet” against malaria. In 1974, the World Health Organization (WHO) launched the Special Program for Research and Training in Tropical Diseases (TDR). In the same year, the WHO invited Roche to take part in the regular malaria task force meetings. This is where Roche and WRAIR delegates came into contact.1
A prototype of the antimalarial drug Lariam® was tested in clinical studies in 1976, which were co-organized or organized individually by WRAIR, Roche, and the WHO in endemic areas. WRAIR had conducted phase I and phase II clinical studies with mefloquine mostly on American prisoners and students to determine the suitable dosage of mefloquine for therapy and prophylaxis.2 On account of the size and urgency of the research task—chloroquine resistance, side effects, and the need for the American military and others to find a suitable antimalarial agent for their personnel—WRAIR collaborated with 175 external governmental, academic, and commercial companies and organizations.3 In 1986, Roche applied to the Food and Drug Administration (FDA) to license Lariam® and presented twenty studies in which the curative efficacy of mefloquine mostly in falciparum malaria patients was tested in endemic countries such as Thailand, Brazil, Burma, Nigeria, Zambia, China, Gabon, and Burkina Faso. The studies determined the best dosage for prophylaxis and therapy as well as the efficacy of mefloquine in comparison to standard antimalarial agents. There was never a phase III study (requiring 1,000 to 3,000 people) before market launch, which has been a part of drug approval ever since the Declaration of Helsinki of the World Medical Association (1964). Even though the market launch, registration, and production process of Lariam® left much to be desired and generated considerable controversy, Roche began manufacturing the pills. A 1983 marketing report indicated that Roche Nutley had already received an order for 2.4 million tablets in mid-1982 to be delivered to the US Army from mid-1983 to mid-1984.4
African Researchers’ Sacrifices to Turn TDRC Ndola into a Model for Research into Tropical Medicine
In the wake of World War II, the WHO emerged as a major player in mitigating the effects of so-called tropical diseases. However, it was not until 1974 – with the creation of the TDR—that the WHO started to take cautious steps towards collaborations with the pharmaceutical industry for the development of drugs for tropical diseases. The TDR marked a key decision by the WHO to study tropical diseases in endemic areas. Tropical Diseases Research Centers (TDRCs) were created across the globe. On the African continent, the hospital in Ndola, Zambia, was chosen due to “its proximity to Lusaka University[’s medical school],” the new building, the “booming copper mining industry” and “the necessary computer facilities.” Zambia’s relatively central location on the continent, Ndola’s good location for recruiting patients, Zambia’s focus on education after independence, as well as its ambitiousness and its interest in science, seem to have also informed the decision.
In 1975, the hospital’s two upper floors were converted into the TDRC, which conducted many clinical trials on six tropical diseases. One of them was malaria. Numerous antimalarial agents were tested. The interest in mefloquine came amid growing scientific concern about the emergence of resistance to older antimalarials in Zambia and abroad. Thus, clinical trials conducted in Ndola between 1979 and 1983 involved testing the effectiveness of mefloquine in comparison to chloroquine in randomized double-blind trials on mainly young men and teenage boys. The results generated by TDRC staff members were forwarded, among other places, to the WHO headquarters in Geneva and Roche in Basel.
Soon TDRC Ndola was showcased as a model for other TDRCs because the staff who led it and conducted the research was entirely African and predominantly Zambian. Tropical medicine experts from around the world visited and admired it. From its very inception, it had been intended to counteract the ongoing brain drain of Zambian scientists to the Global North. This first generation of Zambian medical practitioners demonstrated that research on malaria and other endemic tropical diseases could and should be carried out in endemic areas. Scientists from the Ndola center, in turn, traveled around the world and presented their research at conferences. The WHO presented Ndola as living proof of productive cooperation between public and private partners, as well as global and local ones.
When I spoke with one of the directors of the TDRC, Modest Mulenga (b. 1961), it was striking how much he emphasized his privileged status:
I was actually very privileged. Not so many people would be able to tell a story like I just told because when we were growing up, the country somehow was doing very well with copper mining. It was developing at a very fast pace such as around 1968. I started living in a privileged area. My country, before independence in 1964, was very segregated. The white settlers built themselves very beautiful compounds on the other side; we the indigenous people were thrown on the other side. But after independence everything was changing very quickly. My father got a job at the mines, we moved in[to] a very good area, such as I went to a very good school, free education at that time. I lived in a rich area. We didn’t have much malaria in there because it was very well controlled. I began to understand that it was a problem in the rural places because each time we tried to visit our relatives in the rural places, they’d tell us we’d have to get some chloroquine to prevent the diseases, and if we don’t, we might get the severe disease and might die. Not so many were that privileged in my country. The majority remained in that part. I was privileged in that regard.5
Besides feeling fortunate to be able to study abroad and contribute to research in tropical medicine, many Zambian experts faced staff shortages and encountered resistance from local communities. This was because many locals did not want to participate in the trials, which they believed rendered them guinea pigs for Western drugs. In addition, there was stiff competition among the Zambian experts to gain the attention of international organizations and companies and to become sponsored and part of their programs. Consequently, many of the TDRC Ndola staff made numerous personal sacrifices, such as working many more hours than they were paid for, not being allowed to take part in international conferences, and using their own cars to drive to field sites, which they mentioned in their correspondence to the WHO.
Lariam® Unused in Malaria-endemic Areas
In Ndola, side effects such as “neuropsychiatric condition[s] (restlessness, non-cooperation, and tendency to violence when under restraint),” “epileptic fit,” “convulsions,” “severe dizziness,” and “myoglobinuria” (the presence of myoglobin, an iron- and oxygen- binding protein usually found in muscle tissue, in a person’s urine) were reported. Yet those in charge could not imagine that the drug caused these effects. Dizziness was associated with blood collection, and nightmares were deemed “possibly but not probably drug related.” A 1986 “Expert Report on the Clinical Documentation” submitted to the FDA with the request that it approve Lariam® explained away most of the side effects that had been uncovered:
A causal connection between the neuropsychiatric side effects described and the administration of mefloquine cannot be definitely ruled out, but appears to be improbable. A causal relation is unlikely because the symptoms always occur only in the second or even third week after administration. Moreover, in animal experiments (in squirrel monkeys), no psychotropic effects were determined after oral administration of 10, 50 and 100 mg/kg mefloquine. It is conceivable that the patients suffered psychogenic reactions as a result of being “cooped up” for so long; in the Thai test centre, the patients were hospitalized for 42-63 days after therapy, in Zambia for 42 days. Similar symptoms have never been observed at the other centres to date.6
When I interviewed one of the authors of the report in late 2019, his conviction that, in Lariam®, they had found the “magic bullet” against malaria was quite clear. It was also evident that he and the others on his team were willing to accept minor side effects—which for him were much less harmful than those previous generations of drugs generated—for the greater good this combination of drugs would bring to the world.
Yet the reality in malaria-endemic areas did not match the researchers’ hopefulness. Side effects and cost kept it from being used. In Zambia, for instance, Lariam® has never been adopted in the national malaria treatment guidelines as an official drug for treating malaria. According to interviews with present TDRC staff, this is because of its side effects and the fact that it would have been administered together with other drugs (due to the side effects and resistance occurring in other parts of the world). This would have rendered its use too expensive. The history of Lariam® in Zambia and malaria-endemic areas in Africa in general will require much more research.
Power Structures and Politics in Research
As we have seen, Zambian malariologists were at the very forefront of the clinical trials and the research conducted at the TDRC. As antimalarials were predominantly tested in places such as the TDRC Ndola, Zambian doctors and researchers and their counterparts in similar spaces in the Global South largely produced the latest state-of-the-art malaria treatment. These healthcare professionals determined answers to whether the drugs worked, what side effects accompanied them or were to be expected, and how they had to be dosed. Zambian doctors, in turn, benefited from collaborating with international organizations and companies as such entities often sponsored healthcare professionals’ education abroad (primarily in English-speaking Europe or the US). By interviewing them, I wish to examine their scientific achievements as well as the power dynamics between them and their colleagues from the Global North. As Zambian novelist Namwali Serpell has reminded us in The Old Drift, “Progress is just the word we use to disguise power doing its thing.”7 For Zambian healthcare professionals, being able to help their compatriots and to mitigate their suffering was a dream come true. Thus, they were very grateful to these donors and gladly kept collaborating with and working for them, even though their contributions remained in the shadows. In this, they have followed a long line of overlooked African contributions to medical science.
Tanja Hammel is a historian of knowledge and science; she works as a lecturer and the MOOC-Coordinator in the Department of History, University Basel, in the interdisciplinary project “African Contributions to Global Health.” She also teaches courses in history and interdisciplinary courses in global health at the universities of Basel and Zurich, Switzerland. She has published on the history of natural history in nineteenth-century South Africa, e.g., Shaping Natural History and Settler Society (Palgrave, 2019), and “Thinking with Birds,” Kronos, no. 41 (2015).
- Interview near Basel, 5 December 2019, conducted and transcribed by Tanja Hammel. W.E. Gutteridge, “TDR Collaboration with the Pharmaceutical Industry,” Transactions of The Royal Society of Tropical Medicine and Hygiene 100 (2006): 21–25. ↩︎
- NDA 19–578, Medical Officer’s Review of Original NDA Submission, 1–3; Phase I Clinical Testing. Antimalarial Drugs, Bio-Med Inc Washington DC, National Technical Information Service: ADA044243 (MAR 1976); ADA046648 (OCT 1977); ADA058221 (MAR 1978); ADA073116 (MAR 1979). This was the usual procedure at the time. Approximately 90 percent of drugs that were licensed in the US before 1980 were tested on prisoners. A. Petryna, When Experiments Travel: Clinical Trials and the Global Search for Human Subjects (Princeton/Oxford: Princeton University Press, 2009), 23. ↩︎
- A. M. Croft, “A Lesson Learnt: The Rise and Fall of Lariam and Halfan,” Journal of the Royal Society of Medicine 100, no. 4 (2007): 170–174. ↩︎
- Marketing Report I, March 1983. Roche Historical Collections and Archive: PO.3.1.LRI201816, 24, 40. ↩︎
- Interview conducted by Tanja Hammel via Zoom, 21 September 2021. Andrina Sommer created the transcript. Emphasis added. ↩︎
- NDA Lariam, Part I C: Expert Report on the Clinical Documentation, 0091, 16. ↩︎
- Namwali Serpell, The Old Drift: A Novel(Hogarth, 2019), ebook Kindle edition 2020, Part III: The Children, “Naila,” p. 506. ↩︎