170 170.174

A lesson learnt: the rise and fall of Lariam and Halfan named, and they were still referred to by their respective Lariam (pharmacological name mefloquine) is an antimalaria Walter Reed experimental numbers: WR 142 490 and WR drug discovered by the US Army shortly after the Vietnam 171 669.1,4 Lariam and Halfan were the two main progeny War, and subsequently marketed worldwide by F.
of the WRAIR malaria drug discovery programme, which Hoffmann-La Roche. The first reported trials of mefloquine were in prisoners, and were performed at the Joliet Over a 15-year period, vast resources were voted by the Correctional Center, Illinois, in 1975, and at the Maryland US federal government to fund WRAIR's antimalaria drug research, which at the time was the largest drug discovery Halfan (pharmacological name halofantrine) is an programme ever mounted. The political driving force antimalaria drug chemically related to mefloquine and behind the programme was the severe clinical setback quinine. Like Lariam, Halfan emerged from the US Army's experienced by the US military during the Vietnam War, huge post-Vietnam antimalaria drug discovery programme.3 when at one stage 1% of US combat troops were Halfan was first described in the literature in November succumbing to malaria each day.6 Because of the size and 1982.4 During the 1980s and 1990s, Halfan was marketed urgency of the research task, WRAIR collaborated with numerous governmental, academic and commercial orga- There is no question that safe and effective antimalaria nizations, including 175 external contractors.7 drugs were needed in the second half of the twentieth From the early 1960s onwards, WRAIR screened over century, once it became apparent that the Plasmodium had 250 000 potential antimalaria compounds.8 Lariam was developed resistance to the mainstay of antimalaria therapy, number 142 490 in this long series, and Halfan was number namely chloroquine. Chloroquine resistance was observed 171 669. Because the US military was and remains first in Thailand in 1957, then on the Colombian- forbidden by Congress from operating in the commercial Venezuelan border in 1959, and in Kenya and Tanzania in sector, WRAIR engaged the holding companies F.
1978.5 Within a decade of Lariam and Halfan being Hoffmann-La Roche and Smith Kline Beecham to market marketed, however, the safety of both these novel agents The precise details of the three-way business agreement This essay looks at the unusual developmental history of between WRAIR, the US federal government and the two Lariam and Halfan, explains the circumstances under which multinational drug companies which marketed Lariam and both drugs rose in esteem with policy makers and Halfan have not been made public. It appears, however, prescribers and then fell into disfavour with consumers, that all of WRAIR's phase I and phase II clinical trial data on and summarizes the lessons learnt in the process. These Lariam and Halfan were delivered as a free good to F.
lessons need to be recorded and acted upon, to prevent a Hoffmann-La Roche and to Smith Kline Beecham. Drug repetition of the same mistakes with the next generation of approval was swiftly granted by the Food and Drug Administration (FDA): Lariam was approved in 1989 andHalfan in 1992.
From the perspective of the two drug companies chosen to act as the marketing arm of WRAIR, the primary Both Lariam and Halfan were discovered at the Experi- commercial potential of Lariam and Halfan lay in their mental Therapeutics Division of the Walter Reed Army ability to prevent malaria in tourists and business travellers Institute of Research (WRAIR) in Washington DC.3 In the to the tropics. Prior to their obtaining FDA approval, earliest published reports, these two drugs had not yet been however, no randomized Phase III tolerability study wascarried out on either drug in a normal study population ofhealthy civilian volunteers.9 Likewise, there was no serious Medical Branch, Headquarters 5th Division, Copthorne Barracks, Shrewsbury attempt prior to licensing to explore the potential drug- drug interactions of either Lariam and Halfan; some of the Correspondence to: Lieutenant Colonel A M Croft RAMC fatal drug reactions which followed may have been a direct consequence of the resulting gap in the prescribers' Belatedly, three randomized controlled trials were carried out in healthy volunteer populations, and were Within months of their being licensed, major safety reported between 2001-2003.13-15 The studies confirmed concerns around Lariam and Halfan began to emerge. These mefloquine's potential for causing psychological illness, and two compounds should have been welcomed by the public all three study reports described an excess of neuropsychia- as being safe, effective and lifesaving pharmaceutical tric adverse effects in the mefloquine arm.13-15 Around the weapons in a world where international travel was same time an analysis of the cause of illness in 4524 increasing exponentially and where chloroquine-resistant travellers returning from sub-Saharan Africa to the northern malaria seemed to be spreading just as rapidly.10 Instead, hemisphere found that, excluding diarrhoea and fever as consumers viewed the two new drugs with disquiet, and causes, mefloquine was the fifteenth most common cause of post-travel illness.16 A case control study of 564 Dutchtravellers between 1997 to 2000 found a threefold increasein the incidence of psychiatric events with mefloquine use(OR 3.5, 95% CI 1.4-8.7), and a very high risk of psychiatric events in women users of the drug (OR 47.1, Though still prescribed in most countries, both for 95% CI 3.8-578.6).17 A survey of the recent literature preventing and treating malaria, Lariam is now known to shows that mefloquine has been causally associated with 19 cause neurotoxicity.11 This unexpected property came to deaths in users, including three suicides (Table 1).18-26 prominence in the mid-1990s, when national pharmacov- By 2004, public concern in the US was such that the igilance centres, initially in Europe, began to receive FDA took the exceptional step of insisting that a patient recurring reports of neuropsychiatric adverse effects caused medication guide be given to all recipients of mefloquine by this new antimalaria agent. In the Netherlands during prescriptions.27,28 The FDA thus followed the example of 1998 and 1999, mefloquine was respectively the most and the Committee on Safety of Medicines, which had advised the second most cited drug in spontaneous reports of drug- British doctors in 1996 to warn patients about the incidence related illness made to the Lareb Pharmacovigilance of neuropsychiatric adverse effects with mefloquine. As was Foundation.12 Around the same time, it was reported that pointed out in the British Medical Journal, this advice 60% of all the mefloquine occurrences notified to the overturned accepted clinical practice in the UK, which at WHO's Uppsala Monitoring Centre cited neuropsychiatric that time was to warn patients about common adverse Table 1 Nineteen deaths causally associated with Lariam (mefloquine) use After one mefloquine tablet, patient experienced cardiopulmonary arrest, death.
Malaria recrudesced 21 days after mefloquine treatment. Given halofantrine over 3 days. Experienced sudden cardiac arrest, death.
Developed blistering of lips and oral mucosae. Generalized erythema and blistering, then exfoliation of the mucosae. Ulceration of the mucosae, hair and After taking Lariam for overseas trip, became acutely depressed. Committed suicide by jumping to his death from the roof of a mansion block.
Took two Lariam tablets for suspected malaria. After 4 hours, experienced headaches, 'burning in bones', deafness, dizziness. Confused, panic, depression. Hospitalized. Committed suicide.
Early during mefloquine prophylaxis, experienced fever (102 degrees), chills, headache, cough. Initially treated as malaria. Then, during a 2-hour car ride, experienced a 'head rush.' Collapsed, died.
Eight fatal reactions to mefloquine, reported to the UK Medicines Control Four fatal reactions to Lariam, recorded on the manufacturer's database of Treated with Lariam for 48 hours. Committed suicide 6 weeks later, through self- Also unexpectedly, Halfan was found after licensing to licensing, as it should have been, it is certain that the FDA cause ventricular dysrhythmias that were often fatal.23,31-33 and the other national licensing authorities which approved This unforeseen property of the drug (unforeseen because Lariam for use prophylactically, in and around 1989, would unresearched) came to light serendipitously, in a prospec- not at the time have endorsed this drug.37 tive electrocardiographic study of Karen patients that was It seems probable that in the late 1980s and early 1990s reported in the Lancet in 1993.34 Halfan is no longer the FDA and other national licensing bodies were recommended by WHO for the self-treatment of malaria, influenced, perhaps subliminally, by the powerful mili- and the drug is not listed for this indication in the British tary-industrial-governmental lobby into over-hasty decisions National Formulary or in other national pharmacopoeias.
to approve the marketing of both Lariam and Halfan. These Halfan is not now approved in any country for malaria two drugs were authorized for public use on the basis of an prophylaxis.35 The 2006 edition of Goodman and Gilman incomplete knowledge base, and at too early a stage in the Post-marketing surveillance of Lariam and Halfan took 'Because halofantrine displays erratic bioavailability, poten- the place of normal, responsible, pre-licensing research into tially lethal cardiotoxicity, and extensive cross-resistance with mefloquine, its use generally is not [now] recommended.'36 Travel medicine experts in most countries were slow to recognize the danger signals associated with Lariam and The disappointing performance in clinical practice of Halfan, and for many years the public's concern about these two drugs, developed at enormous cost to the US Lariam, in particular, was dismissed as 'media hype'. A taxpayer, could not have been anticipated 30 years ago. Or senior WRAIR scientist, writing in 2001, deplored what he called '. the ''herd mentality'' of mefloquine associatedpsychoses', and stated defiantly that 'mefloquine (Lariam1)remains the prophylaxis of choice for US soldiers and travellers.'38 As late as 2005 a reviewer in the New England Both Lariam and Halfan are products of what has been Journal of Medicine, also an employee of the US military for called 'the military-industrial complex'. This is an overused over 20 years, continued to maintain, in the face of term, but one that describes a real entity.
compelling empirical and experimental evidence to the The partnership between industry and the military has contrary, that Lariam was a 'well tolerated' drug.39 achieved some astonishing technical feats-witness the However, by the following year a US military research placing of a man on the moon. In the area of patient care, team, based partly at WRAIR, conceded that: however, the health and wellbeing of consumers of health 'Walter Reed Army Institute of Research is currently care is protected by regulations which, however imperfect investigating mefloquine analogues, seeking one with similar and seemingly cumbersome, are derived from decades of efficacy but reduced neuropsychiatric toxicity.'3 use and experience. These regulations reach forward in The victims of this pharmacological muddle have been time, protecting future cohorts of patients from prescriber- those many business travellers, embassy staff, tourists, aid induced harm, but also slowing up pharmaceutical workers, missionaries, soldiers and others who were well at innovations which in some cases may be needed urgently.
the start of their journeys into malaria-endemic areas, were Powerful lobbies, impatient of delay (and acting in what prescribed Lariam or Halfan by their physicians, and who they may see as the public's best interests) may be tempted then suffered unforeseen (because unresearched) harms to disregard those regulations. The clinical consequences of doing so may be unforeseen, however.
Effectively, all users of Lariam and Halfan, from the As stated above, the underpinning safety and pharma- point of licensing onwards, have been involved in a natural cokinetic studies which should have been performed prior experiment to determine the true safety margin, at current to the licensing of Lariam and Halfan, on the main intended dosages, of these two poorly understood antimalaria drugs.
target group for both drugs (namely, tourists and business Consumers have been unwitting recruits to this longitudinal study, rather than informed partners.9,40 The rapid public In the case of Lariam, the first randomized controlled rejection of Lariam and Halfan could have been anticipated, trial of the drug in a mixed population of general travellers since users of malaria chemoprophylaxis differ from normal was not reported until 2001.13 Of the study participants patients in that they are by definition healthy people, and on randomized to receive mefloquine, 67.1% reported 51 this account they are unwilling to accept even relatively adverse event, and in 6% of mefloquine users these events were severe (defined as requiring medical advice). Had this Ironically, for a drug that was discovered by the same understanding of mefloquine been available prior to its military, soldiers have been amongst the most vocal critics of Lariam. Following a Parliamentary enquiry, Canada's structurally related quinoline derivatives, might be auditor general condemned protocol abuses in which 900 mediated. Croft and Herxheimer suggested in 2002 that Canadian soldiers deploying to Somalia were prescribed many of the adverse effects of mefloquine may be a post- Lariam in 1992-1993, at a time when the drug was still hepatic syndrome caused by primary liver damage, with a unlicensed in Canada.42 In the Netherlands, reports of subset of mefloquine users also experiencing thyroid severe adverse drug reactions in soldiers who had used disturbance.50 More recently, Aarnoudse and colleagues Lariam prophylaxis while undertaking peacekeeping duties have hypothesized that the neuropsychiatric effects of in Cambodia prompted questions in Parliament and intense mefloquine are associated with polymorphisms in the public debate.43 In the US, military epidemiologists have MDR1/ABCB1 gene that encodes for the efflux pump investigated the possible role of Lariam in a series of P-glycoprotein.51 Both theories remain speculative, how- murders and suicides among soldiers in North Carolina who ever, since the rigorous studies needed to test the respective had served in Afghanistan.44 Most recently, the Australian hypotheses have not yet been carried out.
military has been threatened with legal action by soldiers Because the harms of mefloquine have never been reporting severe and disabling symptoms which they adequately investigated, and because there appears to be no incentive for the manufacturer of Lariam ever to do this, itis likely that mefloquine, which like halofantrine is apotentially important weapon in the limited pharmaceutical arsenal against malaria, will be discarded along with its Sir Iain Chalmers has pointed out how the biased under- sister drug. A recent British review of the treatment options reporting of research harms and sometimes kills patients.46 for malaria does not mention mefloquine at all.52 This The under-reporting of research, he states, is essentially a apparent willingness to casually sideline two undoubtedly form of misconduct, since it can lead to seriously misleading lifesaving drugs represents a waste of resources, and a loss recommendations for clinical practice and for new also to future travellers and patients. Researchers, policy makers and prescribers must learn from this experience or The case of Lariam and Halfan does not exactly fit the be condemned to repeat it. Many of the individual medical model of scientific irresponsibility which has been high- tragedies detailed in the table need never have occurred.
lighted by Chalmers and others. It is not the case, with Powerful institutional pressures must never again override these two antimalaria agents, that inconvenient research data on their adverse effects was deliberately withheld fromnational drug licensing authorities, and from the public. The necessary pre-licensing research was simply never carriedout.
The prime lesson from the Lariam and Halfan the RSM Section of Pharmaceutical Medicine & Research experience is that drugs intended primarily for use by Prize Essay Competition 2006. I am grateful to the sponsors healthy people must be genuinely well tolerated, and indeed of the Prize and to all those fellow scientists who helped me they must demonstrate much better tolerability under their develop the ideas outlined in this essay. The opinions actual conditions of use than would normally be required for, say, antimitotic agents. Future research studies ofmalaria chemoprophylaxis must address the unanswered questions and outstanding gaps in the evidence.48 Inparticular, planned research studies must be carried out 1 Trenholme GN, Williams RL, Desjardins RE, et al. Mefloquine (WR 142,490) in the treatment of human malaria. Science 1975;190:792-4 on the population of interest (that is, on tourists and 2 Clyde DF, McCarthy VC, Miller RM, Hornick RB. Suppressive activity business travellers) and not on a convenience sample of of mefloquine in sporozoite-induced human malaria. Antimicrobial Agents Despite the public outcry about Lariam and Halfan, it is 3 Kitchen LW, Vaughn DW, Skillman DR. Role of US military research extraordinary that no real attempt has yet been made to programs in the development of US Food and Drug Administration-approved antimalarial drugs. Clin Infect Dis 2006;43:67-71 properly explore the adverse effects of these two drugs in 4 Cosgriff TM, Boudreau EF, Pamplin CL, Doberstyn EB, Desjardins RE, terms of what causes these effects, who is likely to Canfield CJ. Evaluation of the antimalarial activity of the experience them, how long the effects typically last, how phenanthrenemethanol halofantrine (WR 171,669). Am J Trop MedHyg 1982;31:1075-9 the effects can be mitigated, and how they should be 5 Croft AM, Geary K. Chloroquine and its combinations. In: Schlagenhauf P, ed. Travellers' Malaria. Hamilton, Ontario: Decker, 2001 There are several plausible mechanisms through which 6 Bruce-Chwatt LJ. John Hull Grundy lecture. Mosquitoes, malaria and the unwanted effects of Lariam and Halfan, which are war; then and now. J R Army Med Corps 1985;131:85-99 7 Tigertt WD. The Army malaria research program. Ann Intern Med 29 Committee on Safety of Medicines. Mefloquine (Lariam) and neuropsychiatric reactions. Current Problems in Pharmacovigilance 1996; 8 Croft AM, Whitehouse DP, Cook GC, Beer MD. Safety evaluation of the drugs available to prevent malaria. Expert Opin Drug Saf 2002; 1: 19-27 30 Warner J. Advice to warn patients about rare side effects overturns 9 Croft AM, Garner P, Squire SB. Malaria prevention for travelers.
31 Akhtar T, Imran M. Sudden deaths while on halofantrine treatments- 10 Magill AJ. Malaria: epidemiology and risk to the traveler. In: Keystone a report of two cases from Peshawar. J Pak Med Assoc 1994; 44: 120-1 JS, Kozarsky PE, Freedman DO, Nothdurft HD, Connor BA, eds.
32 Malvy D, Receveur MC, Ozon P, et al. Fatal cardiac incident after use Travel medicine. New York: Mosby, 2004: 131-6 of halofantrine. J Travel Med 2000; 7: 215-6 11 Dow G, Bauman R, Caridha D, et al. Mefloquine-induces dose-related 33 Bouchaud O, Bruneel F, Schiemann R, Peytavin G, Coulaud JP.
neurological effects in a rat model. Antimicrob Agents Chemother 2006; Severe cardiac toxicity due to halofantrine: importance of underlying heart disease. J Travel Med 2002; 9: 214-5 12 Heeringa M, van Grootheest AC. Profylactisch gebruik van 34 Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of mefloquine-bijwerking geen reden tot verandering van indicatie.
antimalarial treatment with halofantrine. Lancet 1993; 341: 1054-6 Pharmaceutisch Weekblad 2000; 135: 788-792 35 Shanks GD, Edstein MD. Modern malaria chemoprophylaxis. Drugs 13 Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a 36 Shapiro TA, Goldberg DE. Chemotherapy of protozoal infections: randomized double-blind study. Clin Infect Dis 2001;33:1015-21 malaria. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and 14 Potasman I, Juven Y, Weller B, Schwartz E. Does mefloquine Gilman's The Pharmacological Basis of Therapeutics. 11th edition. New prophylaxis affect electroencephalographic patterns? Am J Med 2002; 37 Croft AM, Beer MD, Herxheimer A. Effectiveness of antimalarial 15 Schlagenhauf P, Tschopp A, Johnson R, et al. Tolerability of malaria chemoprophylaxis in non-immune travellers to sub-Saharan Africa: 38 W Milhous. Development of new drugs for chemoprophylaxis of multicentre, randomised, double blind, four arm study. BMJ 2003; malaria. Bull Soc Pathol Exot 2001; 24: 149-51 39 Baird JK. Effectiveness of antimalarial drugs. N Engl J Med 2005; 352: 16 Freedman DO, Weld LH, Kozarsky PE, et al. Spectrum of disease and relation to place of exposure among ill returned travelers. N Engl J Med2006; 354: 119-30 40 Burke BM. Mefloquine. Lancet 1993; 341: 1605-6 17 Van Riemsdijk MM, Sturkenboom MC, Pepplinkhuizen L, Stricker 41 Croft AM, Garner P. Mefloquine for preventing malaria in non- BH. Mefloquine increases the risk of serious psychiatric events during immune adult travellers. The Cochrane Database of Systematic Reviews travel abroad: a nationwide case-control study in the Netherlands. J 18 Anonymous. Mefloquine for malaria. Medical Letter on Drugs and 42 News report. Canadian soldiers used as 'guinea pigs'? Can Med Assoc J 19 Nosten F, ter Kuile FO, Luxemburger C, et al. Cardiac effects of 43 van Puijenbroek EP, Bouvy M. Mefloquine (Lariam) in het nieuws.
antimalarial treatment with halofantrine. Lancet 1993; 341: 1054-6 20 McBride SR, Lawrence CM, Pape SA, Reid CA. Fatal toxic epidermal 44 News report. Lariam suicide warning. BMJ 2002; 325: 510 necrolysis associated with mefloquine antimalarial prophylaxis. Lancet 45 Burton B. Australian army faces legal action over mefloquine. BMJ 21 News report. Roche's Lariam linked to a suicide in UK. Scrip 1998; 46 Chalmers I. From optimism to disillusion about commitment to transparency in the medico-industrial complex. J R Soc Med 2006; 99: 22 Anonymous. Netwerk aktuell-Suizid nach zwei Tabletten Mefloquin 47 Chalmers I. Under-reporting research is scientific misconduct. JAMA 23 Centers for Disease Control and Prevention. Sudden death in a traveler following halofantrine administration-Togo, 2000. Morb 48 Brown P, Brunnhuber K, Chalkidou K, et al. How to formulate research recommendations. BMJ 2006; 333: 804-6 24 Smith HR, Croft AM, Black MM. Dermatological adverse effects with 49 Richardson WS, Wilson MC, Nishikawa J, Hayward RSA. The well- the antimalarial drug, mefloquine: a review of 74 published case built clinical question: a key to evidence-based decisions. ACPJ Club reports. Clin Exp Derm 1999; 24: 249-54 25 Nosten F, van Vugt M. Neuropsychiatric adverse effects of mefloquine.
50 Croft AM, Herxheimer A. Adverse effects of the antimalaria drug, What do we know and what should we do? CNS Drugs 1999; 11: 1-8 mefloquine: due to primary liver damage with secondary thyroid 26 Jousset N, Guilleux M, de Gentile L, Le Bouil A, Turcant A, Rouge'- involvement? BMC Public Health 2002; 25: 6. Available at http:// Maillart C. Suicide spectaculaire lie' a` une prise de me'floquine. Presse access.asp?man_id=9039985831098605 (Accessed 02/11/2006) 27 News report. FDA requires warnings on anti-malaria drug Lariam.
51 Aarnoudse AL, van Schaik RH, Dieleman J, et al. MDR1 gene polymorphisms are associated with neuropsychiatric adverse effects ofmefloquine. Clin Pharmacol Ther 2006; 80: 367-74 28 Medication guide: Lariam [online]. Available at http://www.fda.gov/ medwatch/SAFETY/2003/LariamMedGuide.pdf (Accessed 02/11/ 52 Whitty CJ, Lalloo D, Ustianowski A. Malaria-an update on treatment of adults in non-endemic countries. BMJ 2006; 333: 241-5

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