The New Mefloquine?
Mefloquine is now well known to be neurotoxic, one of several synthetic quinolines able to cause acute psychotic reactions and/or a chronic central nervous system (CNS) toxicity syndrome in a significant proportion of people given these drugs for malaria prophylaxis. The licencing of mefloquine by national drug regulators in the late 1980s and early 1990s occurred in the absence of phase III clinical safety and tolerability trials among normal study populations of healthy civilian volunteers. Instead the approvals relied on studies among vulnerable subjects including prisoners, military personnel and people in developing countries. The result of this regulatory failure is described by Dr Ashley Croft:
“Effectively, all users of Lariam, from the point of licensing onwards, have been involved in a natural experiment to determine the true safety margin, at current dosages, of [this] poorly understood antimalaria drug. Consumers have been unwitting recruits to this longitudinal study, rather than informed partners.”
Much of the recent media coverage of mefloquine’s adverse health effects has focused on the efforts of military veterans, including drug trial subjects, in seeking appropriate recognition and medical care from their national governments. Prominent among these are Australian veterans who participated in clinical trials conducted by the Australian Army Malaria Institute (AMI) in Timor Leste from 2000 to 2002. With doxycycline malaria prophylaxis having been pioneered by AMI in the 1980s in response to resistance in other drug classes, mefloquine has never been the first line anti-malarial in the Australian Defence Force (ADF) and was prohibited from being used by aircrew and other specialist personnel due to its neuropsychiatric side effects. This has led us to question why the drug was “trialled” for use in the ADF long after it had been registered, with its neuropsychiatric side effect profile so evident in the civilian market and previously published military drug trials. What has become apparent is that ADF personnel given mefloquine during these trials were simply “collateral damage” in an effort to support the development of another synthetic quinoline anti-malarial drug – tafenoquine.
The story of tafenoquine’s development and introduction to date is alarmingly similar to the story of mefloquine – marred by regulatory shortcuts, cosy relationships between military officials and the pharmaceutical industry, breaches of ethical standards, scientific fraud and medical negligence. This is the first in a series of posts that aims to document this misconduct by ADF officials involved in the AMI’s clinical trials of tafenoquine. In this post we will provide background on tafenoquine and an overview of the trials, then in subsequent posts we will describe the conduct of each trial and the emerging evidence of misconduct.
Tafenoquine is an 8-aminoquinoline drug manufactured by GlaxoSmithKline (GSK) that is being investigated for prophylaxis and treatment of malaria. Like mefloquine, tafenoquine is a synthetic quinoline that was first developed by the U.S. Walter Reed Army Institute for Research (WRAIR) as part of an enormous anti-malarial drug discovery program that commenced during the Vietnam war. Two of the drugs developed earlier in this program were mefloquine (Lariam™) and halofantrine (Halfan™).
The first investigation of tafenoquine in this program was in the treatment of relapsing vivax malaria, as a more effective alternative to primaquine. Later it was seen as a useful preventative against multi-drug resistant falciparum malaria. A series of pre-clinical studies were undertaken from the late 1980s to the late 1990s, with clinical studies commencing in the late 1990s using “volunteers” in the U.S., Thailand, Gabon, Kenya and Ghana. Researchers who were instrumental in these studies and later moved to Australia include former AMI Director Karl Rieckmann, the current AMI Head of Drug Evaluation Michael Edstein, and the current AMI Director Dennis Shanks. Further studies were conducted with Australian military personnel in the 1999-2001 clinical trials that are the subject of this post, while Rieckmann was the Director of AMI.
Despite these AMI trials having found tafenoquine to be safe and effective, the drug’s clinical development did not substantially progress towards registration for almost decade. Eventually, in 2008 the manufacturer GlaxoSmithKline (GSK) entered an agreement with Medicines for Malaria Venture (MMV) to develop tafenoquine as a radical cure for vivax malaria. Five years later the U.S. Food and Dug Administration (FDA) granted “breakthrough therapy” designation for tafenoquine, and several months later GSK and MMV announced the commencement of Phase III clinical trials. The FDA states that Breakthrough Therapy designation “is intended to expedite the development and review of drugs for serious or life-threatening conditions”, and “conveys all of the fast track program features, more intensive FDA guidance on an efficient drug development program, an organizational commitment involving senior managers, and eligibility for rolling review and priority review.”
Another parallel with the mefloquine story is that there has been a reluctance to undertake laboratory studies of tafenoquine’s potential neurotoxicity prior to registration. Like another 8-aminoquinoline primaquine, tafenoquine is able to cause haemolytic anemia in individuals with G6PD deficiency, and many of the clinical studies have carefully assessed this toxic property. However the 8-aminoquinoline class includes several other drugs that are also known to be neurotoxic, including pamaquine and plasmocid, based on extensive histopathological testing conducted as long ago as the 1940s. A leading expert in quinoline toxicity wrote in 2013:
“While tafenoquine has been eagerly anticipated for its utility against vivax malaria and potentially against leishmaniasis, the recent granting by the U.S. FDA of Breakthrough Therapy status, in the absence of any published neurohistopathological testing, risks recreating the sense of urgency that contributed to the approval of mefloquine in the absence of appropriate CNS safety data.”
Yet In 2009, long after the AMI tafenoquine trials in Bougainville and Timor Leste, a study comparing in vitro toxicity levels between various anti-malarial drugs co-authored by WRAIR scientists found that tafenoquine is “more neurotoxic than mefloquine.” More recent laboratory studies have also raised doubts about the efficacy of tafenoquine, finding that the CYP2D6 enzyme is involved in metabolising the drug in several ways that affect the drug’s toxicity as well as its effectiveness as an anti-malarial. CYP2D6 levels are highly variable from person to person, which may also answer why the drug’s neurotoxic effects vary from person to person.
Emerging Evidence of Misconduct
Evidence of the misconduct documented in this series is drawn from a variety of sources, many of which are now publicly available. These include published trial reports, related journal articles, minutes of Australian Defence Human Research Ethics Committee (ADHREC) meetings, a review of ADHREC annual reports that matches approved trial protocols to published reports, media reports, and other documents from Defence, GlaxoSmithKline and the Australian Therapeutic Goods Administration (TGA). Additionally, hundreds of the trial subjects have recently formed an Australian Mefloquine and Tafenoquine Veterans group to share and publicise their personal accounts.
Several years after the AMI’s tafenoquine and mefloquine clinical trials in Timor Leste, hundreds of the ADF subjects initiated legal action against Defence, reporting that they were not adequately informed of side effects and complaining of symptoms such as depression, paranoia, and suicide ideation. When this story was first reported in the media in 2004, ADF Surgeon General Tony Austin initially claimed that the number of personnel involved in these trials was in the “dozens rather than hundreds”, however Chief of Army Peter Leahy admitted several days later that the actual number of trial subjects in Timor Leste was 1,351. The legal action was discontinued after the Australian government introduced legislation that would have required them to forfeit veterans entitlements in the event their claim succeeded. The majority of these veterans continue to experience chronic neuropsychiatric disorders including depression, anxiety, misdiagnosed PTSD, personality disorders and conversion disorders. Many of them were discharged from the ADF on medical grounds, now suffering debilitating side effects of anti-psychotic drugs prescribed off-label, and there have been a number of suicides.
The published study findings and other official ADF reports of these trials universally portray tafenoquine as a “safe” and “well tolerated” anti-malarial drug. As public scrutiny has intensified in recent months, senior Defence officials have insisted that serious neuropsychiatric side effects from tafenoquine are rare. However the disturbing truth is that the incidence of acute psychotic reactions and chronic neuropsychiatric illness attributable to the use of tafenoquine in these trials almost certainly meets the MedDRA definition of “common” (1-10%) or “very common” (>10%). There can be little doubt that the published findings of these trials constitute comprehensive scientific fraud, achieved in a number of ways that will be more fully documented in subsequent posts, including:
- Providing false and/or misleading information to the trial subjects.
- Coercing subjects into participating in the trials.
- Relying on the prevailing stigma of mental health problems to minimise subject reporting of neuropsychiatric adverse effects.
- Recording serious adverse events as “withdrawals” to avoid attributing them to the trial drug in the published study report.
- Misattributing adverse events to extraneous causes.
- Failing to include follow up medical examinations in trial protocols, to avoid recording chronic adverse effects attributable to the drug.
- Failing to publish reports for several of the ADHREC-approved trial protocols, most likely to conceal unfavourable findings.
- Failing to note known limitations in malaria reporting systems in the published study reports, resulting in over-estimations of tafenoquine’s anti-malarial efficacy.
The relevant ethical standards for the conduct of these clinical trials are laid down in the TGA’s Note for Guidance on Good Clinical Practice, which is mandated by the National Health and Medical Research Council Act. This standard describes “members of the armed forces” as vulnerable subjects “whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.” Relevant provisions in these standards include:
- “Foreseeable risks and inconveniences should be weighed against the anticipated benefit for the individual trial subject and society.”
- “The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.”
- “During and following a subject’s participation in a trial, the investigator/institution should ensure that adequate medical care is provided to a subject for any adverse events, including those related to the trial.”
- In obtaining the informed consent of trial subjects, the institution should adhere to “the ethical principles that have their origin in the Declaration of Helsinki.”
Chronology of the Tafenoquine Trials
The tafenoquine trials on ADF personnel are summarised in a 2011 PhD thesis by Dr Peter Nasveld and included:
- Bougainville (Papua New Guinea), 1999 (ADMEC protocol 165/98) – tafenoquine (vs primaquine) for terminal malaria prophylaxis (378 tafenoquine subjects).
- Unknown location, 1999 (ADMEC protocol 194/99) – tafenoquine for malaria prophylaxis in “maritime operators” (no published report found).
- Timor Leste, 2000-2001 (ADHREC 216/00) – tafenoquine (vs mefloquine) for malaria prophylaxis (492 tafenoquine subjects).
- Australia, c. 2001-2002 (ADHREC protocols 267/01 and 292/02) – tafenoquine for prevention of vivax malaria relapse (approximately 30 subjects).
Part 2 of this series will examine the emerging evidence of misconduct in the c. 2001-2002 clinical trial of tafenoquine in the treatment of recurrent vivax malaria. Subsequent posts will address the larger prophylaxis trials. These will be updated as additional evidence becomes public.
P. E. Nasveld, Tafenoquine in the prophylaxis and treatment of malaria in Australian Defence Force personnel, PhD thesis, James Cook University, 2011.
P. E. Nasveld, M. D. Edstein, M. Reid et al., Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects, Antimicrobial Agents and Chemotherapy, vol. 54, no. 2, pp. 792–798, 2010.
S. Kitchener, P. Nasveld and M. Edstein, Tafenoquine for the treatment of recurrent Plasmodium vivax malaria, American Journal of Tropical Medicine & Hygiene, vol. 76, no. 3, pp. 494-6, 2007.
P. Nasveld, S. Kitchener, M. Edstein and K. Rieckmann, Comparison of tafenpquine (WR238605) and primaquine in the post-exposure (terminal) prophylaxis of vivax malaria in Australian Defence Force personnel, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 96, no. 6, pp. 683-684, 2002.
Therapeutic Goods Administration, Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), Department of Health and Ageing, Canberra, Australia, 2000.