Australian Army Mefloquine Trials in Timor Leste 2000-2002

Were the Australian Army Malaria Institute’s 2000-2002 Mefloquine
Clinical Trials in Timor Leste Ethical?
Major Stuart McCarthy, Australian Army
October 2015
Submitted for publication
Abstract
The antimalarial drug mefloquine continues to attract controversy. Despite long standing
concerns over its neuropsychiatric side effects, being found in 2006 to be neurotoxic and
more recently to be a cause of a chronic entral nervous system (CNS) toxicity syndrome, the
drug continues to be widely used by military forces including the UK, Ireland and Canada.
Military use of mefloquine is likely to be the subject of a dedicated parliamentary inquiry in
the UK and evidence before a Senate inquiry in Australia has called into question the ethics
of clinical trials conducted by the Australian Army Malaria Institute in 2000-2002. These
trials administered mefloquine to more than 1,300 military personnel deployed on
peacekeeping operations in Timor Leste, but failed to meet applicable ethical standards which
describe military personnel as vulnerable subjects. The subjects did not provide properly
informed consent. Hundreds were coerced into participating under threat of being excluded
from the deployment and investigators provided misleading, deceptive information regarding
the drug’s side effects. Foreseeable risks of lasting or permanent CNS injury were
disregarded and there was no appreciable benefit given the availability of alternative
efficacious drugs. The safety and wellbeing of the subjects were compromised by
administering personnel deployed on military operations with a drug known to cause
neuropsychiatric side effects, without first conducting neurohistopathological testing. Proper
medical care has not been provided for subjects afflicted by chronic CNS toxicity as a result
of the trials. When the trial reports were eventually published, relevant scientific findings
regarding mefloquine CNS toxicity were omitted. According to the applicable contemporary
standards the trials were unethical.

1
Were the Australian Army Malaria Institute’s 2000-2002 Mefloquine Clinical Trials in Timor Leste Ethical?
Major Stuart McCarthy, October 2015
Introduction
The antimalarial drug mefloquine (trade name Lariam) has attracted controversy for the
incidence and severity of its neuropsychiatric side effects since its introduction.1,2 Developed
by the US military in the 1970s and initially tested on prisoners, soldiers and subjects in third
world countries, mefloquine was introduced into the marked in the late 1980s in the absence
of appropriate phase III clinical trials, but fell out of favour among civilian travellers and
clinicians by the late 1990s.2,3 In addition to reports of acute psychiatric reactions, numerous
case reports of encephalopathy and other chronic neuropsychiatric disorders linked to
mefloquine have been published since the late 1980s.2-5 Concerns over the drug’s
neurotoxicity were published by the developers in 2004,5 with veterans’ affairs authorities
raising concerns over possible chronic health impacts in the same year.6,7 In 2006 mefloquine
was found to be neurotoxic, causing permanent lesions in parts of the brain linked to its well-
documented neuropsychiatric side effects.4,8 More recently the drug was found to be a cause
of a chronic CNS toxicity syndrome characterised by a variety of neuropsychiatric disorders,4
many of which are listed by the manufacturer as “common” side effects,6,9 symptomatic of
lasting or permanent injury in parts of the brain particularly the brainstem and limbic system.4
US medical authorities have stated that mefloquine’s neuropsychiatric side effects may
confound the diagnosis and management of post-traumatic stress disorder and traumatic brain
injury,10 while Australian medical authorities have determined that the drug is causally linked
to a variety of psychiatric, neurological, vestibular and cardiac diseases5 consistent with the
pathophysiology of the chronic CNS toxicity syndrome.3,4
Despite these findings mefloquine continues to be widely used by military forces including
the UK, Ireland and Canada.5 Data from the UK Ministry of Defence recently showed that of
17,000 British military personnel administered mefloquine since 2008, 994 subsequently
required psychiatric treatment despite the stigma surrounding mental health issues in the
military.11 The House of Commons Defence Committee is considering an inquiry into use of
the drug on the grounds that “the number of cases of military personnel reporting serious
side-effects after taking Lariam is deeply disturbing,”12 while a class action law suit is
reportedly being prepared against the Ministry of Defence which may involve thousands of
British military personnel who were administered mefloquine during their service.13
Clinical trials of mefloquine in military settings have influenced policies on the use of the
drug throughout its history,2,6 including those conducted by the Australian Army Malaria
Institute (AMI), which has been directly involved in the research and development of
mefloquine since at least the 1980s.6 Two AMI trials administered the drug to more than
1,300 Australian military subjects deployed on peacekeeping operations in Timor Leste
during the period 2000-2002.14,15 A serving military officer recently testified to an Australian
parliamentary inquiry that these trials were “manifestly unethical”, stating that the AMI
investigators who had falsely portrayed mefloquine as a “safe” drug were responsible for
subsequent deaths and chronic illness among coalition military forces that continued to use
mefloquine.16 This article reviews the conduct of those trials to assess whether they met the
applicable ethical standards for human research and clinical drug trials.17,18
Background to the Clinical Trials
Mefloquine is one of a family of synthetic quinolines that includes several drugs known since
the 1940s to be neurotoxic.4,6 The Australian military was involved in the use and research of
two of these historic quinolines in the mid-late 1940s, namely pamaquine and quinacrine,
then the use of chloroquine following the Second World War.6 Mefloquine itself was

2
developed in the 1970s by the US Walter Reed Institute of Army Research (WRAIR) in
response to the emergence of chloroquine resistant P. falciparum malaria in Southeast
Asia.2,4,6 The AMI Director at the time of the trials reviewed here was involved in early
testing of mefloquine on prisoners in the 1970s19 and the institute has been directly involved
in research and development of mefloquine in cooperation with WRAIR and the
manufacturers since at least the 1980s.6
The Australian Defence Force’s (ADF’s) large scale peacekeeping deployment to Timor
Leste commencing in 1999 provided an ideal opportunity for antimalarial clinical drug trials.
The antibiotic drug doxycycline had long been used as the ADF’s first line antimalarial after
its use for that purpose was pioneered by the AMI. Mefloquine was the second line drug,
with ADF malaria policy prohibiting its use by specialist personnel such as aircrew and
divers in recognition of its neuropsychiatric side effects.6 Use of the drug as a second line
agent also acknowledged mefloquine-resistance in Asia-Pacific Plasmodium, with the AMI
Director stating in 2002 that “we have always, for many years, used doxycycline, because
Asia is where mefloquine resistance started.”20 However researchers conducting the trials
considered in this article cited numerous cases of malaria during the first five months of
Australian military operations in Timor Leste that were “believed to have resulted from poor
compliance” with the doxycycline regimen as a rationale for trialling mefloquine and
tafenoquine.14 Mefloquine was approved by the Therapeutic Goods Administration (TGA) in
1993,21 whereas tafenoquine was not approved and remains in phase III investigation.22
The AMI conducted two trials involving mefloquine in cooperation with WRAIR. The first
was a phase III randomised control trial (RCT) for the safety and efficacy of tafenoquine
prophylaxis, with mefloquine used as the comparator drug, from October 2000 to April 2001.
This trial administered 492 subjects with tafenoquine and 162 with mefloquine, on the
rationale that “mefloquine, doxycycline, and atovaquone-proguanil are … highly effective in
preventing malaria but have shortcomings that limit their effectiveness, such as adverse
effects, expense, and the difficulty of monitoring daily compliance within deployed military
populations.”14 The trial found that both drugs were safe and well tolerated,14 with the second
trial report claiming “there were requests for wider use of mefloquine from subsequent
military units and soldiers being deployed to East Timor.”15 The second trial was an open-
label, prospective study, to describe the tolerability of mefloquine malaria prophylaxis in
comparison to doxycycline, involving two contingents of soldiers deployed to Timor Leste
during the period April 2001 to May 2002. This trial administered mefloquine to 1,157
subjects on the rationale that “there are limited data on the tolerability of mefloquine for
long-term prophylaxis in military personnel.”15 Both trials were approved by the Australian
Defence Human Research Ethics Committee.14,15
Two contemporary documents established standards for the ethical conduct of clinical trials.
The first was the National Health and Medical Research Council’s (NHMRC) National
Statement on Ethical Conduct in Research Involving Humans.17 The second was the TGA
Note for Guidance on Good Clinical Practice (GCP), which “is an international ethical and
scientific quality standard for designing, conducting, recording and reporting trials that
involve the participation of human subjects.”18 The GCP specifically 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.”18 The documents establish a number of specific ethical criteria which
provide the basis for this assessment of the trials. These include the requirements for

3
informed consent by the trial subjects;17,18 weighing foreseeable risks against anticipated
benefits;18 prioritising the rights, safety and wellbeing of the trial subjects;17,18 and providing
appropriate medical care to subjects for adverse events during and following the trial.18 The
National Statement also states that the results of research and the methods used should be
published in ways which permit scrutiny and contribute to public knowledge.17
Informed Consent, Coercion and Deception
The National Statement states that “the ethical and legal requirements of consent have two
aspects: the provision of information and the capacity to make a voluntary choice.”17 While
many authors argue that the value of informed consent is that it supports individual
autonomy, the most useful explanation of informed consent is that it simply “provides
assurance that patients and others are neither deceived nor coerced.”23 Although both trial
reports in question state that the subjects provided voluntary, informed consent,14,15 there is
strong evidence that many of the subjects were in fact coerced to participate, provided with
misleading information, and deceived as to the true risks of neuropsychiatric side effects and
lasting or permanent CNS injury.
Since at least 1989 authorities including the World Health Organisation (WHO) recognised
that mefloquine’s safety profile was characterised by a predominance of neuropsychiatric
side effects.1 Yet the information provided to subjects in the first trial stated that
mefloquine’s side effects were predominantly gastrointestinal, namely “nausea, vomiting,
diarrhoea in some subjects … and mild headache”, and that the drug “has … rarely (about
1:10,000) been associated with depression and anxiety.” The subjects were informed
categorically that “tafenoquine and mefloquine are considered to be safe” (Figure 1).
Information provided to subjects in the second trial stated that neuropsychiatric side effects
had been reported “when Mefloquine is used to treat people ill with malaria especially
children less than 45kg,” at incidences of “over 1%” and “less than 1%” for various side
effects, and “fewer than 0.1% had brain damage [or] psychotic events.” The information
stated that “Mefloquine has fewer side effects than Doxycycline in trials among travellers
(including Australians)” (Figure 2). No references were provided in support of these
statements and there was no reference to previously published studies of mefloquine
prophylaxis in adults and military personnel.2-4,6
Numerous sources have reported that the commanding officer of the unit involved in the first
trial directed his subordinates to participate under the threat of being excluded from the
deployment to Timor Leste. Several years after the trial many of the participants informed the
media of their experiences of coercion,24-27 for example one soldier who stated “We were in
no doubt that if we didn’t take the Lariam we would not be going to East Timor.”24 More
recently, one senior participant reported that the commanding officer told his subordinates
that refusal to take part in the trial “means you will not deploy.”16 In 2004, 250 of the subjects
initiated a legal class action against the ADF and the manufacturer on the basis that they did
not provide informed consent and suffered chronic neuropsychiatric side effects,16,24,28 which
was later discontinued due to changes in legislation which meant that if the claimants
succeeded they would forfeit their normal veterans entitlements.29
Notwithstanding any coercion, the information provided to subjects in the first trial relating to
the risk of side effects was misleading. Although advice was given on the risk of haemolytic
anaemia for tafenoquine recipients with G6PD deficiency, gastrointestinal and “mild
headache” side effects similar in both drugs, the true risks of neuropsychiatric side effects
were minimised in the information for participants. The source of the 1:10,000 risk in relation

4
Figure 1 – Information on Risks Provided to Subjects in the Tafenoquine vs Mefloquine
Randomised Control Trial (First Trial)i
RISKS / DISCOMFORTS
There may be some bruising with blood taken from the veins in your arm.
Tafenoquine has a risk of producing a bleeding disorder if given to people who lack a
particular enzyme called G6PD. You have been tested for this enzyme prior to deployment,
and will not receive either drug if you have this deficiency. In eight previous clinical trials
involving human subjects, including studies in ADF personnel on Bougainville, tafenoquine
was noted to produce nausea, vomiting and diarrhoea in some subjects (usually self limiting
and improved by taking the medication with food) and mild headache. Similar side effects are
seen with mefloquine. In addition, mefloquine has also rarely (about 1:10,000) been
associated with depression and anxiety. Both tafenoquine and mefloquine are considered to
be safe, however, neither are recommended for use in pregnant females. Primaquine has
similar side-effects to tafenoquine including the risk of producing the bleeding disorder
related to a lack of G6PD, as described above.
Although you will be taking study medication designed to prevent malaria, there is a very
small chance that you may contract malaria while on the study. However, if you do contract
malaria you will be treated by your company medic or study investigator and followed up
until you are better.
Figure 2 – Information on Risks Provided to Subjects in the Mefloquine vs Doxycycline
Open Label Trial (Second Trial)ii
RISKS / DISCOMFORTS
There may be some bruising with blood taken from the veins in your arm.
When Mefloquine is used to treat people ill with malaria especially children less than 45kg,
side effects have been reported and recorded. These include over 1% reporting sleepiness,
insomnia, abnormal dreams, dizziness, loss of balance, headache, nausea and vomiting,
diarrhoea or abdominal pain. Less than 1% had episodes of anxiety, confusion, depression,
restlessness, forgetfulness, hallucinations and psychotic or paranoid reactions, nerve damage,
convulsions, tiredness, fever, chills, loss of appetite, rash, itchiness, hair loss, visual
disturbances, muscle weakness, cramps, muscle and joint pain, ringing in the ears, hearing
disorders, low or high blood pressure, fainting, palpitations, extra heart beats, slow heart rate,
or lowering of the clotting cells in the blood, or white cells (used for fighting infection) and
fewer than 0.1% had brain damage, psychotic events, severe hypersensitivity reactions in the
skin and heart block.
Overall, Mefloquine has fewer side effects than Doxycycline in trials among travellers
(including Australians).
Notes
iExtract of Army Malaria Institute.Information sheet: Tafenoquine 252263/033 28 September 2000; p. 3.14
iiExtract of Army Malaria Institute. Consent form protocol: Mefloquine version 1.7 2001; p. 15.15

5
to depression and anxiety is not stated, however that figure coincides with a decade-old
estimate by WHO and the manufacturer that was “crudely calculated” from a series of
assumptions early in the drug’s use, in the absence of appropriate phase III studies.1,6 Early
studies using methodologies similar to the AMI trials reviewed here had resulted in systemic
under-reporting of neuropsychiatric adverse events,6 while subsequent trials reported an
incidence of neuropsychiatric side effects including anxiety 100 times more common than
was previously reported.3,6 One study published in 1996 found that as many as 1:5
mefloquine prophylaxis users experienced symptoms of depression and anxiety.30 The
manufacturer now advises that depression and anxiety are “common (≥ 1/100 to < 1/10)” side
effects of mefloquine.9 The statement that “fewer than 0.1% had brain damage” is misleading
in that no systematic neurotoxicology studies have been undertaken to determine the
incidence of lasting or permanent CNS injury among mefloquine users. Many of the
mefloquine’s “very common” and “common” neuropsychiatric side effects are consistent
with the symptomology of toxic encephalopathies and syndromes, with recent research
suggesting that chronic mefloquine CNS toxicity may also be common.6
Similarly misleading information was provided to the subjects of the second trial, although in
this case the study design indicates that the information was deceptive rather than merely
misleading. The trial was an open-label study to describe the tolerability of mefloquine
including a comparison with doxycycline. Those enrolling in the study were advised on the
side effects of mefloquine, with those choosing not to take the drug on that advice instead
receiving doxycycline.15 The information minimising mefloquine’s neuropsychiatric side
effects relative to a 1% incidence was misleading in that similar previous military studies had
reported neuropsychiatric side effects in as many as 43% of subjects.6 The statement that
mefloquine has “fewer” side effects is misleading in that doxycycline is characterised by
gastrointestinal rather than neuropsychiatric side effects.31 In a follow-up study to similar
military trials conducted in 1992-1993, 49.6% of the mefloquine respondents reported
experiencing side effects, compared to 12.5% of doxycycline respondents. The mefloquine
respondents who attributed their symptoms to the drug reported side effects including:
vertigo/dizziness – 21.3%; visual complaints – 14.5%; memory loss – 12.7%; fatigue –
12.2%; headache – 11.8%; and concentration problems – 5.4%.[32] Further, the subjects in
the AMI trial were not advised of the foreseeable risk of lasting or permanent CNS injury
resulting from mefloquine prophylaxis,6 as opposed to merely temporary side effects. Overall
this information was deceptive because it influenced the subjects to participate in the study
and “choose” mefloquine over a safer drug, thereby exposing them to a foreseeable but
undisclosed risk of lasting or permanent CNS injury with chronic rather than temporary
neuropsychiatric side effects.
Foreseeable Risks versus Anticipated Benefits
Both the National Statement and GCP emphasise that foreseeable risks of harm to
participants should be weighed against the anticipated benefits of the study.17,18 By the early
1990s mefloquine was known to accumulate in the human brain following prophylaxis,3,4,6
and a study of the effect of mefloquine on calcium homeostasis suggestive of CNS toxicity
had been published in 1996.33 Several years after the trials mefloquine was found to be
neurotoxic8 and more recently was found to be a cause of a chronic CNS toxicity syndrome3,4
which may be common among mefloquine prophylaxis users.6 A recent review of the
historical, clinical, pharmacoepidemiological and neuropharmacological evidence of
quinoline and mefloquine toxicity, including the AMI’s direct involvement in the research
and development of the drug, found that this risk was foreseeable.6 At the time of the trials

6
there was also strong evidence that the use of tafenoquine prophylaxis posed a similar risk of
lasting or permanent CNS injury, including extensive neurohistopathological studies of the 8-
aminoquinolines dating back to the 1940s that found many of those drugs to cause similar
CNS injury to that caused by mefloquine.4,6,34-39 These foreseeable risks were disregarded in
the AMI trials.
The claimed benefits of the first trial relating to the adverse effects and compliance of
alternative drugs were questionable at best. Doxycycline and atovaquone-proguanil do not
present a realistic risk of neurotoxicity and there is no clear evidence that weekly
chemoprophylaxis regimens provide greater compliance than daily regimens. The comparator
drug mefloquine is from the same class of drug as the study drug tafenoquine, long known as
a class for its neurotoxic properties, and the specific risk of mefloquine causing lasting or
permanent CNS injury was foreseeable.6 The rationale for the second trial, that there was
limited data on the tolerability of mefloquine for long-term prophylaxis in military personnel,
was simply false. Numerous studies of long-term mefloquine prophylaxis had been conducted
involving military personnel, including similar operational settings, indeed some of the
previous studies had incorporated more rigorous methodologies involving standardised
neuropsychometric testing or follow-up studies that were absent from the AMI trials.6 Since
the trials doxycycline has remained the ADF’s first line antimalarial, atovaquone-proguanil
has replaced mefloquine as the second line drug,6 and tafenoquine remains in phase III
investigation almost 15 years later.22
Given the close association between AMI and WRAIR, one possible undisclosed rationale for
the trials may have been to support continued use of mefloquine as a first line antimalarial in
the US military. By the time of the AMI trials in Timor Leste, according to at least one
former senior WRAIR official the US military had become concerned that the manufacturer
would withdraw mefloquine from the market due to growing reports of severe side effects
and resulting law suits. US officials reportedly promised the manufacturer to continue to
support the use of mefloquine,39 which continued to be used as a first line antimalarial in the
US military until 2009 despite having been found to be neurotoxic and being implicated in
numerous murders, suicides and other acts of violence.2-4
Rights, Safety and Wellbeing of the Trial Subjects
The GCP states that “the rights, safety, and well-being of the trial subjects are the most
important considerations and should prevail over interests of science and society.”18 ADF
malaria policy prohibiting the use of mefloquine by aircrew and divers6 partially reflected
safety guidelines from WHO and the manufacturer a decade earlier that “persons operating
machinery and those requiring fine coordination (e.g. airline pilots) should not take
mefloquine prophylaxis.”1 A more prudent application of the same guidelines by the ADF
would logically have excluded all personnel operating vehicles, machinery and loaded
firearms authorised to use lethal force during military deployment such as the operation in
Timor Leste. Regardless of any long term health considerations, standardised
neuropsychometric testing which had been incorporated into previous mefloquine studies to
assess temporary neuropsychiatric side effects6 were not included in the AMI trials in Timor
Leste. This misapplication of long established safety guidelines alone illustrates a failure to
uphold the safety and wellbeing of the trial subjects.
In addition to reinforcing that a human research proposal must demonstrate that the research
is justified, the National Statement points out that it must be “based on a thorough study of
current literature as well as prior observation, approved previous studies, and where relevant,

7
laboratory and animal studies.”17 Although the first trial included detailed safety assessments
of hematological and blood chemistry parameters, phospholipidosis, methemoglobin and QT
interval,14 neither trial incorporated appropriate safety measures to address the foreseeable
risk of lasting or permanent CNS injury posed by mefloquine or tafenoquine. Temporary
neuropsychiatric side effects were assessed during the trials using a combination of self-
reporting and physician interview,14,15 without appropriate neurotoxicological assessment of
chronic side effects during or after the trials.6 Extensive neurohistopathological studies in the
late 1940s, by researchers who were subsequently involved in the development of
mefloquine,40 had found many of the similar quinolines to cause lasting CNS injury in animal
models34-38 consistent with the previously reported symptoms of mefloquine and tafenoquine
prophylaxis.3,4,6 However no such neurohistopathological testing on animal models was
conducted by the AMI prior to exposing the trial participants to long-term use of these drugs.
Inadequate Medical Care Following the Trials
Although the subjects were provided with medical care during the trial, the GCP states that
“the investigator/institution should ensure that adequate medical care is provided to a subject
for any adverse events” both “during and following a subject’s participation in a trial
[emphasis added].”18 The 2006 findings of mefloquine neurotoxicity and recent findings of a
mefloquine induced chronic CNS toxicity syndrome, consistent with the neuropsychiatric
side effects reported in the AMI and other clinical trials, logically warrant a dedicated
program to re-assess the health of the participants and provide necessary medical care.4,6
Recent calls for the ADF to implement such a program have been rejected by senior officials
including the Assistant Minister for Defence, on the basis that this would cause “unnecessary
distress” to the participants. Department of Defence sources have reported that the ADF’s
reluctance to provide this medical care “appears to be designed to protect the reputation of
senior officers.”16
Omission of Relevant Scientific Findings from the Published Trial Reports
According to the National Statement the results of research and methods used should be made
available to research participants and be published in order to allow proper scrutiny.17 Both of
the trial reports concluded that mefloquine and tafenoquine were safe and well tolerated,
without having used appropriate methodologies to investigate foreseeable risks of lasting or
permanent CNS injury. Published in 2005, the report of the second trial makes several key
omissions relating to mefloquine safety. Numerous case reports had been published since the
late 1980s linking encephalopathy and chronic neuropsychiatric disorders with mefloquine
prophylaxis3,4,6 and in 2004 researchers associated with WRAIR begun to study possible
replacement quinolines in recognition that the clinical potential of mefloquine had been
compromised by neurotoxicity.5 The first trial report, published in 2010 almost a decade after
the trial, makes the same and additional omissions. WRAIR and independent researchers
found in a series of studies during the mid-2000s that mefloquine was neurotoxic in animal
models and human neuronal cell lines,8,41-44 at concentrations equivalent to those previously
found in the human brain following mefloquine prophylaxis.3,4,6 These were publicly
acknowledged by the U.S. Army in 2006, when it solicited private industry for proposals to
research mefloquine neurotoxicity, acknowledging:
Unfortunately, as many as 25% of individuals taking mefloquine at prophylactic doses
(250 mg per week) … experience neurological or psychiatric adverse effects.
[Previous studies into the] effects in humans, form a growing body of evidence of a
biological basis of mefloquine neurotoxicity.40

8
A number of 8-aminoquinolines similar to tafenoquine had also been found to cause lasting
CNS injury in neurohistopathological studies on animal models in the 1940s.4,6,34-38
Notwithstanding the ethics of the AMI trials, the published reports falsely conclude that
mefloquine and tafenoquine are safe drugs by omitting these findings.
Conclusion
Assessed against the applicable, contemporary ethical standards for human research and
clinical trials, the AMI’s 2000-2002 trials in Timor Leste using ADF personnel as subjects
were clearly unethical. The subjects did not provide properly informed consent but instead
were coerced into participating and provided with misleading or deceptive information.
Foreseeable risks of lasting or permanent CNS injury were disregarded and there was no
appreciable benefit given the availability of safer alternatives. The safety and wellbeing of the
subjects were compromised by administering a drug known to cause neuropsychiatric side
effects, without conducting appropriate testing before or during the trials. The ADF has thus
far failed to meet its obligation to provide proper medical care for subjects experiencing
chronic adverse effects from the drugs administered during the trials. Finally, relevant
research relating to the toxicity of mefloquine and tafenoquine omitted from the trial reports
that conclude both drugs are safe.
The implications of these unethical trials go beyond the welfare of the trial participants or the
use of mefloquine specifically in the ADF. These and similar trials in military settings which
found mefloquine to be a safe despite methodological shortcomings, provided a basis for the
continued use of the drug by hundreds of thousands of US, UK, Canadian and other troops in
Iraq, Afghanistan and other operational theatres. The full extent of resulting chronic illness
among those troops is not yet known but is likely to be significant, including probable
misdiagnosis in many individuals with of post-traumatic stress disorder, traumatic brain
injury and similar prevalent illnesses. This case should provide renewed impetus for
institutional ethics committees and review boards to conduct more rigorous oversight of
human research activities using vulnerable subjects, particularly those involving preventive
drugs with neuropsychiatric side effects.
References
1. World Health Organisation and F. Hoffmann-La Roche. Review of the Central Nervous System Adverse
Events Related to the Anti-malarial Drug, Mefloquine (1985-1990) (WHO/MAL/91.1063). Geneva:
World Health Organisation 1991. [Link]
2. Croft AM. A lesson learnt: the rise and fall of lariam and halfan. J R Soc Med 2007;100(4):170-4 doi:
10.1258/jrsm.100.4.170. [PubMed]
3. Ritchie EC, Block J, Nevin RL. Psychiatric side effects of mefloquine: applications to forensic
psychiatry.J Am Acad Psychiatry Law 2013;41(2):224-35. [PubMed]
4. Nevin RL. Idiosyncratic quinoline central nervous systemtoxicity: historical insights into the chronic
neurological sequelae of mefloquine. Int J Parasitol Drugs Drug Resist 2014 Apr 5;4(2):118-25.
[PubMed]
5. Dow GS, Koenig ML, Wolf L, et al. The antimalarial potential of 4-quinolinecarbinolamines may be
limited due to neurotoxicity and cross-resistance in mefloquine-resistant plasmodium falciparum strains.
Antimicrob Agents Chemother 2004;48(7):2624-32 doi: 10.1128/aac.48.7.2624-2632.2004 [accepted: 3
March 2004]. [PubMed]
6. McCarthy S. Malaria prevention, mefloquine neurotoxicity, neuropsychiatric illness and risk-benefit
analysis in the Australian Defence Force. J Parasitol Res. 2015; 2015: 287651. [Link]
7. Hamerschlag AS. Under Secretary for Health’s Letter: Possible Long-Term Health Effects from the
Malarial Prophylaxis Mefloquine (Lariam) (IL 10-2004-007). Washington,DC: US Department of
Veterans’ Affairs 23 June 2004. [Link]

9
8. Dow G, Bauman R, Caridha D, et al. Mefloquine induces dose-related neurological effects in a rat model.
Antimicrob Agents Chemother 2006;50(3):1045-53 doi: 10.1128/AAC.50.3.1045-1053.2006 [accepted:
18 November 2005]. [PubMed]
9. Roche. Lariam (Mefloquine Hydrochloride) Product Information 141107, Dee Why,NSW: Roche
Products (Australia) 12 November 2014. [Link]
10. Magill AJ, Forgione MA, Maguire JD, Fukuda MM. Chapter 8: Special considerations for US military
deployments. In: Health Information for International Travel. Atlanta: Centers for Disease Control and
Prevention 2014.
11. Owen J. Soldiers still suffering serious mental illness linked to controversial anti-malarial drug Lariam.
The Independent 28 November 2014. [Link]
12. Lewis J. Lariam. London: House of Commons Defence Committee 8 September 2015. [Link]
13. Giannangeli M. Thousands to sue MoD over anti-malaria drug. Sunday Express 6 September 2015.
[Link]
14. Nasveld PE, Edstein MD, Reid M, et al. Randomized, double-blind study ofthe safety, tolerability, and
efficacy of tafenoquine versus mefloquine for malaria prophylaxis in non-immune subjects. Antimicrob
Agents Chemother 2010;54(2):792-8 doi: 10.1128/aac.00354-09 [published online: 7 December 2009].
[PubMed]
15. Kitchener SJ, Nasveld PE, Gregory RM, Edstein MD. Mefloquine and doxycycline malaria prophylaxis
in Australian soldiers in East Timor. Med J Aust 2005;182(4):168-71. [PubMed]
16. Cleary P. Drug trial a test of ethics. The Australian 11 September 2015. [Link]
17. National Health and Medical Research Council. National Statement on Ethical Conduct in Research
Involving Humans. Canberra, ACT: Commonwealth of Australia, 1999. [Link]
18. Therapeutic Goods Administration. Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95).
Canberra, ACT: Department of Health and Ageing 2000. [Link]
19. Rieckmann KH, Trenholme GM, Williams RL, et al. Prophylactic activity of mefloquine hydrochloride
(WR 142490) in drug-resistant malaria. Bull World Health Organ 1974;51(4):375-7. [PubMed]
20. Staff reporter. Malarial malaise underprobe. Sydney Morning Herald 19 September 2002. [Link]
21. Therapeutic Goods Administration. Public summary for ARTG Entry 43321: Lariam mefloquine 250mg
(as hydrochloride) tablet blister pack. Canberra, ACT: Department of Health and Ageing 19 November
2014. [Link]
22. GlaxoSmithKline. Press release: GSK and MMV announce start of phase III programme of tafenoquine
for Plasmodium vivax malaria. 24 April 2014. [Link]
23. O’Neill O. Some limits of informed consent. J Med Ethics 2003;29(1):4-7 doi: 10.1136/jme.29.1.4
[accepted: 23 September 2002]. [PubMed]
24. McIlveen L, McPhedran I. 1300 troops took ‘guinea pig’ drug. The Sunday Mail 31 October 2004.
25. AAP. Only five adverse effects reported: Defence. The Age 24 October 2004. [Link]
26. AAP. Australian soldiers were drug ‘guinea pigs’. Sydney Morning Herald 24 October 2004. [Link]
27. Staff reporter. Defence confirms drug made soldiers sick. ABC News 24 October 2004. [Link]
28. Burton B. Australian army faces legal action over mefloquine. BMJ 2004;329(7474):1062 doi:
10.1136/bmj.329.7474.1062-b [published: 4 November 2004]. [PubMed]
29. Black S. Questions remain over anti-malaria drug Lariam. Crikey 28 June 2006. [Link]
30. Corbett EL, Doherty JP, Behrens RH. Adverse events associated with mefloquine. Study in returned
travellers confirms authors’findings. BMJ 1996;313(7071):1552 doi: 10.1136/bmj.313.7071.1552b
[published online: 14 December 1996]. [PubMed]
31. Tan KR, Magill AJ, Parise ME, et al. Doxycycline for malaria chemoprophylaxis and treatment: report
from the CDC expert meeting on malaria chemoprophylaxis. Am J Trop Med Hyg 2011;84(4):517-31
doi: 10.4269/ajtmh.2011.10-0285 [published online: 1 April 2011]. [PubMed]
32. De Vries M. Unexplained somatic symptoms in Cambodia veterans: the role of mefloquine, multiple
vaccinations and morbidity. Nijmegen, Netherlands: Katholieke Universiteit Nijmegen, 2002. [Link]
33. Lee HS, Go ML. Effects of mefloquine on Ca2+ uptake and release by dog brain microsomes. Arch Int
Pharmacodyn Ther 1996;331(3):221-31. [PubMed]
34. Smith CC, Schmidt LH. Studies on the 8-aminoquinolines; on the relations between structure and
pharmacological activities. Fed Proc 1947;6(1):372. [PubMed]
35. Schmidt LH, Smith CC, et al. Studies on the 8-aminoquinolines; the toxicities of pamaquine and
plasmocid in different animal species. Fed Proc 1947;6(1):369. [PubMed]
36. Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines; lesions in the central nervous system
of the rhesus monkey induced by administration of plasmocid. J Neuropathol Exp Neurol 1948;7(4):368-
98. [PubMed]

10
37. Schmidt LH. The relations between chemical structure and toxicity among the 8-aminoquinolines. In:
First Symposium on Chemical-Biological Correlation, May 26-27, 1950. Washington,DC: National
Academy of Sciences-National Research Council 1951: 181–190. [Link]
38. Schmidt IG, Schmidt LH. Neurotoxicity of the 8-aminoquinolines. III. The effects of pentaquine,
isopentaquine,primaquine, and pamaquine on the central nervous systemof the rhesus monkey. J
Neuropathol Exp Neurol 1951;10(3):231-56. [PubMed]
39. Weaver C (reporter). News now. Voice of America Radio 17 May 2001. [Link]
40. Schmidt LH, Crosby R, Rasco J, Vaughan D. Antimalarial activities of various 4-quinolonemethanols
with special attention to WR-142,490 (mefloquine). Antimicrob Agents Chemother 1978;13(6):1011-30.
[PubMed]
41. Dow GS, Hudson TH, Vahey M, Koenig ML. The acute neurotoxicity of mefloquine may be mediated
through a disruption of calcium homeostasis and ER function in vitro. Malar J 2003;2:14 doi:
10.1186/1475-2875-2-14 [published online: 12 June 2003]. [PubMed]
42. Dow GS, Caridha D, Goldberg M, et al. Transcriptional profiling of mefloquine-induced disruption of
calcium homeostasis in neurons in vitro. Genomics 2005;86(5):539-50 doi: 10.1016/j.ygeno.2005.07.004
[published online: 18 August 2005]. [PubMed]
43. Caridha D, Yourick D, Cabezas M, et al. Mefloquine-induced disruption of calcium homeostasis in
mammalian cells is similar to that induced by ionomycin. Antimicrob Agents Chemother 2008;52(2):684-
93 doi: 10.1128/AAC.00874-07 [published online: 12 November 2007]. [PubMed]
44. Hood JE, Jenkins JW, Milatovic D, et al. Mefloquine induces oxidative stres s and neurodegeneration in
primary rat cortical neurons. Neurotoxicology 2010;31(5):518-23 doi: 10.1016/j.neuro.2010.05.005
[published online: 24 May 2010]. [PubMed]
45. U.S. Army. Neurotoxicity Associated with Mefloquine, an Anti-Malarial Drug: Small Business
Technology Transfer (STTR): Solicitation Topic Number A06-T034 (Army). Washington,DC: U.S.
Army Research Office 2006. [Link]

Australian Army Mefloquine Trials in Timor Leste 2000-2002

Recommended

Recommended

More Related Content

Similar to Australian Army Mefloquine Trials in Timor Leste 2000-2002

Similar to Australian Army Mefloquine Trials in Timor Leste 2000-2002 (20)

More from Wendy.J. Seymour

More from Wendy.J. Seymour (10)

Recently uploaded

Recently uploaded (20)

Australian Army Mefloquine Trials in Timor Leste 2000-2002