Antimalarial drug trials involving the ADF
This chapter considers the extent to which ADF members can provide informed
consent to participate in research, and presents information on ADF
antimalarial policy. It summarises the consent process undertaken for the antimalarial
drug trials during the late 1990s and early 2000s, as well as outlining perspectives
on the screening processes, responses to adverse events and participant follow up.
Consenting to participate in research
The ethics of human research in military populations is addressed in the
National Health and Medical Research Council (NHMRC) National Statement on
Ethical Conduct in Human Research (National Statement).
This outlines the general requirements for seeking individuals' consent to
participate in research:
...consent should be a voluntary choice, and should be based on
sufficient information and adequate understanding of both the proposed research
and the implications of participation in it.
Pre-existing relationships between prospective research participants and
those involved in facilitating or implementing the research 'may compromise the
voluntary character of participants' decisions, as they typically involve
unequal status, where one party has or has had a position of influence or
authority over the other'.
The relationship between a soldier occupying a subordinate position and their
senior officer is an example of an unequal relationship.
The National Statement suggests that an unequal relationship 'always
constitutes a reason to pay particular attention to the process through which
consent is negotiated'.
However, it is not automatically sufficient to prevent research being
undertaken, rather, 'you have to think about extra ethical considerations when
approving and conducting that research'.
Views on whether the ADF should
participate in medical research
The committee heard different perspectives on whether ADF members can truly
consent to participate in research.
Opposition to ADF participation
The participation of ADF members in research was viewed by some
submitters, such as Mr Greg Jose, as 'cruel and unethical'.
Some veterans suggested that drug trials on ADF members should be prohibited.
This was echoed by others including the Royal Australian Regiment (RAR) Association
and the wife of a veteran.
Colonel Ray Martin (Rtd) opposed mass drug trials as members cannot:
...give truly informed and voluntary consent and...drug trials
with untested or potentially harmful drugs will likely detract from operational
effectiveness of the ADF, and or produce ineffective results.
Mr Benjamin Fleming proposed 'legislation be put to parliament that
prevents the testing of drugs on deployed personnel, who, by the mere fact of
the environment they are working in, have enough to deal with'.
The submission by Associate Professor Quinn on behalf of the Australian
Quinoline Veterans and Families Association (AQVFA) further recommended that
'veterans are precluded by law from being engaged as subjects in clinical
Support for ADF participation
Other submitters argued that ADF members should not be prohibited from
participating in research, because it is vital for advancing medical science
and force protection measures, and because members should have the right to
choose and to access higher levels of care through trials. Vice Admiral David
Johnston AO, Vice Chief of the Defence Force, explained Defence needs to retain:
...the ability to conduct clinical studies for improved and
emerging medications to be evaluated to ensure they are effective and safe in
military populations. It's an accepted scientific fact that studies of
therapeutic agents need to be conducted in the population in which they will be
The committee heard from doctors and scientists who agreed, such as
Associate Professor Harin Karunajeewa, who stated that the ADF:
...has both a duty of care to protect and maintain the health
of its personnel, and a strategic imperative to maintain the fitness and
battle-readiness of its troops. It is therefore perfectly logical and ethically
appropriate that the ADF should endeavour to understand what the most effective
and safest ways are to protect its troops from the high risks of a potentially
debilitating and lethal disease...the best way to find out what works best is to
actually perform a test in the population for which the treatment is intended.
Clinical trials in the military have done a great deal to improve the health,
safety and effectiveness of soldiers throughout modern history. It is in the
best interest of all soldiers that they continue.
Based on evidence from hospitals in the United Kingdom and his own experience
conducting trials, Associate Professor Karunajeewa noted that 'clinical trial
participants are likely to receive better medical care and have better outcomes
to patients receiving routine care'.
Mr Mark Reid, coordinator of one of the trials involving the ADF, reiterated
this point and noted this trial involved the:
...only infantry battalion that has ever deployed into a
malarious area with no clinical cases [of malaria] in the field. And it wasn't
just the drugs that achieved that; it was the actual awareness of having people
there with a specific mandate of force protection under a controlled clinical
Defence rejected 'claims that informed consent is not possible in
military populations and the assertion that clinical studies should not be
conducted on these personnel'. It underscored its
support for individuals' rights to decide whether to participate or not in
research, and cautioned any constraints on research:
...must be balanced against the considerable direct benefits
that have been obtained by participants in clinical studies of novel drugs
to treat a variety of medical conditions. While some research may not infer
direct benefit to the individual, everyone has the right to choose whether or
not to participate for their own future benefit, or the benefit of others.
Considerations for future research
involving ADF members
The National Statement identifies that people in unequal relationships
'are vulnerable to being over-researched because of the relative ease of access
to them as research populations'.
Therefore, it suggested that researchers 'should take account of this
vulnerability in deciding whether to seek out members of these populations as
Similarly, a report by the Inspector-General of the Australian Defence Force
(IGADF) into issues concerning some of the trials recommended:
The ready acceptance by soldiers of advice or encouragement
provided to them by military persons in authority, combined with a potential
belief that participation in the trial was expected is an issue worthy of
further consideration in the conduct of any future medical trials, particularly
in the context of a pre-deployment for an overseas operation.
Defence noted that each time the Departments of Defence and Veterans'
Affairs Human Research Ethics Committee (DDVA HREC) examines a research
proposal it considers the issue of informed consent in military populations.
DDVA HREC is 'acutely aware' that military personnel may be vulnerable due to
their unequal relationships 'and is very stringent in its review of research
proposals to ensure that there is no coercion, real or perceived, in the
recruitment of participants from the ADF'.
Membership of the current DDVA HREC includes a contemporary veteran, Defence
health graduate, a lawyer, lay people, a pastoral care member, a civilian
clinical care provider and others with experience in the types of research
being considered by the DDVA HREC.
The DDVA HREC terms of reference establish that 'at least one third of the
members are to be external to Defence and DVA'.
The National Statement further suggests that researchers should:
...invite potential participants to discuss their participation
with someone who is able to support them in making their decision. Where
potential participants are especially vulnerable or powerless, consideration
should be given to the appointment of a participant advocate.
The committee did not hear evidence on examples of where participant
advocates have been appointed elsewhere.
AVM Tracy Smart AM recently wrote to DDVA HREC to request that it
'consider additional measures to ensure participants in clinical studies, and
particularly Phase 3 clinical trials, are fully informed of all aspects of the
studies and that there is no belief created that Command is endorsing or actively
encouraging the study'.
AVM Smart suggested initiatives could include providing a standard script to Command
and standard briefing materials to prospective participants, and having an
external agency observe, monitor, evaluate and report on the consent process.
ADF antimalarial prescribing policies and practices
Defence provided a summary of its malaria policies since 1990.
The committee heard the claim that some ADF members had been prescribed
mefloquine as a first-line antimalarial.
HoweHowever, Defence indicated that doxycycline
has been the antimalarial medication of choice for prevention since the
During the start of the trials, doxycycline was the first line antimalarial,
and mefloquine was the next option if doxycycline was contraindicated.
If both doxycycline and mefloquine were contraindicated, Atovaquone/proguanil
(MalaroneTM) was the third option. However, at that time Malarone had
not been approved for malarial prophylaxis by the Therapeutic Goods
Defence stated that its 'health policy regarding malaria has consistently
provided guidance regarding potential side effects of each antimalarial
medication, based on what was known at the time, and on reporting of adverse
Guidance on monitoring and reporting adverse effects has been 'refined and
expanded over the years'.
The committee's inquiry largely focused on mefloquine and tafenoquine. VCDF
Johnston emphasised that Defence has been cautious in its use of mefloquine,
noting it 'has always acknowledged that this drug has side effects and has
never used it as a first-line antimalarial medication'.
Tafenoquine was only registered in 2018, and, to date, Defence has only
permitted its use during the trials.
The term 'loading dose' refers to the practice of prescribing a higher
dose of a medication for a short period at the beginning of a course, before
reducing the dose to maintain the level of protection. Defence noted that:
Taking a three day loading dose at the start of a course of
mefloquine when used for prevention is standard Defence practice. A three day
loading dose was also used for those taking tafenoquine during the studies.
The committee heard that a 1985 study sponsored by the World Health
Organization found a mefloquine loading dose for the treatment of malaria
caused some mild and transient side effects, but concluded the drug was highly
effective, well tolerated and safe.
It also heard that another study
compared 250 milligrams (mg) weekly versus 250 mg daily for three days
(loading dose), and found:
...more sleep disturbances, vivid dreams and depressive
feelings in the patients who took the loading dose, which diminished over time.
The authors concluded that the loading dose should be considered as an option
for short-term travellers or military personnel...
The committee heard some concerns that ADF members took loading doses inappropriately,
including during the trials.
Defence responded that:
Mefloquine and tafenoquine both have a long half-life and
therefore it can take several weeks for sustained protective levels of the drug
to be reached. This is a problem when preparing forces for deployment at short
notice as it could mean that soldiers are unprotected for periods during the
initial deployment period. A loading dose prior to deployment achieves protective
levels more quickly... [and] allows any side effects to be identified before
deployment and for the medication to be stopped if necessary.
The product information for Lariam™ (mefloquine) in Australia does not
specifically recommend a loading dose, though the product
information for New Zealand recommends a loading dose for 'lastminute'
Mefloquine loading doses were found to be tolerable in the United States (US) Marine
Corp in the early 1990s.
Other militaries experienced malaria outbreaks when mefloquine was used during
deployment without a loading dose, including the British in Sierra Leone and
the US in Somalia.
Professor Dennis Shanks, Director of ADFMIDI, reasoned that if the ADF had not provided
loading doses it 'would be doing something that we knew had not worked
operationally at least twice instead of what we knew was tolerable based on
Period of time taking antimalarial
The committee heard concerns that some ADF members took antimalarials
for too long and negatively affected their health.
However, the American Centers for Disease Control and Prevention 'recommends
that mefloquine be started two or more weeks before entering a malarious area
and does not specify a maximum duration of treatment, judging it to be suitable
for long term prevention'.
Mefloquine had been successfully used for long periods in
Africa by the US Peace Corps prior to the Timor-Leste studies with no evidence
of long term health effects. Long term follow-up of the US Peace Corps, a
majority of whom took mefloquine, showed no serious adverse effects
attributable to the medication after more than 10 years.
Also referring to evidence from the Peace Corps, Professor James
McCarthy, Royal Brisbane Hospital and QIMR Berghofer Medical Research
Institute, noted the rate of side effects went down as people took mefloquine
Some people could not tolerate mefloquine so stopped taking it very quickly, however
another group were able to take it for a very long time without side effects.
Use of antimalarial drugs outside
At the time of the trials, mefloquine was registered by the TGA, so
personnel could take it if they had issues tolerating doxycycline, as was the
case for some submitters.
Personnel who were deployed at the time of the tafenoquine prevention trial,
but not actually participating in the trial, could choose to take doxycycline
Defence explained that '[t]he exact number of individuals who were prescribed
mefloquine during Timor-Leste deployments outside of the studies is unknown as
Defence did not have a complete electronic dispensing record until 2001'.
Excluding trial participants, 664 ADF personnel were prescribed
mefloquine from 2001 to 20 June 2018.
Prescriptions have decreased in recent years:
...on average 76 members being prescribed the drug each year
during 2001–2005, 33 members each year during 2006–2010 and 19 members each
year during 2011 to 2015. In the past two years, the figure has been five and
Current ADF antimalarial policy
Defence provided its current policy, which lists doxycycline as the
first line antimalarial, MalaroneTM second and mefloquine third.
The Defence submission indicated that tafenoquine would be considered for use
if it was registered by the TGA (as it has been), and a new
Defence policy is expected to be released in late 2018.
Details of the antimalarial drug trials
The maximum number of Defence personnel who have taken
mefloquine and tafenoquine in the ADFMIDI [ADF Malaria and Infectious Disease
Institute] studies, and the number of prescriptions of mefloquine outside of
these studies since 2001, is 3,523. It is likely that this is an overestimate
as there may be some overlap in these groups.
This 3,523 comprises a maximum of 1,983 people who took mefloquine and
1,540 who took tafenoquine.
The following table presents information on the trials, though it 'does
not include every single unit that made up the deploying Battalion Group', and
the tafenoquine 'eradication and treatment studies included personnel from a
large number of units in addition to those listed'.
Table 1: ADF antimalarial studies 1999 to 2002
||Number of participants taking antimalarial
||Tafenoquine 1017 (378/639)
|February 1999 to April 2000
|3 RAR, 5/7 RAR, others
||Tafenoquine: over 3 days either: 400mg daily; 200mg twice daily; or
in Timor-Leste only, 200mg daily
|October 2000 to April 2001
||Tafenoquine: 200mg daily for 3 days then 200mg weekly Mefloquine: 250mg daily for 3 days then 250mg weekly
||2 RAR and 4 RAR
||Mefloquine: 250mg every other day on 3 occasions, then a 250mg weekly
||Tafenoquine: 200mg daily for 3 days then 200mg weekly for 8 weeks
Sources: Defence, Submission
1, pp. 20–21; Submission 1.1, p. 8; papers listed in footnotes to
Reasons for ADF involvement
Defence indicated that the broad purpose of the trials was to consider
the use of alternatives to the standard medications in use at the time,
including primaquine and doxycycline.
Prior to the trials there were cases of relapsing malaria during deployments,
and it was not known whether this was due to compliance problems with
primaquine or if the malaria parasite was developing resistance.
Moreover, during the 1999 INTERFET operation, 64 cases of malaria were recorded
while using doxycycline, and 212 soldiers experienced the onset of malaria
after returning to Australia.
Defence noted this could have been due to poor compliance or possible
resistance to doxycycline, so sought to assess the use of other medications.
Some submitters suggested the mefloquine prevention trial was
unnecessary, as 'studies of long-term mefloquine prophylaxis had by this time
already been conducted involving military personnel...providing seemingly ample
evidence to adequately inform ADF policy'.
Compared to other militaries, 'the ADF has been conservative in its use of
and sought to define the safety and tolerability of mefloquine and assess its
effectiveness under operational conditions.
Allegations regarding conflicts of
Some submitters claimed there were conflicts of interest during the
trials, such as Associate Professor Quinn, who pointed out 'the doctors, the
medical officials and the senior ADF members who are managing that deployed
cohort are also invested in the development and delivery of a third-party
pharmaceutical-funded drug trial'.
She suggested the 'close interdependency' between organisations and:
The implicit pressures
on the AMI [Army Malaria Institute] staff carrying out the trial to deliver
positive outcomes for these agencies likely biased results an[d] resulted in
drug continuation for some participants where withdrawal from treatment was
As another example, Mrs Mary Bush told the committee that she perceived
the trials involving tafenoquine to be unethical as she alleged participants
'were used as human guinea pigs for the government's own gain, namely money and
The conduct of the trials has been scrutinised several times. It was
reported in 2015 that the chair of the ethics committee that preceded the DDVA
HREC reviewed documentation available at the time of the trials and the conduct
of the researchers.
It determined that Defence and the ethics committee applied appropriately
rigorous scientific and ethical evaluation of the trials.
The 2016 IGADF report found the trials undertaken from 2000 to 2002 in
East Timor involving mefloquine 'were conducted ethically and lawfully'.
More details on the IGADF report are included later in this chapter. In 2018,
the US Food and Drug Administration (FDA) conducted an audit of Defence's
tafenoquine trials, and 'confirmed compliance with the approved protocols and
conformity with the Declaration of Helsinki (1996) and International Conference
of Harmonisation Guidelines for Good Clinical Practice'.
The audit found 'no conclusion of impropriety' and 'no indication that good
clinical practice was not followed'.
Defence characterised the audit as representing 'a thorough, independent
validation of all aspects of the conduct of the studies'.
Allegations of misconduct were also refuted by pharmaceutical companies
and Defence. Organisations such as ADFMIDI, the US Army's Walter Reed Army
Institute of Research and Medicines for Malaria Venture (MMV) collaborate, but
Defence emphasised it does not have 'direct financial relationships with the
drug companies associated with the development of tafenoquine'.
Associate Professor Karunajeewa, who was not involved in the trials, stated:
...AMI and its members are very well-respected as scientists
and academics and their contributions to this effort are genuinely very highly
valued throughout our small community. We all do our best to co-operatively
draw on a wide variety of resources including government, academia,
public-private partnerships, non-government organizations and industry...I am not
aware of any evidence to support suggestions that clinical trials in
Bougainville and Timor Leste were ethically compromised by pecuniary interests
or collusion with the pharmaceutical industry.
In its submission, Defence noted that malaria is more prevalent in
poorer countries, so it is difficult for pharmaceutical companies to recoup the
development costs of antimalarials.
While not directly involved in the trials, the pharmaceutical company Roche
confirmed that mefloquine represents a very small portion of their business at
less than $1 million per year and less than one per cent of turnover. The
pharmaceutical company GlaxoSmithKline (GSK), sponsor of some tafenoquine
studies, emphasised that its 'aim is to make that drug available in malaria-endemic
countries at an affordable price' and reiterated that this 'is not a commercial
opportunity for GSK'.
Defence also refuted the claim that pharmaceutical companies stand to make
millions of dollars from the registration of tafenoquine, pointing out that its
global roll out will cost more than an estimated US$100 million, and probably
require continued subsidy.
The US military 'also continues to invest a great deal of money in tafenoquine
because it is required for force health protection'.
Tafenoquine was not registered for nearly two decades following the
trials, a length of time described as 'unusual' by Adjunct Professor John
Skerrit, Deputy Secretary, Health Products Regulation, Department of Health.
However, GSK explained that it initially worked with the US Army in the early
2000s, and then changed direction to focus on developing a radical cure with
MMV, noting 'a 10-year time frame to develop the medicine for that setting is
not that unusual'.
Concerns about access to research
The AQVFA expressed concerns that data from the tafenoquine prevention
trial were provided to 60P without the re-consent of trial participants.
60P responded that its use of de-identified data in regulatory dossiers and for
pharmacovigilance reporting was appropriate. The original information and
consent form signed by participants informed them that 'data collected as part
of the studies would be kept for 75 years'.
Professor Sandy McFarlane AO, Director, Centre for Traumatic Stress
Studies, University of Adelaide, raised the broader issue of how to 'allow
access to and use of data collected in Defence and DVA sponsored research
programs' to ensure it is used optimally while protecting the privacy of
The consent process during the trials
This section summarises the trial consent process, including ethics
committee approval and the provision of information and choice to prospective
participants. In its submission, Defence provided the consent forms and
information sheets for most of the trials.
Defence also provided the original and amended study protocols relating to the
tafenoquine prevention trial (study 033) as well as related documentation in
its supplementary submission.
The AQVFA provided some documentation related to the mefloquine prevention
The Australian Defence Medical Ethics Committee (ADMEC) was created in
1988 to be a committee of impartial experts responsible for ensuring trials are
'both ethically permissible and scientifically correct'.
It was called the Australian Defence Human Research Ethics Committee (ADHREC)
from 2001–2017, and then replaced by DDVA HREC. ADMEC considered research
protocols in line with a precursor to the current National Statement, the 1999
National Statement on Ethical Conduct in Research Involving Humans (National
The provisions pertinent to research involving ADF members are almost directly
the same in the 1999 National Guidelines and as the current National Statement.
ADMEC reviewed and approved the protocols for the antimalarial trials.
Disclosure of risks and provision
Providing sufficient information to prospective participants involves giving
them 'an adequate understanding of the purpose, methods, demands, risks and
potential benefits of the research'.
Some submitters suggested that though participants were provided with
information and signed consent forms, this did not constitute consent because
they did not understand the information. Lieutenant General John Caligari AO
DSC (Rtd) explained:
Informed consent for a lot of these soldiers would have been:
'Hey, it's all right for the boss. He thinks it's okay. It's in the army
newspaper. It must be okay. Someone's let them on the base to describe it. It
must be okay.'...they've probably walked in and the doctor started explaining it
to them, and they're not really listening...That's not informed consent, because
they're not listening. They don't understand what they're reading.
A veteran described that prior to the tafenoquine prevention trial they
were too focused on preparation for deployment to 'fully understand medical
terminology used or the drugs that we were being exposed to'.
Another veteran told the committee: 'Truthfully, I didn't even read it. The
sergeant just gave out a piece of paper and we all just signed it so that we [could]
go to Timor'.
Inspector-General of the Australian
Defence Force investigation
The statutory role of IGADF was established to 'provide a means for review
and audit of the military justice system independent of the ordinary chain of
In 2015, then Major Stuart McCarthy lodged a wide-ranging submission with the
IGADF alleging 'unethical, unlawful and negligent use by Defence of the
anti-malarial drug mefloquine' during the trials held between 2000 and 2002
involving members deploying to East Timor.
He claimed that Defence failed to comply with National Guidelines because
members were compelled to participate in one of the trials as a condition of
deployment and there was a lack of informed consent in both trials.
Major McCarthy's complaint also focused on the purported 'neurotoxic' effects
of mefloquine and the claim that the AMI failed to ensure prospective
participants were 'informed of the foreseeable likelihood of permanent brain
injury with long term or permanent side effects'.
Similar allegations were outlined in submissions to this inquiry from Mr McCarthy,
the AQVFA, the American Quinism Foundation and some individuals.
The IGADF concluded that Defence and AMI investigators did not accept
the claim that mefloquine caused 'mefloquine neurotoxicity'.
As noted above, the IGADF also found that the trials undertaken by the AMI from
2000 to 2002 in East Timor involving mefloquine 'were conducted ethically
and lawfully by the AMI, in accordance with the National Guidelines issued by
the NHMRC and the TGA'.
Details on the provision of information in specific trials are below.
Tafenoquine prevention trial
This trial compared tafenoquine and mefloquine. The Quinism Foundation,
led by Dr Remington Nevin, raised concerns that:
...guidance in the then-current Australian mefloquine Patient
Information to stop taking the drug and to 'tell your doctor immediately or go
to casualty at your nearest hospital' for 'change in mood, for example,
depression, restlessness, confusion, feeling anxious or nervous' do not appear
to have been communicated to subjects.
However, the consent form and information sheet stated:
Should you experience any medical problems, including
suspected side effects to the study drugs, you should report these promptly to
your Company medic, RAP or study investigator. If you want any further
information on the study, please contact the study investigator...
Fourteen witnesses were interviewed as part of the IGADF inquiry, and
while most of them 'had a limited and vague memory of the informed consent
process', almost all accepted that 'the medical briefings dealt with the
potential side effects of both drugs and that the trial was voluntary'.
The IGADF reported that participants:
...undertook a comprehensive three phase medical briefing
process culminating in a witnessed consent form being signed before a medical
officer. This process ensured that participants were aware of the potential
side effects of both drugs and that the trial was a voluntary trial, without
detriment to deployment, and they could withdraw at any time.
The IGADF was 'satisfied the trial participants were appropriately
informed by the medical investigators of the potential side effects of both
tafenoquine and mefloquine, and understood that participation in the trial was
voluntary without detriment to deployment or future career'. Lieutenant
General Caligari (Rtd) said participants were:
...individually briefed by a doctor, and a witness with the
doctor, and signed the documents after they were asked, 'Do you believe you
understand enough about the trial?' I was very satisfied with the way the AMI conducted
the introduction of everyone into the trial...There were also group sessions
that were held which I made them all attend. They received briefings on
whiteboards and PowerPoint presentations on what this drug was all about, what
the purpose of the trial was and what the possible implications of it were....every
soldier signed in front of a doctor, or at least the RAP sergeant, with a
Mefloquine prevention trial
This trial compared mefloquine and doxycycline. Mefloquine had already
been approved and registered in Australia at the time of the trial.
On direction from the ethics committee of the time, the information and consent
form for the trial were amended to 'clearly outline in quantitative terms the
side effects of the medication'.
The information on mefloquine's potential side effects provided in the 4 RAR
and 2 RAR trial medical briefings and consent form was consistent with the
detailed 1998 Lariam (mefloquine) product information.
The IGADF judged that this 'provided sufficient relevant information in
a form comprehensible to participants, to allow them to make an informed
decision whether or not to participate in the trial'.
The IGADF inquiry found:
Participants in the 4 RAR and 2 RAR mefloquine anti-malarial
drug trials received a comprehensive medical briefing, during which they were
informed of the side effects of mefloquine, that the trial was completely
voluntary, and non-participation would have no effect on deployment or career.
These aspects were reinforced at individual doctor/participant consultations
when mefloquine was prescribed to the soldiers taking part in the trial. After
the loading dose was administered in Australia and prior to deployment, the
soldier had a further opportunity to discuss any side effects with a medical
officer and to withdraw from the trial.
Some submitters recounted memories of receiving briefings about the
Tafenoquine eradication trial
This trial compared tafenoquine and primaquine. Mr McCarthy recalled
receiving a briefing from trial investigator Colonel Peter Nasveld, but noted:
...In Bougainville there was no internet. We literally wrote
letters home. We had a satellite phone there. We were given one two-minute
phone call home per week. So there was absolutely no way to check the veracity
of the information we were told.
Mr Stuart McCarthy and Mr Brian McCarthy also expressed concerns that
they had not viewed evidence that the TGA approved the export of tafenoquine to
East Timor for use by 3 RAR participants in the tafenoquine eradication trial.
Defence reiterated that tafenoquine 'was administered in accordance with ADMEC
approved study protocols and participation was voluntary'.
These personnel were briefed about the study, given a written
information sheet and the opportunity to ask questions. Those who chose
to participate then signed the study consent form and were provided a
copy. The consent form included information on their right to withdraw
from the study at any time without any consequences. Those who chose not to
participate received the standard primaquine eradication course.
A participant from 3 RAR recalled being briefed, but stated: '[d]uring
the enrolment in this clinical trial I was not examined by a doctor'.
The study requirement was for 'all individuals to be briefed and consented by a
doctor', but perhaps not physically examined as the participant appeared to
The committee understands that ADF members underwent pre-deployment medicals as
part of the usual preparation process external to the trials.
Tafenoquine treatment trial
Defence noted giving tafenoquine to 31 members with relapsing malaria 'was
not a study per se but a quality assurance activity'.
Tafenoquine was not registered at the time of the trials, so TGA approval was
required to import the medication under the Special Access Scheme.
An academic paper stated:
The proposal to conduct this treatment trial was reviewed and
approved by the [ADHREC], and each individual patient signed an informed
consent and information sheet and their treatment was approved by the
Australian Therapeutic Goods under the auspices of the Therapeutics Goods Act
(1989), Section 19(1).
Defence reiterated that participation was 'voluntary and those who
agreed to take tafenoquine to treat their relapsing malaria provided consent'.
There are two conditions for consent: the provision of sufficient
information and voluntary choice to prospective participants. Consent must be
able to be withdrawn even once the trial has started, and prospective participants
should be informed of the consequences of this as part of the consent process.
The National Statement explains that someone 'declining to participate in, or
deciding to withdraw from, research should not suffer any
The committee heard concerns that the unequal relationships within the
ADF prevented members fully exercising their right to choose whether or not to
participate in the trials. The following extract from a submission exemplifies
I was 19 years old, have been in the army for approx 7–8
months at this stage, new to the battalion and would be deploying overseas in
approx 2 month's time. Who am I to be questioning anything we are taught,
trained or advised of especially in an organisation like the Australian Defence
Force. From the moment you get off that bus at Kapooka for basic training you
now or soon learn very quickly to shut your mouth, do what you are told and
don't ask questions.
The wife of a veteran reiterated that the military 'culture doesn't
allow them [soldiers] to say no'.
Some submitters suggested even though members signed consent forms, this
could not be understood to be voluntary consent because they felt pressured to
participate. Mr Kel Ryan, National President of the Defence Force Welfare
Association, told the committee 'I suppose they've
consented, and I suppose they've agreed with it—they've been informed—but it
might be based on a degree of peer pressure'.
Mr Mark Armstrong, a veteran who did not participate in the trials, stated:
Nothing is consensual in the military. Once you sign, if
you're going to be a good soldier you say yes. You don't get a choice. If you
do, you get hammered...It's a team and you don't want to let that team down.
Lieutenant General Caligari (Rtd) shared his view that:
I don't think there is any such thing as informed consent in
the military. We do things because we are ordered to do things; we don't have
the opportunity to say yes or no to some things; we shouldn't have a say in
anything....People signed a form and that is what was considered by the trial
conductors as informed consent—which was a requirement of the human research
and ethics committee.
In contrast, Vice Admiral Johnston stated:
My view is that informed consent is available, and important,
for military people...on the general comment by General Caligari that it's
impossible to have informed consent: we exercise informed consent over a range
of our career choices, not just limited to our participation in medical
He conceded 'these people's recollections now are such that they don't
believe they were given informed consent' and 'that's very concerning'.
The IGADF found:
In compliance with
NHMRC guidelines, participants in the 2000 to 2002 anti-malarial drug trials conducted
by AMI were required to voluntarily confirm their willingness to participate in
the trial, that is, exercise a voluntary choice, after having been informed at
their level of comprehension of relevant aspects of the trial including the
risks and discomforts (side effects) associated with taking the drugs. There
were not to be any adverse consequences for failing to participate in the trial.
Details on the voluntary nature of consent in specific trials are noted
Tafenoquine prevention trial
Principal investigator Colonel Nasveld was responsible for obtaining
informed consent from participants and 'was personally present for all of it'.
He assured the committee that the consent process:
...was done according to the best practice and in fact at a
level that probably had greater rigour than that generally experienced in the
civilian community...they were consented in pairs, at matched ranks, was so there
could be no suggestion that there was coercion from a senior person because he
said yes and a junior person still had doubt. That briefing
period, that consenting period, ran over several weeks. The implication that it
was done on the spur of the moment is incorrect...I understand that many, many
years later the recollection of that 10 or 20 minutes while you're preparing to
go on your first deployment may not flag as strongly as it does with those who
have to actually deliver the consenting process. I am extremely comfortable—as
was the FDA, the TGA and our internal audits by the ethics committee—in the
He explained the regimental medical officer firstly provided an outline
of the trial as part of a briefing to companies about general health risks.
In smaller groups, members were given information and consent forms and briefed
by medical officers as part of their general health screening, which included
the opportunity to ask questions about the trial.
Members did not return their signed forms until at least two days later, to
enable them to consider their choice and consult with friends and family.
Defence has a duty of care to ensure its members are protected from
malaria when they deploy to malarious areas.
Colonel Nasveld acknowledged that ADF members would not deploy in such
situations without taking an antimalarial, but stressed that this is 'not the
same as saying, 'You must be on this study'.'
The IGADF investigated the allegation that the Commanding Officer (CO), then
Lieutenant Colonel Caligari, told 1 RAR troops they would not deploy if
they did not participate in the trial.
This claim was made in then Major McCarthy's submission to the IGADF, and in
information provided to the committee's inquiry.
Lieutenant General Caligari (Rtd) denied the allegation.
The IGADF inquiry found witnesses' 'overall memory of events surrounding
the anti-malarial drug trial, conducted during a busy pre-deployment 16 years
ago is generally poor and lacking in detail'. The
There is differing but credible evidence provided by the six
witnesses identified by MAJ McCarthy, and the former command group officers and
LTGEN Caligari concerning voluntary participation in the trial. The sufficiency
and quality of the evidence does not satisfy the required standard of proof to
make an adverse finding that the CO used the alleged words (or a similar threat
or direction) to the effect that participation in the trial was required in
order to deploy to East Timor.
ADF members did not have to participate in the trial, and could deploy
while taking other antimalarial drugs such as doxycycline. Colonel Nasveld
...we had people who would come up and say, 'Listen, I'm not
comfortable with being part of the study.' They all knew they had an option of
not being there or commencing on another antimalarial. They even had a choice of
taking any of the antimalarials that were available, having had a discussion on
what the side-effect profiles of those were.
The IGADF inquiry heard that over 400 deployed members of the battalion
group did not participate in the trial and were taking doxycycline.
It was noted that such large numbers of non-participants was not consistent
with the CO threatening that those who refused to participate would not deploy.
The AQVFA suggested that the majority of these would have been excluded from
the trial for medical or administrative reasons, because they were due to be
posted in or out of 1 RAR partway through the deployment, or because they were
not initially members of 1 RAR.
Colonel Nasveld noted that, in addition to these reasons for not participating,
some prospective participants 'basically just said no'.
According to trial records, '95 personnel were recorded as being unwilling or
unable to enrol and another 24 were excluded as they were found unsuitable on
Defence stated that '[n]o evidence has been presented that anyone was stopped
from deploying because they refused to participate'.
The IGADF report was criticised by veterans and commentators who did not accept
Mefloquine prevention trial
The IGADF noted 'investigators went to some lengths to ensure voluntary
participation', including offering soldiers opportunities to withdraw.
This 'may not have impacted on the soldiers' decision to automatically
participate', as they perceived the trial as just 'one of the many
pre-deployment matters that had to be completed in order to deploy'.
For example, Mr Fleming recalled the trial was not:
...high on my priority list with fitness and preparation for
deployment taking higher priorities. It very much sounded like it made sense at
the time, having to take one tablet a week instead of daily and in general as
soldiers we trusted that our medical support had our best interest in mind.
Nevertheless, the IGADF concluded members 'were not compelled or coerced
by command to participate in the 4 RAR and 2 RAR anti-malarial drug trials and
to take mefloquine'.
Tafenoquine eradication and
The committee did not receive as much evidence on voluntary consent for
these trials, but it appears that consent was provided.
For instance, Major Phillip Chapman (Rtd) described his experience of the
tafenoquine eradication trial:
...I was a volunteer for this trial and volunteered because the
benefits of taking Tafenoquine as a post-deployment eradication were 'sold' to
us, at the briefing for the trial (three days pre-departure for Tafenoquine),
as the being a far better option than the arduous task of taking the
alternative 'standard' 14 day post-departure eradication program.
Colonel Nasveld explained that the 'screening process was different for
each of the trials'.
Generally, ADF members could be excluded from the trials by choice or for
reasons including pregnancy, allergic reactions, enzyme G6PD deficiencies or previous
experiences of mental illness such as serious depression.
The committee heard some concerns that the mental health of prospective
participants was not checked prior to them consenting to participate. For
example, Ms Anne-Maree Baker noted '[w]e had no specific psych testing prior to
deployment as part of this trial'.
...uncovered a small number of cases of other individuals who
were included in the mefloquine studies despite having a history of mental
health issues...Defence acknowledged the error, apologised, and offered to
provide assistance to help access support services and engage with DVA.
For example, AVM Smart wrote to apologise to a veteran whose previous
history of depression was not identified prior to participating in a trial,
partly due to the reliance on paper records.
It was noted that such a situation would 'not happen today as Defence
introduced an electronic Health System in 2014 making it easier for health
providers to access documentation'.
Tafenoquine and mefloquine
Colonel Nasveld explained the tafenoquine prevention trial screening
...going into the health records and reviewing what was written
inside them. That's not to say that with doctors handwriting we might not have
missed one or two, but certainly that was the focus. That was also secondarily
checked by an audit team from USAMMDA, the United States Army Medical Materiel
Development Activity. They had independent people come over and confirm that we
were fairly well on the mark.
Mr Fleming recounted his experience prior to participating in the mefloquine
prevention trial: 'There was certainly no review of suitability to take the
medication, no examination by a doctor or medic etc other than signing the
waiver form and self-assessing your own suitability'. However,
Defence stated that each participant of that trial 'was medically assessed
prior to starting the study, during deployment and before return to Australia'.
This discrepancy may be due to the expectation that prospective participants
would have undergone a physical medical examination specifically to assess
their suitability for the trial, compared to the approach described by Colonel
Response to adverse events
The Defence submission included a summary of the adverse events
experienced by ADF members while participating in the trials.
Defence defined an adverse event as 'an untoward occurrence associated with
(but not necessarily caused by) a medication'.
These included events that had not been causally linked to the medication, for
example, trial records 'include adverse events such as 'spider bites' which are
obviously not related to the use of medication'.
Colonel Nasveld stressed that the details of any adverse events were recorded,
including when they started and ended.
Members could report:
...to the study team doctors through the structured interviews
conducted at programmed intervals during the study, or by reporting to their
supporting health element. If reported by the former, individuals were referred
to the supporting health element...If symptoms were severe and thought to be
associated with the antimalarial medication being taken, or if requested by the
individual, the medication was ceased and an alternative provided.
Adverse events reported by participants were recorded in both the study
Case Record Form to gather data for the trial, and the health treatment data
forms for individuals, which were later filed in individuals' medical
Some submitters agreed that adverse events were documented in their records,
such as Major Chapman (Rtd) and Mr King.
Some submitters claimed that adverse events were systematically
underreported during the trials. The committee heard various reasons for this,
including differing perceptions or memories of the events. For instance, Ms
Baker indicated that while the adverse events she experienced during the trial
were documented as 'mild', she felt that they should have been recorded as more
Another potential reason for the claimed underreporting was that participants
were reluctant to report their experiences. Mr Ben Whiley explained:
The minute you show any kind of weakness or anything, there's
the mental stigma and your career is over. So many guys have had to hide what
was going on to continue with their careers.
Mr Michael Kruizinga suggested that participants were unlikely to disclose
issues when they were about to deploy, go on leave or go home:
When the soldiers hit the ground back in Townsville, the
psych comes up to them and says, 'How was the deployment?' They say, 'Great,'
because they are just about to go on post-deployment leave...I think these psych
sessions were specifically designed to receive the answers that they got.
Dr Nevin posited that confusion could also cause underreporting:
...the user will confuse or misattribute side effects from the
drug to the stresses of travel, to the effects of crossing time zones and to
the effects of stress on deployment...Because of the tendency to misattribute
adverse effects from mefloquine to the environment, it's inherently unsafe to
use mefloquine and, I believe, tafenoquine, in a military environment.
Mr Kruizinga made a similar point:
Are there negative side effects? Yes. But does the soldier
equate them with the drugs that they're taking when the doctor, who tells them
that they're going to be taking these drugs, says, 'This drug is safe'? No, the
soldier doesn't. When the psych says, 'Was there anything wrong?' they say,
'No, there's nothing wrong at all,' because then the soldier's thinking: 'Maybe
it's all in my head. Maybe it's because I've been deployed. This is the first
time I deployed. Maybe it's negative side effects. Maybe I've got PTSD.
A few submitters alleged that the trial investigators themselves underreported
adverse events. Dr Nevin compared the reports of psychiatric symptoms
including abnormal dreams and insomnia in the trials to those indicated in the
most recent meta-analysis of published data, and found rates of reported
adverse events for mefloquine during the tafenoquine prevention trial were
significantly lower than those reported in the meta-analysis.
He alleged this represented 'strong and compelling evidence that adverse drug
reactions to mefloquine and tafenoquine, particularly neuropsychiatric adverse
reactions, were significantly underreported among ADF personnel by the [AMI]'.
The AQVFA also made a range of allegations of systematic underreporting of
adverse events by researchers.
For example, it raised concerns that not all instances of adverse events
identified in the tafenoquine prevention trial were reported to the TGA
However, as summarised in the next section, the committee heard that this was
because there was no clinical reason to do so as it would not change the course
of the follow up for participants, rather than due to clinical malpractice.
When asked broadly about allegations of underreporting of adverse events
by researchers, Professor Shanks, responded:
It's not true. You can't do that and get your drug
registered. The reporting of adverse events is quite detailed, and you don't
know what you're going to get till the end. These clinical research forms are
filled out as you go, and you report what you find. What that basically says is
that we've been conducting fraudulent trials. We reject that assertion and say
that the FDA and the TGA also assert that our trials were valid.
Other witnesses including Mr Reid reiterated that there was no
'underreporting of adverse events during ADF studies; and
these studies were audited by both the TGA and the FDA, including the
He noted the tafenoquine prevention trial involved a high rate of adverse
reporting when compared to other tafenoquine studies.
Details on responses to adverse events in specific trials are summarised below.
Tafenoquine prevention trial
Some participants in this trial stopped taking the trial medication in
response to adverse events.
For instance, a corporal who reported an adverse event to Mr Reid saw a
psychologist, was put on anti-depressive treatment and was taken off the study
Defence summarised the adverse events during the trial as follows:
The most common side effects of the tafenoquine prevention
study were nausea, vertigo, diarrhoea, abdominal pain, abnormal dreaming and
somnolence (drowsiness). 18 (4%) severe adverse events were recorded in the
prevention study. These were not all necessarily drug related; for example
three were injuries and six were gastroenteritis. No major side effects were
observed in the eradication study and no severe neuropsychiatric adverse events
were observed in any individuals taking tafenoquine in Defence.
Some participants taking tafenoquine experienced benign, reversible 'changes
on the surface of the eye (cornea) called vortex keratopathy'.
This did not affect participants' vision:
...and would probably not have been found if the additional eye
examination had not occurred. This reflects the high level of care afforded to the
participants of the studies.
The committee heard concerns that this finding was underreported, as
only the first five cases were reported to ADHREC, TGA and the US Army Human
Subject Research Review Board (HSRRB), rather than each of the 69 individual
The trial study protocol required that:
The [Ethics Review Committee] ERC/[Institutional Review
Board] IRB must be informed by the investigator of all subsequent protocol
amendments and of serious or unexpected adverse experiences occurring
during the study which are likely to affect the safety of subjects or the
conduct of the study'.
However, Mr Reid explained that the corneal deposits did not constitute
a Serious Adverse Event as they were 'asymptomatic findings'.
He added that a safety report was submitted to the US FDA and provided to the
TGA. He emphasised that '[t]here was no clinical reason to submit all 69
reports to ADHREC initially as this did not change the course of the individual
follow-up actions with the ADHREC, US Army HSRRB, US FDA and TGA for all
subjects for this unexpected finding'.
The study records of each of the 69 participants who were found to have
experienced the corneal deposits were updated to include the findings.
At the direction of ADHREC, the follow up was extended from 6 to 12 months.
Defence noted that the 'volunteers were subsequently followed up by an
ophthalmologist until the changes had fully resolved and all resolved within
six months of return to Australia'.
Participants were also sent a letter with information on the vortex
Tafenoquine treatment trial
Treatment was terminated early in four patients due to the finding of
vortex keratopathy in the tafenoquine prevention trial.
However, no adverse events were reported during the treatment trial, and the
medication was well tolerated.
Mefloquine prevention trial
Participants 'who did not report side effects were still questioned
about symptoms', and some received routine blood tests to check that there were
Participants experiencing significant adverse side effects:
...were examined by medical and nursing officers, the
medication was ceased, and the findings recorded while in Timor-Leste. 75
individuals (6.5%) were unable to tolerate the specific antimalarial they were
assigned and had to be switched to an alternative...
Defence stated that:
57%...of soldiers using mefloquine reported at least one
adverse event, compared with 56% using doxycycline. The most commonly reported
adverse effects of both drugs were sleep disturbance, headache, tiredness and
nausea. There were three serious neuropsychiatric events reported in people
taking mefloquine. Two of these individuals had undisclosed medical conditions
that would have prevented the prescription of mefloquine if they had been known
to medical staff.
Defence 'has only identified two instances in which members may have had
long term, continuing neuropsychiatric side effects after ceasing mefloquine,
and no cases among those who took tafenoquine'.
Defence noted that it does not have details on the ongoing health of individuals
once they leave the ADF.
The IGADF investigation found that the:
...medical support provided to the participants before, during
and following the [mefloquine and tafenoquine prevention trials] was
appropriate. There is no evidence any medical issue at the time was not
followed up with appropriate and proper medical care.
Follow up with trial participants
The AQVFA noted those who stopped participating in the trials early
'appear to have experienced little or no follow-up from the study team'.
Colonel Nasveld explained that some who withdrew 'would not have been in
location in East Timor to go through the exact rigorous follow-up'.
A submitter from 4 RAR whose file was marked 'lost to follow up' stated:
Due to my early return to Australia at no time did I have any
contact from AMI staff in regards to the trial, I had received no debrief in regards to the trial...AMI had neglected in its duty
of care to follow up on me...
AVM Smart indicated that those who withdrew due to illness 'wouldn't
have been followed up for the study purposes per se through the normal means',
but they would have been 'followed up in terms of the most appropriate medical
In addition, the committee heard varying perspectives on the adequacy of
follow up with participants who completed the trials. Defence described
participants receiving 'intense monitoring and health support' during and after
the trials, more regular health reviews and blood tests.
After the trials, participants:
...were followed up for six to 12 months from the end of the
studies, which was considered enough time for late onset side effects to
present. Participants were also given a study card that advised them and their
medical practitioner of what to do and who to contact if they were to develop
fever during or in the six months after the study.
While many submitters recalled experiencing something similar to
Defence's description, they did not perceive this to be sufficient. For
example, Mr Colin Brock reflected that the study card 'was the only thing we
received ever, in 18 years, from them'.
Details on the follow up for specific trials are outlined below.
Tafenoquine prevention trial
Mr Wayne Karakyriacos recalled undergoing tests, providing blood samples
and speaking with medics at the end of his deployment.
However, he viewed this as insufficient to address his ongoing challenges
during subsequent years, stating: 'All that time I was untreated. I not once
had Defence approach me or the AMI approach me to follow up to see how I was
going. Not once did they come back'.
Defence conveyed a different view of the adequacy of the follow up,
noting that 'personnel were monitored closely during the study and for six
Colonel Nasveld insisted the 'follow-up was conducted according to the
protocol, and that's well documented in the case record forms for all the
participants' apart from those who withdrew from the trial early.
The FDA audit only made a minor finding relating to the final telephone
follow-up of the trial. Some participants were followed up two months late,
The variance demonstrated the diligence of researchers in
continuing to conduct telephone follow-up until all study participants could be
contacted, even when outside the stated time limits of the protocol. It was acknowledged
that this was indicative of the study team personnel doing all possible to
ensure the ongoing welfare of the study participants.
The committee understands that all participants in the trial received
letters informing them that they had taken mefloquine, though 492 had taken
tafenoquine. This was corrected with subsequent correspondence.
As noted above, tafenoquine recipients were advised that some participants had
developed vortex keratopathy.
AVM Smart explained to the committee that:
...as well as the actual specific follow-up that we did as part
of the study and interactions during the study we had ongoing health
surveillance activities happening. That included post-deployment psychological
screening...conducted with proper psychological screening instruments. It is
actually designed to pick up things like PTSD and other stressors.
The '100 Club'
Approximately 100 participants were selected for additional testing and
assessment before, during and after deployment.
This included 'eye and lung function tests that were done before (within three
weeks) and after (within four weeks) deployment, and the taking of an
additional 20mls of blood'.
Several submitters described this testing, such as Mr Aaron King, who recalled
having blood, lung and eye tests.
A few submitters suggested that they were also anticipating other medical
checks that did not occur.
For example, Mr Brock underwent tests after six or seven months on deployment,
and recalled being 'told there would be follow-up tests in six months and in 12
months, but these never eventuated'.
Mefloquine prevention and
tafenoquine eradication trials
Submitters differed in their view of what adequate follow up entails.
For example, Defence indicated that follow up, including the provision of an
information card, was provided over several months following return to
However, Mr Fleming indicated that this was insufficient, recalling that a
review was not undertaken following the mefloquine trial (other than a one-page
survey), and noting that he was never spoken to by a doctor or a trial
facilitator about his experience.
Similarly, Major Chapman (Rtd) described the follow up from the tafenoquine
eradication trial as 'pretty poor', and stated:
I completed the trial documents. They were forwarded away and
that was it—I didn't hear a thing afterwards. No-one came to me and said,
'You've been reporting headaches and nausea; let's see what's going on with
it.' That was it; it was up to me to look after myself.
In contrast, Defence stated '[a]ll participants were followed up for 12
months after completion of the eradication course'.
General healthcare available to ADF
Submitters did not appear to consider general health services to count
as trial follow up:
There was no specific
test or survey conducted for soldiers with regards to assessing their mental
health following the drug trial...All soldiers returning from East Timor
conducted post screening psychology interviews but I believe this was in no way
linked to the drug trial...
Nevertheless, trial participants (including those who ceased the
trial early) would have had access to the range of healthcare services available
to ADF members. Defence detailed the comprehensive health services available to
all members (including trial participants) throughout their service careers,
return to Australia medical examinations at the end of
Return to Australia Psychological Screen (RtAPS) (questionnaire
and screening interview);
post-deployment assessments conducted three months after return
Post Operational Psychological Screening (questionnaire and
screening interview) between three and six months after RtAPS;
general GP services;
access to psychology and mental health services;
annual health assessments (prior to 2011), now periodic health
separation health assessments, including formal psychological
Following separation from the ADF, veterans can access the ADF
post-discharge GP health assessment, and other services through DVA.
The next chapter includes more information on services available to veterans.
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