Part 1 of this series provided some background to the Australian Army Malaria Institute’s (AMI) tafenoquine trials in 1999-2002, including an outline of the preceding trials and more recent laboratory studies relating to the drug’s efficacy and toxicity. This post provides a more detailed examination of the chronology of the trials and the numbers of personnel involved. During recent months senior Australian Defence Force (ADF) officials have reinforced their commitment to transparency in relation to these trials, however much of the information provided in official responses to the AMI drug trial scandal is simply incorrect, suggesting that AMI officials may be misleading senior Defence officials including the Minister for Defence.
The information provided here refers to publicly available documents on the locations of each trial and the numbers of personnel involved, in order to correct some of the misinformation provided by Defence in various media statements. This 19 February 2016 statement from Vice Admiral Ray Griggs for example claims that media reports relating to the tafenoquine trials are based on “exaggerated” figures:
The claim that mefloquine and tafenoquine was [sic] given to 5,000 Australian soldiers is exaggerated. Between July 2000 and June 2015 approximately 1,897 ADF personnel were prescribed mefloquine, most of which were part of the AMI studies in Timor Leste from 2000-2002 (1,319). Another 492 took tafenoquine during trials conducted from 2000-2001.
The Department of Defence tafenoquine information page refers to only two of the five AMI trials documented below, accounting for less than one third of the total number of ADF personnel administered tafenoquine during these trials:
The Army Malaria Institute (AMI) conducted a study of tafenoquine in ADF troops deploying to Timor-Leste in 2000 and 2001, and a smaller study in 1998/99 in soldiers deploying to Bougainville.
The ethical standards applicable to the conduct of these trials are documented in the National Health and Medical Research Council’s 1999 National Statement on Ethical Conduct in Research Involving Humans. These include the requirement for the research results to be published:
The results of research (whether publicly or privately funded) and the methods used should normally be published in ways which permit scrutiny and contribute to public knowledge. Normally, research results should be made available to research participants.
The results of three of the tafenoquine trials listed below have been published in medical-scientific journals, however the results of the remaining trials have not been published. Figures relating to those trials are drawn from other sources, including a 2011 PhD thesis by Lieutenant Colonel (Dr) Peter Nasveld.
Peace Monitoring Group, Bougainville, 1998-1999
The first documented tafenoquine study using ADF personnel as trial subjects occurred in 1998-99 among members of the Peace Monitoring Group in Bougainville, Papua New Guinea. This trialled the drug for post-exposure, terminal prophylaxis, and was approved by the Australian Defence Medical Ethics Committee (ADMEC) in 1998 (protocol ADMEC 165/98):
Evaluation of etaquine for the prevention of vivax malaria (south west pacific type) in non-immune Australian soldiers.
This study is one of the trials documented in a 2001 journal article written by authors affiliated with AMI:
In 1999, another study was started on the island of Bougainville to compare the effectiveness a 3-day course of tafenoquine and a 14-day course of primaquine for radical cure of vivax malaria. At the present time, 411 soldiers have completed the study including 201 in tafenoquine arm and 210 in primaquine arm. Seven soldiers in each arm developed vivax malaria after returning to Australia. These results indicate that tafenoquine is not superior to primaquine in preventing vivax malaria.
The conduct of the Bougainville trial and a subsequent cohort in Timor Leste (see below) is described in Chapter 4 of the Nasveld PhD thesis:
This was an open-label, randomised, parallel group study in male and female members of the Australian Defence Force who had been deployed in the Southwest Pacific. Subjects had been taking daily doxycycline as malaria prophylaxis during deployment. Three distinct cohorts were enrolled into the study – AMI 001 (Bougainville, Papua New Guinea), AMI 002 and AMI 003 (Timor Leste).
Subjects who met the entry criteria (healthy, G6PD-normal, free from malaria) were randomised to receive primaquine (PQ at 7.5 mg daily for 14 days) or tafenoquine (TQ):
• 400 mg once daily for 3 days (AMI 001 & 002)
• 200 mg twice daily for 3 days (AMI 001 & 002)
• 200 mg once daily for 3 days (AMI 003)
The numbers of trial subjects are also detailed in the Nasveld thesis, at Table 4-1, which shows that the total number of personnel administered tafenoquine in Bougainville (288 + 158) was 446.
The Bougainville study was conducted from November 1998 to September 1999, as described in the published trial report, noting that the tafenoquine figures reflected in this report total only 378 (not the 446 above):
Ethical approval was obtained from the Australian Defence Medical Ethics Committee to conduct this open design, randomized study involving 586 ADF personnel completing their 2-4 month deployments to Bougainville Island between November 1998 and September 1999. Glucose-6-phosphate-dehydrogenase deficient individuals were excluded from the study. Volunteers gave informed consent before 214 received primaquine 22.5 mg base daily for 14 d, 292 received tafenoquine 400 mg base daily for 3 d and 86 received tafenoquine 200 mg base twice daily for 3 d as post-exposure malaria prophylaxis.
These 446 Bougainville tafenoquine subjects are excluded from the figures in the above media release from Vice Admiral Griggs.
3 RAR, Timor Leste, 2000
Following the Bougainville trial, a similar trial for tafenoquine as an alternative to primaquine for terminal malaria prophylaxis was conducted with personnel from 3rd Battalion, Royal Australian Regiment (3 RAR) in February 1999. This is described in a journal article on the history of AMI:
The deployment of the ADF to Timor Leste (see above), commencing in September 1999, provided a further opportunity to assess the value of tafenoquine in another area with falciparum and vivax malaria. Volunteers from the Third Battalion, Royal Australian Regiment preparing to return to Australia following InterFET service in February 2000, were randomly allocated to receive a 3-day tafenoquine course (either 400mg or 200mg daily) or the standard 14-day primaquine course.
The numbers of personnel involved in this trial are reflected in the above table from the Nasveld PhD thesis, which shows that 406 subjects from cohort “AMI 003” were administered tafenoquine. What remains unclear is whether this trial was conducted as a continuation of the ADMEC 165/98 protocol or the ADHREC 195/99 protocol approved by the Australian Defence Human Research Ethics Committee (ADHREC) in 1999:
Evaluation of tafenoquine for the prophylaxis of malaria in
non-immune Australian soldiers.
The results of this 3 RAR trial have not been published other than in the Nasveld PhD thesis and the numbers are also excluded from the figures in the above media release from Vice Admiral Griggs.
1 RAR, Timor Leste, 2000-2001
The most well documented of the AMI tafenoquine trials occurred in Timor Leste in 2000-01, with 492 subjects from 1 RAR administered tafenoquine. This is described in the published trial report:
This study represents the first phase III trial of the safety, tolerability, and effectiveness of tafenoquine for malaria prophylaxis. In a randomized (3:1), double-blinded study, Australian soldiers received weekly malaria prophylaxis with 200 mg tafenoquine (492 subjects) or 250 mg mefloquine (162 subjects) for 6 months on a peacekeeping deployment to East Timor.
The 492 subjects from this trial appear to be those referred to in the above media release from Vice Admiral Griggs.
“Maritime Operators”, Unknown Location, 1999
Documents relating to the 1 RAR trial also assist to clarify the numbers of ADF personnel who were administered tafenoquine during previous trials. The information sheet for the participants stated that:
… tafenoquine has been given to several thousand individuals safely (including more than 1,000 ADF personnel during trials in Bougainville and East Timor) …
Assuming that these “more than 1,000 ADF personnel” include the 446 Bougainville and 406 Timor Leste 3 RAR veterans detailed above, there are more than 148 tafenoquine trial subjects unaccounted for in published trial reports or other publicly available documents.
One possible explanation for these additional personnel is a trial of tafenoquine for “maritime operators” approved by ADHREC in 1999 (ADHREC 194/99):
Evaluation of tafenoquine for the prophylaxis of malaria for maritime operators.
No published report of a tafenoquine for “maritime operators” has been identified despite an extensive literature search.
Vivax Malaria Relapse Prevention Study, Australia, 2001-02
In 2001-02 AMI conducted a study of tafenoquine in the treatment of patients with recurrent Vivax malaria, administering the drug to 31 ADF personnel. The conduct of this trial is described in the published trial report:
Tafenoquine was used to treat Plasmodium vivax malaria cases who had previously failed treatment with chloroquine and primaquine. Chloroquine was followed by a loading dose of tafenoquine (200 mg base/day for 3 days) and 200 mg a week was given for 8 weeks.
Thirty-one patients were enrolled and commenced study medication; 27 patients completed the full tafenoquine treatment. Treatment was terminated early for four patients when all tafenoquine clinical trials were suspended by the sponsor (GlaxoSmithKline) because of an unexpected adverse event (vortex keratopathy) occurring in a long-term prophylaxis trial being conducted concurrently.
ADHREC approved the conduct of this trial in 2001 (ADHREC protocol 267/01), then apparently under a revised protocol in 2002 (ADHREC protocol 292/02). These approvals featured in a recent Canberra Times article, revealing documents from the Therapeutic Goods Administration (TGA) which rescinded it’s initial approval when it was determined that Defence did not satisfy the regulatory requirements for the clinical trial:
Military doctors were initially granted full access to tafenoquine although this was overruled once the TGA realised the doctors would not comply with relevant safety regulations.
The letter, sent by the TGA’s director of drug safety Dr Leonie Hunt, told doctors they were not authorised to use the drug outside a controlled clinical environment and without the approval of a hospital ethics committee.
“It has been brought to my attention that you do not satisfy these requirements and therefore the authorisation should not have been issued,” Dr Hunt said.
“Accordingly you are no longer authorised to supply or prescribe tafenoquine for use in defence personnel for the treatment of recurrent vivax malaria.”
According to the Department of Defence, the warning was the result of “an administrative error” caused when military doctors applied for the drug under the wrong subsection of the relevant act.
A TGA spokesperson responded to the concerns raised by affected veterans by stating:
“Were the TGA to become aware that unregistered products were being supplied without obtaining appropriate exemption, the matter would be investigated.”
Based on publicly available information, there are 1,375 documented cases of tafenoquine being administered to ADF personnel during AMI clinical trials in Bougainville, Timor Leste and Australia from 1998 to 2002. When the “more than 1,000” figure from the AMI information sheet provided to 1 RAR trial participants in 2000 is taken into account, the total figure comes to more than 1,523. This is more than three times the figure provided by Vice Admiral Griggs in his media statement criticising journalists of exaggerations. Contrary to the applicable ethical standards, results of at least two trials approved by ADHREC have not been published. Defence has a long way to go if its commitment to “transparency” in relation to these drug trials is to be believed.
Part 3 of this series will examine the question of regulatory approvals for the use of tafenoquine during the AMI clinical trials. The TGA has been requested to provide documents relating to the approvals required under the Therapeutic Goods Act.
*The manufacturer of tafenoquine, GlaxoSmithKline, has requested those affected by the toxicity of the drug to contact them on 1800 033 109.*
National Health and Medical Research Council, National Statement on Ethical Conduct in Research Involving Humans, Australian Government, Canberra, 1999.
Therapeutic Goods Administration, Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95), Department of Health and Ageing, Canberra, Australia, 2000.
M. Edstein et al., Malaria prophylaxis/radical cure: recent experiences of the Australian Defence Force, Medecine Tropicale, vol. 61, no. 1, 2001.
P. Nasveld et al., Comparison of tafenpquine (WR238605) and primaquine in the post-exposure (terminal) prophylaxis of vivax malaria in Australian Defence Force personnel, Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 96, no. 6, pp. 683-684, 2002.
S. Kitchener et al., Tafenoquine for the treatment of recurrent Plasmodium vivax malaria, American Journal of Tropical Medicine & Hygiene, vol. 76, no. 3, pp. 494-6, 2007.
P. Nasveld, Tafenoquine in the prophylaxis and treatment of malaria in Australian Defence Force personnel, PhD thesis, James Cook University, 2011.
P. Nasveld et al., Randomized, double-blind study of the safety, tolerability, and efficacy of tafenoquine versus mefloquine for malaria prophylaxis in nonimmune subjects, Antimicrobial Agents and Chemotherapy, vol. 54, no. 2, pp. 792–798, 2010.
K. Rieckmann et al., Army Malaria Institute – its evolution and achievements. Fourth decade (1st half): 1995-2000, Journal of Military and Veterans’ Health, vol. 22, no. 1, 2014.
K. Rieckmann et al., Army Malaria Institute – its evolution and achievements. Fourth decade (2nd half): 2000-2005, Journal of Military and Veterans’ Health, vol. 23, no. 1, 2015.