Documents summarising or analysing data on subjects in Army Malaria Institute tafenoquine and mefloquine clinical trials during the period 1998-2002

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-----Original Message-----
From: Stuart McCarthy [mailto:[FOI #1512 email]]
Sent: Monday, 25 January 2016 00:31
To: FOI requests at Defence
Subject: Freedom of Information request - Documents summarising or analysing data on subjects in Army Malaria Institute tafenoquine and mefloquine clinical trials during the period 1998-2002

Dear Department of Defence,

During the period 1998-2002 the Army Malaria Institute (AMI) conducted clinical trials of the anti-malarial drugs in Bougainville and East Timor, which administered tafenoquine to 1,512 Australian Defence Force (ADF) personnel and mefloquine to 1,319 personnel.[1-5] These drugs are known to be neurotoxic,[6-8] able to cause permanent brain injury resulting in a range of chronic neuropsychiatric symptoms.[7-9] The Department of Defence recently advised serving and former ADF personnel affected by the neurotoxicity of these drugs "to raise their concerns with a medical practitioner so they may receive a proper diagnosis and treatment."[10]

Since August 2015 numerous serving and former ADF personnel involved in these clinical trials have requested their subject records from AMI. The Commanding Officer of AMI has replied that there have been large numbers of such requests and despite the fact that these records are held at AMI that "participant study files are being processed and released through Joint Health Command (JHC) in Canberra". Many of the trial subjects have waited months to receive their files. Given the recent media coverage, one possible reason for "processing" these files in Canberra may be to compare them with individual medical records and summarise the resulting data indicating the adverse health impacts of these drugs on ADF personnel.

I hereby request to be provided with Department of Defence documents since August 2015 that summarise and/or analyse data on subjects in AMI tafenoquine and mefloquine clinical trials during the period 1998-2002, including but not limited to:

a. Emails, minutes, memos, written briefs and/or presentations.

b. Documents that include data on the numbers of requests for AMI study files, the numbers of those who experienced adverse health effects regardless whether these were attributed to the drug, the numbers subsequently diagnosed with psychiatric, neurological and/or cardiac disorders, and/or the numbers subsequently discharged on medical grounds.

c. Documents that include consideration of follow up research or health studies of the trial subjects.

d. Documents that consider the development or implementation of diagnostic methods, clinical guidelines, treatment and/or rehabilitation for affected personnel.

Yours faithfully,

Stuart McCarthy

References:

1. P. Cleary, "Drug Trial a Test of Ethics", The Australian, 11 September 2015. http://www.theaustralian.com.au/news/inq...

2. P.E. Nasveld, S.J. Kitchener, M.D. Edstein, K.H. Rieckmann, "Comparison of Tafenoquine (WR238605) and Primaquine in the Post-exposure (Terminal) Prophylaxis of Vivax Malaria in Australian Defence Force Personnel", Transactions of the Royal Society for Tropical Medicine & Hygiene, vol. 96, no 6., pp. 683-4, 2002. http://dx.doi.org/10.1016/s0035-9203(02)...

3. N.J. Elmes, P.E. Nasveld, S.J. Kitchener et al., "The efficacy and tolerability of three different regimens of tafenoquine versus primaquine for post-exposure prophylaxis of Plasmodium vivax malaria in the Southwest Pacific", Transactions of the Royal Society for Tropical Medicine & Hygiene, vol. 102, no. 11, pp.
1095-101, 2008. http://dx.doi.org/10.1016/j.trstmh.2008....

4. P.E. Nasveld, M.D. Edstein, M. Reid et al., "Randomized, Double-Blind Study of the Safety, Tolerability, and Efficacy of Tafenoquine Versus Mefloquine for Malaria Prophylaxis in Nonimmune Subjects", Antimicrobial Agents and Chemotherapy, vol. 54, no. 2, pp. 792-8, 2010. http://dx.doi.org/10.1128/aac.00354-09

5. S.J. Kitchener, P.E. Nasveld, R.M. Gregory, M.D. Edstein, "Malaria and Doxycycline Malaria Prophylaxis in Australian Soldiers in East Timor", Medical Journal of Australia, vol. 182, no. 4, pp. 168-71, 2005. http://www.ncbi.nlm.nih.gov/pubmed/15720...

6. R.L. Agboruche, D. Yourick, D. Caridha, "In-Vitro Toxicity Assessment of Antimalarial Drugs on Cultured Embryonic Rat Neurons, Macrophage (RAW 264.7), and Kidney Cells (VERO-CCl-81)", FASEB Journal, vol. 529, no. 3, supp. 23, 2009. http://m.fasebj.org/cgi/content/meeting_...

7. R.L. Nevin, "Idiosyncratic Quinoline Central Nervous System Toxicity: Historical Insights into the Chronic Neurological Sequelae of Mefloquine", International Journal for Parasitology:Drugs and Drug Resistance, vol. 4, no. 2, pp. 118-25, 2014. http://dx.doi.org/10.1016/j.ijpddr.2014....

8. E.C. Ritchie, J. Block and R.L. Nevin, "Psychiatric Side Effects of Mefloquine: Applications to Forensic Psychiatry, Journal of the American Academy of Psychiatry and the Law, vol. 41, no. 2, pp. 224-35, 2013. http://www.ncbi.nlm.nih.gov/pubmed/23771...

9. S. McCarthy," Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence Force, Journal of Parasitology Research", vol. 2015, Article ID 368064, 2015. http://dx.doi.org/10.1155/2015/287651

10. Department of Defence, Media Release: Statement on the Use of Mefloquine in the ADF, Canberra, 30 November 2015. http://news.defence.gov.au/2015/11/30/st...

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UNCLASSIFIED

Good afternoon Mr McCarthy,

I write in regards to the five FOI requests you have recently submitted
via the Right to Know website, each of your requests was registered on
receipt in our office as follows:

208/15/16

I hereby request to be provided with the following documents relating to
the safety and ethics of ADF clinical trials of tafenoquine in
Bougainville:

a. Correspondence between the US military (particularly but not limited to
the Walter Reed Army Institute of Research [WRAIR]), ADF (particularly but
not limited to AMI) and the manufacturer GlaxoSmithKline on the toxicity
of tafenoquine, from 1998 to the present.

b. All previously unpublished studies relating to tafenoquine toxicity
held by the Department of Defence, including but not limited to
organisations within the Department (for example AMI), other military
organisations (for example WRAIR), drug manufacturers (for example
GlaxoSmithKline), academic institutions, other researchers or service
providers.

c. Documents from AMI and senior ADF medical officials to the ADF
operational chain of command proposing the conduct of the tafenoquine
clinical trial in Bougainville, the documents approving the conduct of the
trial, and those responding to AMI and other senior ADF medical officials
regarding the conduct of the trial and participation of ADF personnel
deployed on operations in Bougainville.

d. The tafenoquine clinical trial protocols proposed by AMI and those
approved by ADHREC, including the original and subsequently amended
protocols. Please note the following excerpt from Nasveld (2011, pp.
111-12):

"This study was conducted under approvals from the Australian Defence
Medical Ethics Committee – ADMEC (now known as the Australian Defence
Human Research Ethics Committee – ADHREC). The protocol and statement of
informed consent were approved by the Australian Defence Medical Ethics
Committee (ADMEC) prior to study initiation on the 5th November 1998 and
recorded as ADMEC 165/98.

"The study was conducted in accordance with Good Clinical Practice and the
Declaration of Helsinki. Two protocol amendments were made, and approved
by ADMEC for the following changes to the protocol.

"Amendment 1, approved 27th September 1999 This amendment was requested
due to a higher than expected adverse event rate. ADMEC approved the
requested change in tafenoquine dosing from 500 mg (equivalent to 400 mg
base) once a day to 250 mg (equivalent to 200 mg base) twice a day.

"Amendment 2, approved 19th April 2000

This amendment was requested because drug levels being observed were
higher than that required for 2-4 weeks protection. ADMEC approved a
further change in tafenoquine dosing from 250 mg (equivalent to 200 mg
base) twice a day to a single daily dose of 250 mg (equivalent to 200 mg
base)."[5]

e. Minutes of the ADHREC meetings relating to the conduct of AMI
tafenoquine clinical trials in Bougainville.

f. Written advice on the safety of tafenoquine provided to the trial
subjects, including but not limited to the forms used to obtain their
written consent to participate in the trials. Please note the following
excerpt from Nasveld (2011, p. 112):

"Written informed consent was obtained from each subject prior to entry
into the study. Subjects were recruited using non-coercive means and no
inducements were offered. The subjects invited to take part in the trial
were entitled to make a choice based on full and complete information
presented in a manner that was both understandable and ethnically
appropriate. The Consent Form was designed to assure the protection of the
subject’s rights. Consent was obtained from all subjects within 5 days of
the start of treatment."[5]

g. All other information provided to the trial subjects on the safety of
tafenoquine, including but not limited to presentation notes, presentation
material or leaflets, audio and/or video presentations.

209/15/16

I hereby request to be provided with Department of Defence documents since
August 2015 that summarise and/or analyse data on subjects in AMI
tafenoquine and mefloquine clinical trials during the period 1998-2002,
including but not limited to:

a. Emails, minutes, memos, written briefs and/or presentations.

b. Documents that include data on the numbers of requests for AMI study
files, the numbers of those who experienced adverse health effects
regardless whether these were attributed to the drug, the numbers
subsequently diagnosed with psychiatric, neurological and/or cardiac
disorders, and/or the numbers subsequently discharged on medical grounds.

c. Documents that include consideration of follow up research or health
studies of the trial subjects.

d. Documents that consider the development or implementation of diagnostic
methods, clinical guidelines, treatment and/or rehabilitation for affected
personnel.

210/15/16

I hereby request to be provided with the following documents relating to
the health of ADF personnel who were administered mefloquine in Somalia
and Cambodia during the period 1992-93:

a. Correspondence between the US military (particularly but not limited to
the Walter Reed Army Institute of Research [WRAIR]), ADF (particularly but
not limited to AMRU and its successor AMI) and the manufacturer Roche on
the toxicity of mefloquine, from 1992 to 2006.

b. All previously unpublished studies relating to mefloquine neurotoxicity
held by the Department of Defence, including but not limited to those
conducted by organisations within the Department (for example AMRU, AMI),
other military organisations (for example WRAIR), drug manufacturers (for
example Roche), academic institutions, other researchers or service
providers.

c. The clinical trial protocols proposed by AMRU and those approved by the
Australian Defence Medical Ethics Committee (ADMEC), including the
original and subsequently amended protocols.

d. Minutes of the ADMEC meetings relating to the conduct of AMRU clinical
trials in Somalia and Cambodia.

e. Written advice on the safety of mefloquine provided to the trial
subjects, including but not limited to the forms used to obtain their
written consent to participate in the trials.

f. All other information provided to the trial subjects on the safety of
mefloquine, including but not limited to presentation notes, presentation
material or leaflets, audio and/or video presentations.

g. Documents that refer to the adverse health effects experienced by
personnel administered mefloquine in Somalia and/or Cambodia, particularly
but not limited to neuropsychiatric health effects.

h. Documents that refer to consideration of follow up research or health
studies of the trial subjects, the conduct of those studies and/or the
results.

213/15/16

I hereby request to be provided with the following documents relating to
the health of ADF personnel who were administered mefloquine in Papua New
Guinea in 1989:

a. Correspondence between the US military (particularly but not limited to
the Walter Reed Army Institute of Research [WRAIR]), ADF (particularly but
not limited to AMRU and its successor AMI) and the manufacturer Roche on
the toxicity of mefloquine, from 1988 to 1995.

b. All previously unpublished studies relating to mefloquine neurotoxicity
held by the Department of Defence, including but not limited to those
conducted by organisations within the Department (for example AMRU, AMI),
other military organisations (for example WRAIR), drug manufacturers (for
example Roche), academic institutions, other researchers or service
providers.

c. The clinical trial protocols proposed by AMRU and those approved by
ADMEC, including the original and subsequently amended protocols.

d. Minutes of the ADMEC meetings relating to the conduct of this trial or
"evaluation" of mefloquine in 1989.

e. Written advice on the safety of mefloquine provided to the trial
subjects, including but not limited to the forms used to obtain their
written consent to participate in the trials.

f. All other information provided to the trial subjects on the safety of
mefloquine, including but not limited to presentation notes, presentation
material or leaflets, audio and/or video presentations.

g. Documents that refer to the adverse health effects experienced by
personnel administered mefloquine in Papua New Guinea, particularly but
not limited to neuropsychiatric health effects.

h. Documents that refer to consideration of follow up research or health
studies of the trial subjects, the conduct of those studies and/or the
results.

217/15/16

I hereby request to be provided with the following documents relating to
the health of personnel subjected to the 2000-01 clinical trial of
tafenoquine for the treatment of recurrent vivax malaria:

a. Correspondence between the US military (particularly but not limited to
the Walter Reed Army Institute of Research [WRAIR]), the ADF (particularly
but not limited to the Army Malaria Institute [AMI]) and the manufacturer
GlaxoSmithKline on the toxicity of tafenoquine, from 1998 to the present.

b. All previously unpublished studies relating to tafenoquine toxicity
held by the Department of Defence, conducted by organisations including
but not limited to those within the Department (for example AMI), other
military organisations (for example WRAIR), drug manufacturers (for
example GlaxoSmithKline), academic institutions, other researchers or
service providers.

c. TGA approval for the treatment of ADF personnel with tafenoquine in
this clinical trial, and any correspondence between Defence and the TGA
relating to this approval and/or the conduct of the trial.

d. The tafenoquine clinical trial protocols proposed by the investigator/s
and those approved by ADHREC, including the original and subsequently
amended protocols.

e. Minutes of the ADHREC meetings relating to the conduct of the clinical
trial.

f. Written advice on the safety of tafenoquine provided to the trial
subjects, including but not limited to the forms used to obtain their
written consent to participate in the trials.

g. All other information provided to the trial subjects on the safety of
tafenoquine, including but not limited to presentation notes, presentation
material or leaflets, audio and/or video presentations.

h. Documents relating to psychiatric, neurological, cardiac or other
health disorders in the trial subjects following their participation in
the trial, including PTSD, regardless if these were attributed to the use
of tafenoquine.

i. Correspondence between Defence and DVA relating to the health status,
health care and/or administration of the tafenoquine clinical trial
subjects.

j. Correspondence between Defence and the RMA relating to the health
status, health care and/or administration of the tafenoquine clinical
trial subjects.

Upon review of each of your requests, and in accordance with section
24(2)(b) [power to refuse request - diversion of resources etc.] of the
FOI Act, I consider that your requests should be treated as a single
request (FOI 208/15/16). After discussion with the relevant area it is
evident that all of your requests relate generally to clinical trials for
Malaria vaccines. The Office of the Australian Information Commissioner
Guidelines paragraph 3.108 also provides advice that multiple requests can
be combined as a single request under section 24(2) of the FOI Act if
there is a clear connection between the subject matter of the documents.

As mentioned above, I have contacted the area which would be responsible
for processing the majority of your now combined request. The area in
question is a very small team of around four officers at the working
level. The work involved in identifying, locating and retrieving
documents that may meet the scope of your request would in itself be an
onerous task. Furthermore, the department has only one accredited FOI
decision maker with the required specialist knowledge to consider and make
an access decision on your request, and this officer is required to
balance his responsibilities under the FOI Act as a decision maker with
his usual work duties and tasks.

Taking the above into consideration, under section 24AA of the FOI Act and
for the purposes of section 24 of the FOI Act,  I consider that a
'practical refusal reason' exists in relation to your FOI request.
Specifically, Defence considers that the work involved in processing the
request in its current form, would substantially and unreasonably divert
the resources of Defence from its other operations.

This diversion would constitute a significant drain on the resources of
the agency, and would have an unreasonable, substantial and adverse effect
in the ability of the small area to conduct their normal business.

In accordance with section 24AB of the FOI Act, Defence is required to
consult with you advising of the intention to refuse access to your
request in its current form.

In accordance with paragraph 24AB(2)(c) of the FOI Act, I am the nominated
person with whom you should contact with a view to agreeing to one of the
following options:

    a.    withdraw your request
    b.    revise your request; or
    c.    indicate that you do not wish to revise your request.

In accordance with section 24AB(9) of the FOI Act, Defence is only
required to undertake this consultation process once, and you must contact
me within 14 days to discuss.

If we have reason to correspond with you further, unless you advise
otherwise, we will correspond with you by email at:
[1][email address]

Kind regards

Theresa Stinson
Assistant Director - Media Case Management FOI
Ministerial and Executive Coordination & Communication Division

Building F065
Level 2-012
Gallipoli Barracks
ENOGGERA   QLD   4051

Ph: (07) 3332 6359

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