Roll of Honour – Corporal Scott Smith

Lest we Forget


Canadian Flag

Corporal Scott Smith, 5 May 1971 – 25 December 1994

_20170603_163850

Scott Smith, Canadian Airborne Regiment


Posted in Our Stories, Roll of Honour | Tagged , , , | Leave a comment

Featured Research – R. L. Nevin and E. C. Ritchie, Service-Connected Disability Claim for Chronic Neuropsychiatric Adverse Effects From Mefloquine

“In 2014, a 56-year-old nondeployed U.S. Marine Corps veteran submitted a claim to the VA for disabling conditions. The veteran alleged these conditions were due to his exposure to mefloquine while in military service more than 2 decades earlier. The veteran enlisted in 1975 and experienced a motor vehicle accident with prolonged loss of consciousness in 1978 but had no other significant medical history.

“Thirteen years later, stationed in Hawaii in 1991, he was encouraged to volunteer for a double-blinded postmarketing study, evaluating the adverse effects (AEs) of chloroquine and mefloquine. As documentation following the trial revealed, he was randomly assigned to the mefloquine arm and received a loading dose of 250 mg daily for 3 days, followed by 250 mg per week for 11 weeks.

“During the study he experienced insomnia, abnormal dreams, and nightmares. He also developed symptoms of anxiety, depression, cognitive dysfunction, and changes in personality—including anger and irritability—that were severe enough to be noted by his family members. The patient had not been advised of the significance of these symptoms and therefore did not report them during the clinical trial, nor did he report their intermittent presence after the study’s conclusion through his retirement in 1996, fearing adverse career consequences. Subsequent exacerbations of these chronic symptoms later contributed to the patient’s loss of civilian employment in 2010.

“After becoming aware of the 2013 boxed warning that these chronic symptoms could be due to his earlier exposure to mefloquine, the veteran sought evaluation by a VA clinician. On evaluation, the clinician noted no history of deployment, and no history of posttraumatic stress disorder (PTSD) criteria A stressors, and posited that the veteran’s chronic neuropsychiatric symptoms were most likely a consequence of his earlier use of mefloquine. The VA subsequently awarded the veteran 50% disability for an anxiety disorder characterized by chronic sleep impairment and frequent panic attacks, attributing these to his service-connected use of the drug.”

_20170109_100809

R.L. Nevin and E.C. Ritchie, FDA Black Box, VA Red Ink? A Successful Service-Connected Disability Claim for Chronic Neuropsychiatric Adverse Effects From Mefloquine, Federal Practitioner, vol. 33, no. 10, October 2016.

Posted in Clinical Drug Trials, Our Stories, Research | Tagged , , , , , , , | Leave a comment

Stuart McCarthy – Disband the Army Malaria Institute and Prohibit Drug Trials on Australian Troops

The anti-malarial drug trial scandal that has embroiled the Australian Defence Force for the last two years simply won’t go away, despite the government’s best efforts to whitewash the controversy with a flawed “military justice” inquiry.

There are growing calls for a public inquiry to investigate ethical breaches which occurred during a series of Army Malaria Institute (AMI) clinical trials conducted in Bougainville and Timor Leste from 1999 to 2002.

The drugs in question are mefloquine, a neurotoxicant able to cause a “lasting or permanent” brain injury in a sizeable minority of users, and the experimental drug tafenoquine. The latter was found to be “more neurotoxic than mefloquine” by scientists from the US military research institute which developed both drugs.

Tafenoquine was given to more than 1,500 ADF personnel during these trials, while mefloquine was used on 1,300 personnel. Mefloquine has probably been given to an additional 2,000 personnel since its introduction in the early 1990s.

Hundreds of Australian veterans have since been diagnosed with serious neurological and psychiatric disorders, often mistaken for post-traumatic stress disorder. Many maintain they were compelled to participate in the trials. The Department of Veterans Affairs (DVA) has belatedly launched a health outreach program, admitting that the first cases “could be the tip of the iceberg”.

Media attention has to date focused on the health concerns of those affected and the ethical question of whether the subjects provided fully informed consent.

Yet a deeper question is emerging, namely a fundamental conflict between the commercial interests of the pharmaceutical industry and the public interests of the ADF. This could even result in criminal charges against ADF medical officials who conducted the trials and now hold senior military appointments.

How could the ADF leadership have allowed this to happen?

Mefloquine and tafenoquine are both products of the US Walter Reed Army Institute of Research (WRAIR) anti-malarial drug discovery program which commenced during the Vietnam War. The results of early military tests of mefloquine were given to the manufacturer Roche in one of the first public-private partnerships of its kind. These questionable results were then used to shortcut the approvals process by the US Food and Drug Administration (FDA) and other regulators.

By the late 1990s mefloquine was well known for its serious side effects and fell out of favour to the extent it is no longer manufactured by Roche in many countries. Linked to numerous war crimes, murders and suicides over the last 15 years, mefloquine is now banned or regarded as a drug of last resort.

Tafenoquine is already repeating this tragic history, with the direct involvement of WRAIR and the closely affiliated AMI.

The ADF’s deployments to Bougainville and Timor Leste provided an ideal opportunity for AMI and WRAIR to conduct large-scale drug trials on a captive pool of “volunteers”. Tafenoquine and mefloquine were tested on almost every battalion of the Royal Australian Regiment. The results of several of these trials have not been published, presumably because they were unfavourable.

Of the reports that were published, none commented on the serious adverse effects that emerged from the trials. One report that was published found there was “no statistical difference” between tafenoquine and mefloquine in the rate of neurological and psychiatric side effects. Many of the subjects are to this day admitted to psychiatric hospitals or have subsequently suicided — yet the ADF has refused to conduct follow up health studies.

A co-author of the published study has been stonewalling the proposed outreach program for years. Recently, he falsely informed doctors involved in the outreach program that there were “no recorded neuropsychiatric side effects” from tafenoquine; contrary to his original report which found one in eight of his subjects experienced such side effects.

The results of this trial were re-analysed in a 2014 paper co-authored by the current Director of AMI to find that tafenoquine is 100% effective in preventing malaria. The lead author of this paper is a former WRAIR employee who now owns a niche pharmaceutical company awarded a contract by the US Army to develop the drug for registration with both the FDA and the Australian Therapeutic Goods Administration. Should the FDA approve, his company would be given a tradeable “priority review voucher” worth several hundred million dollars.

In the 1990s the Canadian government responded to a similar scandal involving an unlawful mefloquine drug trial on peacekeeping troops in Somalia by disbanding the regiment that was subjected to the experiment.

On the evidence already publicly available, a more appropriate response from the Australian government would be to disband AMI and prohibit the conduct of clinical drug trials on ADF personnel deployed on military operations. The ADF is clearly incapable of providing the corporate oversight needed to protect the interests of its troops against those of the pharmaceutical industry.

Stuart McCarthy is an Australian Army officer who served in Afghanistan, Iraq, Ethiopia & Eritrea, and Bougainville. He is undergoing rehabilitation for an acquired brain injury after being exposed to mefloquine and tafenoquine.

*This article was first published in The Spectator Australia on 28 December 2016.

Posted in Advocacy, Clinical Drug Trials, Research | Tagged , , , , , , , , , , , , , , , , , , , | Leave a comment

Nebojsa ‘Vic’ Zlatanovic – Congress, Peanuts & Mefloquine

In a November 9th letter to the Pentagon and the Department of Veterans Affairs, Senator Bob Menendez (D-NJ) urged them to create a registry to monitor the long-term health of veterans who took mefloquine, a once-weekly anti-malarial that the Food and Drug Administration has warned can heighten the risk of schizophrenia.

Ever the optimist that I am, I think this letter is a positive step in the right direction, since a registry is necessary to compile enough data to study the long-term effects of mefloquine exposure and to form smart policy to address any problems arising from its use. Unfortunately, it’s slow going in the United States Congress. Rep. John Carter (R-TX) had introduced an amendment to the House version of the defense bill. When there are differences in proposals between the House and Senate, a conference committee is formed to hash out a compromise.

The conferees tossed the House mefloquine provision out. Despite this, the conferees noted that they were “concerned” that “mefloquine may produce serious neuropsychiatric side effects such as depression, auditory and visual hallucinations, anxiety, and suicidal ideation.” Continuing, they wrote that “[t]he conferees urge the Department of Defense to limit the prescription of mefloquine to those servicemembers who may be unable to take other first-line anti-malarial drugs.”

rtr4hija

Senator Bob Menendez (Larry Downing/Reuters)

The conferees made no mention of those veterans who have already used mefloquine and are no longer in the United States military. Nor did they mention the FDA’s 2013 warning. Considering that the military has already started to quietly back away from mefloquine, the conferees’ statement seems a little out of place.

Let’s put mefloquine into context and see where Congress’s priorities are. I think actions speak louder than words. In the 114th Congress (2015–2016), there have been only three pieces of legislation introduced that mention mefloquine. Before the 114th Congress, the last time anyone introduced a bill that mentioned mefloquine was a decade ago, during the 109th Congress; there were three bills, to be exact.

Now, let’s compare mefloquine to peanuts. I love peanuts like the next guy and I have nothing against hardworking peanut farmers or peanut butter distributors or the American Peanut Council. But it’s a little odd that: two bills in the 114th Congress involved peanuts; 17 in the 113th Congress; 20 in the 112th Congress; 4 in the 111th Congress; 17 in the 110th Congress; and 25 in the 109th Congress. Adding that all up, and if my math is right, that would be 85 bills that involved or otherwise referenced peanuts. Eight-five for peanuts, six for veterans’ use of mefloquine.

You see a similar trend when you dig through the Congressional Record. After all, while actions speak louder than words, words are still important. In the past decade, mefloquine was mentioned five times in the people’s diary. Peanuts? In only the 114th Congress alone — to be clear, in only the past two years — over 60 times.

If the conferees urged the Pentagon to limit mefloquine use because of its serious side effects, why wouldn’t they consider keeping a proposal to have the Pentagon maintain data on the long-term health of service members who took mefloquine? More to the point, with veteran suicides attracting so much media attention, why would people in Congress be so flippant toward neuropsychiatric side effects of mefloquine, including suicidal ideation?

This article was first published on medium.com.

*Nebojsa “Vic” Zlatanovic deployed to Iraq and Afghanistan as member of the US Army’s 73rd Airborne Brigade. Several years after leaving active duty, he became an attorney. He is admitted to practice before New Jersey state courts, the US District Court of New Jersey, and the US Court of Appeals for Veterans Claims, and he’s accredited to represent veterans before the US Department of Veterans Affairs (VA). Vic advocates on a number of veterans’ issues, including mefloquine awareness and the establishment of veterans diversion programs, and in addition to representing veterans before the VA, he offers other services, such as discharge upgrades, guidance for veteran-owned businesses, representation before other government agencies (such as the Social Security Administration), and estates and trusts.

Posted in Advocacy, Media, Research | Tagged , , , , , , | Leave a comment

Major Stuart McCarthy – Prime Minister Turnbull Must Support Diggers Used as Drug Guinea Pigs

WHEN you sign up to fight for your country, you accept you have to put your life on the line. In recent years, scores of those who have served in dangerous or inhospitable places haven’t made it home. To them we are grateful.

Those such as the 41 who were killed in 14 years of the Afghanistan War, faced traditional opponents. That enemy carried weapons. They laid roadside bombs. And the horrors of what many experience last well beyond deployment and into an unsettled civilian life. Many, as revealed by government figures last week, have taken their own lives.

a7c49856528b0332fc7b63a02aa81acd

Stuart McCarthy serving in Iraq, 2006.

But PTSD isn’t the only hazard that can cause impairment in our Australian veterans. Since the late 1980s, 5000 personnel were administered two antimalarial drugs — mefloquine and the experimental tafenoquine — when sent on military service in countries with a malaria risk.

Many of them have since suffered an illness classified as an Acquired Brain Injury. There is sturdy scientific proof that ABI can occur after treatment with mefloquine. Scientists from the US military research institute that developed the drugs found that mefloquine was able to cause a “lasting or permanent” brain injury. Other scientists at the same institute found tafenoquine, an experimental drug that has not been registered for sale anywhere in the world, “is more neurotoxic than mefloquine”.

Prime Minister Malcolm Turnbull said in August, on the evidence of an alarming veteran suicide rate, that “we have to go beyond the memorials and the monuments and focus on the men and women, the real challenges they face, ensuring that they are supported”. This week, Veterans’ Affairs Minister Dan Tehan and Health Minister Sussan Ley are expected to launch the government’s veteran suicide prevention initiative. With more than 60 veterans having taken their own lives this year, this response is welcome.

Mefloquine veteran Chris Stiles begs senior Australian government officials for help, before ending his own life.

Turnbull’s words are encouraging, but there is a glaring omission from his government’s response thus far — an outreach and treatment program for veterans affected by exposure to mefloquine and tafenoquine. Although Defence has recognised that mefloquine can have long-term health effects, Defence and Veterans’ Affairs have initiated no consultation to ensure the advice they are providing to those affected is suitable. Yet Australian veterans who suffer serious, chronic illness since their exposure to the drugs are in the hundreds. 

Difficulties in correctly diagnosing this type of brain injury have meant that few of those affected have been able to access the appropriate rehabilitation, medical and other support services. Most who have sought medical help have been diagnosed and medicated for PTSD or other mental illnesses without having been referred to brain injury specialists. That misdiagnosis has led to further disabling drug reactions, family breakdowns, homelessness and suicide.

During this year’s election, the government committed to formal consultation with affected veterans and their families to address these concerns. Despite news of an “outreach” event in Townsville this month, the consultation has not happened. Discussions with senior Veterans’ Affairs medical officers indicated that “consultation was not required”. Meanwhile, Defence and Veterans’ Affairs officials have trivialised the nature and extent of the problems, unfairly suggesting those affected are exaggerating or inventing their symptoms.

bcbc9d97c881a49ecc4bda5728851c48

Lisa Alward, sister of the late Chris Stiles, appeals for her brother to be the last veteran suicide.

The numerous diagnoses of bipolar disorder, schizophrenia, major depression and anxiety, seizures, hallucinations and psychosis, suicide attempts and suicide indicate this is a serious issue. Equally serious steps need to be taken by the government to embrace those suffering and give them suitable assistance.

Providing the right assistance is not hard. There are existing ABI outreach and rehabilitation programs available in every state that receive significant federal funding. Indeed, some fortunate veterans who have persisted to obtain the right treatment are already receiving those services. Sadly, these are in single figures.

If Turnbull is serious about addressing veteran suicides — and there is no reason to believe he isn’t — he should now direct both ministers to make those programs available to all veterans who were exposed to these neurotoxic drugs during their service to the country.

Stuart McCarthy is an army officer who served in Afghanistan, Iraq, Ethiopia and Eritrea and Bougainville. He is undergoing rehabilitation for an acquired brain injury after being exposed to mefloquine and tafenoquine.

*This article was first published in the Herald Sun on 7 December 2016.

Posted in Advocacy, Clinical Drug Trials, Our Stories, Support | Tagged , , , , , , , , , , | 1 Comment

Media Release: Australian Veterans Welcome UK Drug Report

Australian veterans have today welcomed the release of UK Parliamentary report: ‘An acceptable risk? – the use of Lariam for military personnel’ confirming the Ministry of Defence had prescribed the controversial antimalarial drug mefloquine to thousands of troops without proper medical supervision.

The Australian Quinoline Veterans and Families Association (QVFA) Scientific Advisor Dr Jane Quinn said the UK has now joined Australia in admitting that mefloquine had been given to troops without medical supervision or subsequent clinical follow up for manufacturer acknowledged neuropsychiatric side effects.

“The UK report follows recent admissions by the Australian Defence Force (ADF) that their troops were also given the drug without proper prescribing practices. Subsequently many now require long term specialist clinical care as a result,” Dr Quinn said.

“What remains to be seen now is a rehabilitation program for those veterans with acquired brain injuries resulting from the use of mefloquine during their service.”

“Affected veterans and their families are eager to work with the government to find a way forward. Tangible and pragmatic support could be made very quickly.”

“The QVFA remains optimistic following recent talks with the government and the ongoing support of peak veteran advocacy body, the Alliance of Defence Service Organisations, that our calls for a dedicated rehabilitation program for veterans are finally being taken seriously. This has given new hope to hundreds of veterans and their families who make up our group,” Dr Quinn said.

A growing body of compelling international scientific research now acknowledges that mefloquine can cause both long-term and permanent neuropsychiatric side effects, causing permanent brain injury in some people.

Dr Quinn said Canadian and Irish veterans also affected by mefloquine are now hopeful their governments will also make similar admissions to end institutional denial and now focus on veteran rehabilitation.

Following the ADF’s 2001-02 East Timor antimalarial drug trials numerous reports emerged that participants had experienced neuropsychiatric side effects, consistent with the manufacturer’s warnings.

Subsequently hundreds of veteran drug trial participants report long-term mental health issues. Few veterans, if any, have received proper care or support for their mefloquine-related illness. Most recently, some have suicided, either as a direct result of mefloquine use or an indirect result of inadequate care.

Posted in Advocacy, Media, Support | Tagged , , , , , , , | Leave a comment

A Clinical Drug Trial Gone Wrong and the Unfinished Business of the Somalia Affair

As public awareness has grown in relation to the adverse health effects of the anti-malarial drug mefloquine in military veterans, much of the media attention has focused on a series of drug trials conducted by the Australian Defence Force in Bougainville and Timor Leste from 1998 to 2002. Although mefloquine is also known to have been widely used in the military forces of Canada, the United States, the United Kingdom and Ireland among others, what is less well known is that Canadian veterans were also subjected to a drug trial that seriously contravened numerous health regulations. This pre-license clinical trial involved the administration of mefloquine to 1,400 Canadian troops deployed to Somalia in 1992-1993 and played a significant role in a series of incidents that became known as the Somalia Affair.

During this drug trial many of the soldiers commonly experienced adverse psychiatric side effects of mefloquine. Two local Somali civilians were killed by members of the contingent, one of whom was shot and the other was captured then beaten to death, during episodes consistent with mefloquine intoxication. When photos of these incidents were released a public inquiry and criminal investigation were launched, resulting in one soldier attempting suicide, one being sentenced to five years in jail, and several others disciplined. The head of the Canadian military was forced to resign, as was his successor. The Minister for Defence also resigned. Most significantly of all, the entire Canadian Airborne Regiment was disbanded. Yet when the Somalia inquiry began to examine “the mefloquine issue” in 1996 it’s work was mysteriously “truncated” by the Liberal government:

THE MEFLOQUINE ISSUE

Mefloquine is a relatively new anti-malarial drug, first made generally available to the Canadian public in 1993. It is used both to prevent malaria (that is, as a prophylactic) and to treat malaria. Mefloquine is used in areas where the local strains of malaria have developed a resistance to other anti-malarial drugs. Somalia is one such place.

Some suggestion has been made to this Inquiry that mefloquine caused severe side effects, including abnormal and violent behaviour, among some Canadian Forces personnel in Somalia. We were not able to explore fully the possible impact of mefloquine. This would have required additional hearings dedicated specifically to the issue, which time did not permit. However, we report here our general findings about mefloquine and its possible impact on operations in Somalia.

It is clear that mefloquine caused some minor problems in Somalia, as might be expected from a review of the medical literature. We learned of several incidents of gastrointestinal upset, vivid dreams, nightmares referred to by soldiers as “meflomares”, and inability to sleep following the use of this drug. Side effects – or at least the minor side effects, and possibly also the major side effects – appeared to be most pronounced in the 24 to 48 hours after taking mefloquine.

If mefloquine did in fact cause or contribute to some of the misbehaviour that is the subject of this Inquiry, CF personnel who were influenced by the drug might be partly or totally excused for their behaviour. However, for reasons described more fully in Chapter 41, we are not able to reach a final conclusion on this issue. We can offer only general observations about the decision to prescribe mefloquine for personnel deployed to Somalia.

TRUNCATION OF THE INQUIRY AND THE UNFINISHED
MANDATE

Under the revised terms of reference given to us in the aftermath of the Federal Court of Canada decision characterizing as unlawful the Governments decision to curtail our Inquiry, we were instructed to report on the pre-deployment phase of the Somalia operation and were given discretion to report on all other matters in our original mandate to the extent that we deemed advisable. In compliance with this adjusted mandate, our report describes in detail all the many matters that we have been able to canvass in the time available. It also traces the outline of what we were originally asked to investigate but were unable to complete due to the truncation of our work.

There is an obvious public interest in discovering the answers to questions about the Somalia affair that remain unexplored.

Chapter 42 begins with an account of our efforts to gain the time needed to do justice to the Inquiry’s mandate. We go on to examine the Governments decision to truncate that mandate. We conclude with a review of the portions of the mandate that we were forced to abandon – the Inquiry’s unfinished business.

some of our work remains undone. We obviously could not address, in full detail, the overall post-deployment response of the chain of command to the problems encountered during the Somalia mission, and the behaviour of senior officers and officials for the purpose of assessing their personal accountability, because our hearings were brought to an end before the most important witnesses relevant to that issue and time period could be called.

… The Minister of National Defence at the time of the Government’s decision to truncate the Inquiry, Mr. Young, also asserted frequently and to our amazement, that all that needs to be known about “what happened” in Somalia is known. We continue to believe that important facts concerning the deployment and its aftermath are not yet known or remain obscure. We thought, because of its public statements, that the Government also believed that it was essential, and in the interests of the Canadian military and its renewal, to expose, understand, confront, and analyze the facts publicly and in an independent, non-partisan setting, as well as address all the important matters raised in the terms of reference. Obviously, we were mistaken, as the Government abandoned its earlier declared interest in holding to account senior leaders and officials who participated in the planning and execution of the mission and responded to the problems that arose. Once again, history repeats itself, in that only the lower ranks have been made to account for the marked failures of their leaders.

We fear that the implementation of hastily crafted and mostly cosmetic reforms, coupled with the abandonment of an interest in accountability or an implementation of reforms unrelated to specific facts and problems identified and assessed in a thorough, independent, and impartial process, will serve merely to postpone the day of reckoning that must surely come.

One of the few journalists to follow up on this use of mefloquine in Somalia was Peter Worthington, who wrote for the Edmonton Sun in January 1998:

Many believe mefloquine may have been responsible for some of the bizarre behavior of our troops in Somalia, since the drug was still in experimental stages in 1992 and not legally sold in Canada. W5 discovered that when the now-disbanded Airborne Regiment was sent to Somalia, Health Canada sanctioned the use of mefloquine (under the brand name Lariam, manufactured by Hoffman-La Roche) only on condition it was a controlled study with soldiers monitored and effects recorded.

None of this was done. As we now know, side-effects can lead to severe psycho-neurological problems. Dr. Michelle Brill-Edwards, a Health Canada drug regulator, quit in protest of possible dangerous psychiatric reactions – full-blown psychoses in cases, as well as hallucinations, nausea, nightmares, paranoia and suicidal impulses.

… Reform MP John Cummins is a vociferous critic of mefloquine, and speculates it could be responsible for Master Cpl. Clayton Matchee’s rampage when he beat a Somali prisoner to death in 1993. I’ve had soldiers, both serving and discharged, say their behavior was affected for a year or so after they had extended use of mefloquine in Somalia or Rwanda. Some are investigating a class action suit against the government.

Not given a choice, Canadian soldiers were ordered to take mefloquine in Somalia and Rwanda. One soldier, Scott Smith, who went from Somalia to Rwanda and was on mefloquine for most of a year, inexplicably committed suicide on Christmas Day, 1995.

… Getting back to Somalia, in October 1994 Hoffman-La Roche’s office in Mississauga formally notified DND it had received no response about shipments of mefloquine sent to the army in Petawawa, Ont., and the medical centre in Debert, N.S., in 1992. The understanding was that the military would be a “co-investigator” in a study that required them to “maintain logs of distribution,” complete with consent forms from soldiers.

Health Canada demanded an answer within 24 hours. DND responded that it did not consider troops to be part of a “safety monitoring study,” and no mefloquine consent forms were necessary for soldiers.

These documents weren’t given to the Somalia inquiry which, according to Cummins, wasn’t aware our soldiers were, in effect, guinea pigs for a drug at the time illegal in Canada.

What’s disquieting is that there seems no awareness in government circles that mefloquine, while effective against malaria, might indeed be dangerous, with unknown victims among our military.

The Auditor General of Canada did eventually investigate the conduct of this clinical trial, making a series of damning findings in its April 1999 report, summarised as follows:

National Defence participated in a clinical trial of an anti-malarial drug, but did not follow the study protocol when the drug was administered to Canadian Forces personnel deployed to Somalia. Despite a requirement in the protocol to do so, the Department did not obtain consent from the personnel who received the drug, did not systematically monitor for efficacy, and did not provide to the study sponsor records of the drug’s administration or reports of adverse reactions to the drug.

Once Health Canada approved the conditions for the clinical trial of the drug, it made no attempt to monitor the study to ensure that the trial was adhering to the protocol with its reporting requirements and procedures to protect patients’ well-being.

_20160713_192852.JPG

Despite these findings, little or no action was taken to hold Department of National Defense or Health Canada medical officials to account. Now almost two decades later, with an extensive body research on mefloquine’s adverse neuropsychiatric effects now published, several of the key witnesses have again called for this matter to be properly addressed.

Among these is Dr Greg Passey, a former army psychiatrist who said in an interview earlier this year:

“I thought the military should be aware of — that the courts should be aware — that it has the potential to have an extreme effect on individual behaviour.

“I wrote a letter to the committee in January 1996 and stated my opinion that mefloquine had significant side-effects … of paranoia and aggression.”

“Unfortunately, the Liberal government shut down the inquiry the week before I was to testify. And that was the end of my involvement in the issue until now.”

Dr Passey had previously written to one of the affected Somalia veterans:

In regards to Kyle Brown, I still have a book about him and his time in the Airborne that I read in the 90s. Being a trauma therapist and reading about his upbringing and personality before being deployed to Somalia, there were a number of issues I would have liked to testify about at the Somalia Inquiry in regards to what appeared to be a dramatic change in his personality and behaviour. I would have testified that there was a high likelihood that the mefloquine altered his behaviour. I can’t remember now if any alcohol was involved but if it was, then even just a couple of beers (we were still allowed to drink on deployment back then) when coupled with the mefloquine could have had potentially disasterous effects on a person’s ability to curtail aggressive thoughts or behavior. I’m sorry I never got the chance to at least voice those concerns.

2013 interview with Dr Michele Brill Edwards about her experiences with Health Canada

Former Health Canada official Dr Michele Brill-Edwards, who resigned in protest over this issue, has also called for the government to properly recognise the harmful effects of mefloquine on these veterans:

The federal government should recognize the anti-malaria drug mefloquine was not used safely in a trial during the fateful Somalia mission and address veteran concerns, a former top Health Canada bureaucrat says.

The defence and health departments failed to do their due diligence when the drug was released under a clinical trial to 900 Canadian Airborne soldiers going to Somalia in 1992, Dr. Michele Brill Edwards says.

“We owe a duty to them to recognize mefloquine may have caused great harm,” Brill Edwards told The Journal in a rare interview on the subject.

“It’s high time we stopped pretending mefloquine was used safely.”

Most compellingly, John Dowe – an eye witness of the events in Somalia – described in an interview last year the psychotic behaviour of two of the soldiers involved in the killings, in addition to the overall conduct of the drug trial.

More recently, Mr Dowe has written about his determination to see the historical record of these events corrected to include the role played by mefloquine:

As a member of 2 Commando, The Canadian Airborne Regiment, I was one of the soldiers who witnessed the psychotic reaction of Master Corporal Matchee, and was ordered by him to remain and observe the carrying out of a standing, unlawful order. I carry with me the weight of that event to this day, and am haunted by it every day. In Brian Bergman and Luke Fisher’s piece titled appropriately enough ‘A night of Terror’ (Maclean’s, March 1994) the authors ominously wrote how ‘Canadians may never know the full story of what happened that March night of the 16th … they will almost certainly never understand why some members of Canada’s elite military force behaved so abominably.’

I believe I now understand why. Like the piece mentioned above, we in the Commando also called March 16th ‘Fright Night’. Then again, we called every Tuesday night that nickname – it was the weekday of issue for mefloquine. I have just recently connected with Trooper Brown and we have spoken at length. Prior, we had been separated after the incident for 21 years through his imprisonment, life, and other circumstances. Further, the psychologically dissociative symptoms from PTSD – and the lasting effects of mefloquine – conspired to prevent our meeting and subsequent discussion to break-down these events and grasp all the variables.

Time’s objective lens and new positive, supportive facts have also highlighted the need for further investigation. It is therefore my intention, with the full support and cooperation   of Mr Brown, to determine all causal factors involved in the play of actions of that frightful evening. Many families’ lives, military careers and no less than the full honour of a disbanded Canadian regiment, are owed a full account that your help – and the possible help of other supportive voices – will provide to this imperative. So we all can understand why … and heal.

A central component of the Trudeau Liberal Government’s recent election platform was this commitment to Canada’s veterans:

For a decade, Stephen Harper’s Conservatives have dishonoured us all by failing to uphold this sacred obligation. They have not been truthful to, or respectful of, our veterans …

A Liberal government will live up to our obligation to Canada’s veterans and their families. We will demonstrate the respect and appreciation for our veterans that Canadians rightly expect, and ensure that no veteran has to fight the government for the support and compensation they have earned.

The government’s commitment that “no veteran has to fight the government” has already proven hollow. Veterans Affairs Minister Kent Hehr has ignored repeated requests over the last six months from affected veterans to simply meet with them. A measure of the Trudeau government’s genuine commitment to Canada’s veterans will be the manner in which it addresses, or continues to ignore, this unfinished business from the Somalia Affair.


Related Stories

Sheila Pratt, Stop pretending mefloquine was used safely on soldiers: former top Canadian drug bureaucrat, Ottawa Citizen, 7 February 2016.

Sheila Pratt, Veterans anxious to hear from Hehr on mefloquine issue, Ottawa Citizen, 1 February 2016.

Sheila Pratt, New push for ban on mefloquine in the Canadian military, Ottawa Citizen, 29 January 2016.

Sheila Pratt, Life after Somalia: Kyle Brown, PTSD and the pastOttawa Citizen, 29 January 2016.

Peter O’Neil, Opposition MPs demand government act on dangerous anti-malaria drug, Vancouver Sun, 28 January 2016.

Peter O’Neil, B.C. military veteran calls for federal apology for controversial anti-malaria drug, Vancouver Sun, 27 January 2016.

Grant Lafleche, Put an end to mefloquine, The Standard, 24 December 2014.

Dave Lazzarino, The Canadian Airborne Regiment’s Somali Affair, 20 years later, The Edmonton Sun, 15 March 2013.

Posted in Advocacy, Clinical Drug Trials | Tagged , , , , , , , , , , , | 1 Comment

PTSD as a “Diagnosis of Convenience”: Mefloquine, Tafenoquine and the Prevalence of Neuropsychiatric Disorders in ADF Veterans of East Timor and Bougainville

One of the problems that has perplexed many Australian government officials and veterans advocates in recent years is the disproportionately high number of Australian Defence Force (ADF) East Timor veterans who have been diagnosed with post-traumatic stress disorder (PTSD). PTSD is a mental health disorder that can develop after a person is exposed to a traumatic event or events. The types of traumatic events specified in the PTSD diagnostic criteria are “death, threatened death, actual or threatened serious injury, or actual or threatened sexual violence.”

PTSD is one of the most commonly diagnosed, service-related health conditions among East Timor veterans. The number of PTSD claims accepted by the Department of Veterans Affairs (DVA) from East Timor veterans is very similar to the number from Afghanistan veterans. Although the duration and numbers of personnel involved in each of those military commitments was similar, the nature of the conflicts and health exposures were quite different, leading respected veterans advocates such as former SAS officer John Burrows to speculate on the disproportionately high PTSD numbers among East Timor veterans:

Mr Burrows was contacted by News Corp Australia to explain an apparent statistical anomaly that shows the 1999 operations to liberate East Timor from Indonesia had produced more sufferers of post-traumatic stress disorder than either the Iraq or Afghanistan wars.

This was despite the fact that few ADF personnel came close to serious combat action in East Timor.

… Mr Burrows also said that while few — if any — service person in East Timor lived with dodging air strikes, rocket-propelled grenades, cannon fire or even sustained firefights, DVA initially took the view that it had to process all claims quickly.

This was because the government had failed so many veterans in its last major action, in Vietnam 27 years earlier, and was initially nervous of repeating its mistake.

Added to that, said Mr Burrows, many serving in the ADF in its initial commitment to Timor were not acquainted with the realities of conflict.

“It was a Defence Force that hadn’t been to war for many years and many had an overwhelming feeling they were in imminent danger anywhere in the operational zone,” said Mr Burrows, even though the expected battles with the Indonesian military and citizen forces did not eventuate.

… “In Afghanistan, I believe from my dealings with veterans who have served there, is that the numbers of enemy being contacted is much higher and the intensity much greater than was the case in most actions in Vietnam,” he said.

_20160708_145322

DVA accepted conditions for veterans of selected conflicts, as of March 2016

Along with PTSD, two of the three most prevalent, service-related health conditions among East Timor veterans are tinnitus (ringing in the ears) and sensori-neural hearing loss, which are commonly associated with noise exposure. The disproportionate DVA figures among East Timor veterans in comparison to those from Afghanistan also led Burrows to speculate on this, in the same article quoted above:

Likewise, claims for both tinnitus and sensori-neural hearing loss from East Timor veterans far exceed claims from Iraq and Afghanistan, where combat forces routinely experienced close proximity to loud and damaging live fire.

… Timor vets with accepted claims for tinnitus (892) and sensori-neural hearing loss (882) far outnumber those from Afghanistan and Iraq.

… Mr Burrows said many hearing disorders from East Timor vets likely came from live firing exercises.

This speculation overlooks the most plausible explanation for the high prevalence of these disorders among East Timor veterans, which is the extensive use of the anti-malarial drugs mefloquine and tafenoquine in the ADF during the early years of this military operation. There is a high likelihood that a large proportion of those personnel have simply been misdiagnosed with PTSD and/or suffer from hearing problems, as a result of the toxicity of these drugs.

Mefloquine and tafenoquine were administered to at least 2,842 ADF personnel in a series of drug trials conducted by the Army Malaria Institute (AMI) in Bougainville and East Timor from 1998-2002. Excluding the Bougainville tafenoquine trials but including a conservative estimate of East Timor veterans given mefloquine (which had been in use as the ADF’s second line anti-malarial since 1993) beyond those trials, brings the East Timor figure to approximately 2,500, if not significantly greater.

Both drugs are known to be neurotoxic. Mefloquine, along with several other synthetic quinoline antimalarials including 8-aminoquinolines (tafenoquine is an 8-aminoquinoline) has been found to be a cause of a central nervous system toxicity syndrome resulting in chronic neuropsychiatric symptoms. Many of these psychiatric symptoms mimic those of PTSD, to the extent that the U.S. Centres for Disease Control (CDC), the U.S. Army Surgeon General, and researchers from the U.S. Walter Reed Army Institute of Research (WRAIR) have acknowledged that mefloquine toxicity can confound the diagnosis of PTSD, particularly in military veterans:

Intoxication with the antimalarial drug mefloquine (previously marketed as Lariam) is a potentially life-threatening condition marked by changes in affect, behavior, cognition, and thought that may be associated with a risk of central nervous system (CNS) neuronal injury as well as chronic neurological and psychiatric sequelae. The acute symptoms of mefloquine intoxication may mimic and be mistaken for a number of acute psychiatric disorders including posttraumatic stress disorder (PTSD). Particularly in deployed settings, this may delay the correct diagnosis of mefloquine intoxication, risking subsequent morbidity. As the subacute and chronic psychiatric and neurologic sequelae of acute mefloquine intoxication may also confound the later diagnosis and management of PTSD, as well as other chronic neuropsychiatric disorders prevalent among deployed cohorts, health-care providers must screen for prior mefloquine exposure and consider the diagnosis of mefloquine intoxication in patients with appropriate history and findings on clinical evaluation.

The conclusion of a recent report describing a case of mefloquine toxicity in a U.S. military veteran authored by WRAIR (the research institute that originally developed mefloquine) researchers found:

This case documents the potential long-term and varied mefloquine-induced neuropsychiatric side effects, ranging from a central vestibulopathy to significant behavioral changes and sleep disorders. Especially pertinent to the military population, it demonstrates the difficulty in distinguishing from possible mefloquine-induced toxicity versus PTSD, and raises some questions regarding possible linkages between the two diagnoses.

Mefloquine is also a known ototoxicant, i.e. a toxic substance able to cause problems including tinnitus and hearing loss. Although there is less published research on the toxicity of tafenoquine, researchers from WRAIR (which also developed tafenoquine) found in 2009 that “tafenoquine is more neurotoxic than mefloquine.”

A large proportion of East Timor veterans administered these two drugs have been diagnosed with PTSD, without having experienced the traumatic exposures required for this diagnosis, as well as tinnitus, sensori-neural hearing loss and other neuropsychiatric disorders symptomatic of quinoline neurotoxicity. Many of them are included in the above DVA figures, although others who were medically discharged from the ADF have had their claims perversely rejected by the Veterans Review Board on the basis that they were not involved in combat. Having met with a group of these veterans and families at a forum in Townsville earlier this year, the Surgeon General of the ADF is fully aware of these concerns.

This situation has developed despite Defence and DVA having poured literally tens of millions of dollars into extensive research on neuropsychiatric illness among East Timor and Bougainville veterans, including studies of PTSD, tinnitus and sensori-neural hearing loss. These studies have examined a variety of health factors while systematically excluding exposures to neurotoxic anti-malarial drugs that are fully documented in files held at AMI, for example:

One of the above studies, published in 2012, compared traumatic events and “other operational stressors” between 1,704 Bougainville veterans and 1,333 East Timor veterans and examined subsequent health outcomes:

Two cross sectional studies of the Australian Defence Force were used to contrast the prevalence of exposures reported by a group deployed on a peacekeeping operation (Bougainville, n = 1704) and those reported by a group deployed on operations which included warlike and non-warlike exposures (East Timor, n = 1333). A principal components analysis was used to identify groupings of non-traumatic exposures on deployment. Multiple regression models were used to assess the association between self-reported objective and subjective exposures, stressors on deployment and subsequent physical and mental health outcomes.

The study found that 7.2% of East Timor veterans had symptoms of PTSD and 6.9% had a high level of psychological distress, while the corresponding numbers in the Bougainville group were 5.9% and 5.5% respectively. These findings were based on self-reported DSM-IV symptoms of PTSD:

The Post-Traumatic Stress Disorder Checklist Civilian Version (PCL-C) was also used. This is a self-report rating scale for assessing 17 symptoms of PTSD. A cut-off of 50 on the PCL-C has previously been used as an indicator of PTSD prevalence in military populations.

Despite the fact that approximately 3,000 ADF personnel were administered mefloquine and tafenoquine during these deployments, this factor was not considered during the study. A 2014 paper on mefloquine and PTSD published by the U.S. Army Surgeon General highlights the questionable validity of this research, finding that many of the symptoms of mefloquine toxicosis may “be erroneously deemed as meeting [DSM-IV] diagnostic criteria”:

In deployed settings where US military personnel may have been exposed to mefloquine, the ubiquity of potentially traumatic experiences may have had the effect of significantly reducing the specificity of DSM- IV diagnostic criteria. For example, in an early study of returning service members from Afghanistan and Iraq, encompassing the period of widespread mefloquine use, between one-quarter and one-half of subjects reported feeling “in great danger of being killed;” more than one-third to one-half reported witnessing individuals wounded or killed, consistent with DSM-IV criteria of experiencing, witnessing, or being confronted by events involving “actual or threatened death or serious injury” (criterion A1). Similarly, intense fear, helplessness, or horror (criterion A2), while seemingly specific to external traumatic stressors, may be readily confounded by the onset of panic attacks or certain symptoms of psychosis, which may solely result from mefloquine’s effects but whose specific symptoms may reflect fearful or horrific content that may risk being attributed to an external stressor in the context of military deployment.

Other symptoms of mefloquine intoxication may also closely mimic many criteria B (re-experiencing) and C (avoidant/numbing) symptoms. For example, intrusive recollections (criterion B1), possibly reflecting the effects of daytime or hypnopompal hallucinations, are a common feature of case reports. Similarly, distressing nightmares (criterion B2), frequently described as “vivid” and “terrifying,” are a pervasive feature of intoxication, affecting more than one-third of military users during prophylactic dosing. Similarly, again possibly reflecting the effects of hallucinations, symptoms consistent with flashbacks (criterion B3) are commonly reported with reports of directed actions in response to perceived threats. As the symptoms of mefloquine intoxication may present independent of a specific external traumatic stressor, individuals suffering from its effects may not exhibit psychological distress or physiological reactivity specifically in response to traumatic reminders (criteria B4 and B5), but instead may experience such reactions unpredictably and without obvious triggers. In certain environments, where traumatic reminders are prevalent or where ascertainment or recall bias may identity these preferentially on examination, such symptoms may be erroneously attributed to traumatic reminders, which confounds diagnosis.

Similarly, while the effects of mefloquine intoxication may result in nonspecific avoidance behaviors, these may risk being similarly misattributed to an external traumatic stressor (criteria C1 and C2) on examination. Conversely, because of the lasting effect of mefloquine on memory and its association with anterograde amnesia, the inability of those suffering intoxication to recall specific aspects of a presumed trauma (criterion C3) coincident with dosing may—in some contexts—be erroneously deemed as meeting diagnostic criteria.

Another of the Australian studies published in 2011 specifically examined tinnitus and ototoxic exposures in a sample of 4,175 veterans of Bougainville and East Timor:

The objective of this study was to investigate the effect of chemical and environmental exposures during deployment on tinnitus among Australian Defence Force personnel previously deployed to Bougainville and East Timor. Participants were asked to self-report recent occurrence and severity of “ringing in the ears,” and identify any chemical and environmental exposures during their deployment. Self-reported exposure to loud noises, heavy metals, intense smoke, engine exhaust, solvents and degreasing agents, and chemical spills increased the risk of self-assessed moderate or severe tinnitus.

The ototoxic exposures considered in this study included heavy metals, intense smoke, engine exhaust, solvents/degreasing agents, chemical spills and pesticides. Quinoline anti-malarial drugs were excluded from consideration in this study despite the fact that mefloquine and tafenoquine were administered to approximately 3,000 ADF personnel during these deployments.

_20160711_160938

K. Kirk et al, 2011, Table II.

During the recent Senate inquiry into ADF mental health, a serving Army officer testified that PTSD has become a “diagnosis of convenience” that is preventing many veterans receiving appropriate health care. The same inquiry also heard evidence from neuroscientist Dr Jane Quinn, emphasising the importance of correct diagnosis:

“Proper diagnosis is key. It is important that mefloquine toxicity is recognised as being a significant and identifiable neuropsychiatric disease state, because this has a severe impact on the way personnel need to be dealt with in terms of psychiatric treatment. Drugs that are administered for standard post-traumatic stress disorder can often exacerbate the clinical symptoms of mefloquine toxicity due to the underlying neurological damage. Therefore, a correct diagnosis is key. Implementation of an institutional recognition of mefloquine toxicity in the defence force is critically required and, further, a program to identify, assist and treat appropriately those who have suffered.”

One of the key recommendations from this inquiry was for Defence and DVA to implement an outreach program for veterans affected by quinoline toxicity, to ensure they receive proper health care:

Recommendation 5

4.79      The committee recommends that Defence and DVA contact ADF members and veterans who have been administered mefloquine hydrochloride (mefloquine) during their service to advise them of the possible short-term and long-term side effects and that all ADF members and veterans who have been administered mefloquine during their service be given access to neurological assessment.

The Australian government has thus far refused to implement this recommendation. This situation poses serious questions about the validity of tens of millions of dollars worth of veterans health research and the resulting inadequate support being provided to seriously ill veterans and their families. Many of these veterans remain at risk of suicide. Health care professionals, researchers and government officials involved in veterans affairs need to urgently rectify this situation with appropriate follow up studies and other necessary support for those affected.


*The manufacturer of tafenoquine, GlaxoSmithKline, has requested those affected by the toxicity of the drug to contact them on 1800 033 109.*


Additional References

R. L. Nevin and E. C. Ritchie, FDA black box, VA red ink? A successful service-connected disability claim for chronic neuropsychiatric adverse effects from mefloquine, Federal Practitioner, in press, 2016.

J. Livezey, T. Oliver and L. Cantilever, Prolonged neuropsychiatric symptoms in a military service member exposed to mefloquine, Drug Safety: Case Reports, vol. 3, no. 7., 2016.

S. McCarthy, Malaria Prevention, Mefloquine Neurotoxicity, Neuropsychiatric Illness and Risk-Benefit Analysis in the Australian Defence ForceJournal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

J. C. Quinn, Complex Membrane Channel Blockade: A Unifying Hypothesis for the Prodromal and Acute Neuropsychiatric Sequelae Resulting from Exposure to the Antimalarial Drug Mefloquine, Journal of Parasitology Research, vol. 2015 , Article ID 368064, 2015.

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. 118-125, 2014.

R. L. Nevin, Mefloquine and post-traumatic stress disorder, in Elspeth C. Ritchie (ed.), Forensic and Ethical Issues in Military Behavioural Health, Borden Institute, Surgeon General U.S. Army, Falls Church, 2014.

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. 224-235, 2013.

R. L. Nevin, Limbic encephalopathy and central vestibulopathy caused by mefloquine: A case report, Travel Medicine and Infectious Disease, vol. 10, no. 3, pp. 144-151, 2012.

Posted in Advocacy, Clinical Drug Trials, Research | Tagged , , , , , , , , , , , , , | 2 Comments

Scientific Misconduct in the Australian Army Malaria Institute’s Clinical Trials of Tafenoquine – Part 2

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.

_20160708_225804

Army Malaria Institute personnel during the tafenoquine trial in Bougainville, March 1999, including Lieutenant Colonel Peter Nasveld (second from left) and Lieutenant Colonel Michael Edstein (right).

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.

Ethical Standards

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.

_20160708_204836

Nasveld PhD thesis Table 4-1, showing the number of tafenoquine trial subjects in Bougainville (AMI 001 & 002) and Timor Leste (AMI 003).

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.”

Summary

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

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.*


References

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 ForceMedecine 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): 1995-2000Journal 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): 2000-2005Journal of Military and Veterans’ Health, vol. 23, no. 1, 2015.

 

Posted in Advocacy, Clinical Drug Trials, Research | Tagged , , , , , | Leave a comment

Loren Ries – Mefloquine, Tafenoquine and Lariam … Oh My

This is an excellent post by Loren Ries, shared with kind permission from her blog Loren Land. Loren is the wife of an Australian Army mefloquine and tafenoquine veteran who served in Timor Leste. This is her reaction the misinformation provided by the Department of Defence in relation to the continuing Army Malaria Institute drug trial scandal.


1458156454937

Vice Chief of the Australian Defence Force, Vice Admiral Ray Griggs

As many of you already know my husband was a participant in the AMI (Army Malaria Institute) trials for the drug tafenoquine. But we have learned a great deal more since I first posted about the ADF lackadaisical trials of anti-malarial drugs. We at first believed my husband had only been given tafenoquine, however since requesting his trial documents we were truly horrified to learn he also had mefloquine tested on him entirely without his knowledge.

What’s the big deal here you might ask?

Well it’s actually a REALLY big deal when any organisation decides to conduct covert human drug trials outside of the legislation designed to protect trial participants.

The Department of Defence produced an online portal to supposedly “help” trial participants. I am not sure how much help an entire portal of damage control propaganda can be to anyone other than those trying to cover their own failings. There are gaping holes in the info provided and some of the info provided I consider misleading.

I can’t even begin to make a decision about the safety of these drugs until we clear up the issues relating to the poor risk management procedures employed by the ADF during these drug trials.

The Australian department of Defence’s web portal states many large claims about the integrity of the trials. However the numbers of affected persons who claim that this web portal is full of misinformation and un-truths prompts me to take a closer look at the statements in question. read more

Posted in Advocacy, Clinical Drug Trials, Our Stories | Tagged , , , , , , , , , | Leave a comment