Leaked emails reveal how the U.S. Army’s tafenoquine project manager stonewalled a crucial follow-up safety study on Australian Army drug trial subjects, 18 months before landing a post-Army job with the drug manufacturer

Since taking over as the product manager for our lead antimalarial drugs we’ve continued to work closely together on tafenoquine’s development program, with key attention being paid to how best to adequately and accurately address and potential central nervous system (CNS) toxicity liabilities that it may have.

Colonel Bryan Smith, “Colonel Jennifer Caci USASOC request,” USAMMDA leaked email, February 10, 2014

LAST week we revealed how a recently retired U.S. Army Colonel – Dr Bryan Smith – raised serious concerns about the safety and efficacy of tafenoquine in a series of papers published in scientific journals from 2013 to 2015, before landing the Washington DC-based company 60 Degrees Pharmaceuticals an exclusive $18+ million government contract for the drug’s continued development.

Today we continue the story by revealing a series of leaked emails from Colonel Smith and his current boss Dr Geoff Dow – the CEO of 60 Degrees Pharmaceuticals – showing how Smith stonewalled a crucial follow-up safety study on injured Australian Army drug trial subjects, presumably to facilitate the drug’s FDA approval.

Tafenoquine is from a class of 8-aminoquinoline antimalarials which were discovered to have been neurotoxic during a WWII-era drug discovery program, on par with the Manhattan project in terms of scientific scale, which found more than 85 of these drugs caused lasting or permanent brain damage in primates subjected to pre-clinical safety testing. Eight years after tafenoquine had been tested on 1,540 Australian soldiers deployed on peacekeeping operations in Bougainville and East Timor, laboratory studies at the Walter Reed Army Institute of Research (WRAIR) found that tafenoquine “is the only antimalarial more neurotoxic than mefloquine.”

One senior Australian soldier who was subjected to the trials said to a 2018 government inquiry that “the fraud and corruption involved in these drug trials is huge.” In one of more than 100 written submissions to the inquiry, the daughter of another soldier subjected to the same trial wrote:

I will never get my father back … He was mistreated and used as a guinea pig along with many other people who served our country.

In 2014, Colonel Smith was the product manager for tafenoquine at the U.S. Army Medical Materiel Development Activity (USAMMDA) in Fort Derrick MD. USAMMDA is the organization which commercializes medical products developed by the Army, ensuring they are safe and effective prior to regulatory approval by the Food and Drug Administration (FDA).

A series of emails obtained from a source at USAMMDA now show that Colonel Smith was approached by military colleagues concerned about tafenoquine’s safety, to approve a follow-up study on a group of the Australian soldiers subjected to the notorious Australian Army drug trials at the turn of the century. The report of “Study 033”, which involved 492 tafenoquine subjects and 162 mefloquine subjects, published in 2010 almost a decade after the trial, had found:

In total, 64 (13.0%) tafenoquine subjects and 23 (14.2%) mefloquine subjects reported neuropsychiatric adverse events, the most common being vertigo, dizziness and various sleep disorders.

On February 10, 2014, Colonel Smith emailed retired U.S. Navy Commander Bill Manofsky, seeking his advice on how best to approach the continued development of tafenoquine “in a much more open, transparent and thorough way than was done during mefloquine’s development.”

In the same email, Colonel Smith wrote:

Weve also had a number of recent interactions with mutual colleagues in the Special Operations community, including with Colonel [Jennifer] Caci as we product developers continually attempt to support their medical and materiel needs.

Several months earlier, in September 2013, Colonel Caci – a senior medical officer at U.S. Army Special Operations Command (USASOC) – had drafted the order banning mefloquine from use in that command and establishing dedicated follow up care for those affected by the drug’s neurotoxic effects. This followed the FDA’s 2013 “black box” warning, which stated mefloquine can cause “lasting or permanent” neurological damage.

Three days before Colonel Smith’s email to Commander Manofsky, Dr Geoff Dow had also emailed Commander Manofsky and Colonel Caci regarding concerns over the drug’s safety. In his email of February 7, 2014, Dr Dow wrote in part:

None of us engaged on tafenoquine wish to repeat the mistakes of the past or to move a drug forward that harms soldiers.

As CEO of 60 Degrees Pharmaceuticals (60P), a company he established in 2010 after having worked as a U.S. Army employee at WRAIR, in 2014 he was engaged by USAMMDA as a contractor for the development of tafenoquine. According to information removed from the company’s website in 2018, 60P has received more than $18 million from the U.S. Army for the continued development of this drug.

These funds included payments for the work undertaken by Dr Dow as part of the 2014 Cooperative Research and Development Agreement (CRADA) between 60P and USAMMDA, which awarded 60P an exclusive license for the drug on the proviso that the company work with USAMMDA to have the drug approved by the FDA and the Australian Therapeutic Goods Administration (TGA).

For additional background, having obtained this license and funding from the U.S. Army, in 2015 Dr Dow stated in an interview with CEO-CFO Magazine that his motivation in seeking tafenoquine’s registration with the FDA was to obtain a “priority review voucher” valued at up to $350 million dollars:

Those vouchers can be sold to another company that allows fast track review at the FDA of an unrelated therapeutic. They are freely salable on the open market. The most recent sale was for three hundred and fifty million by United Therapeutics to Abbvie. Three out of four of our products are eligible for the PRV and it is a financial incentive independent of your actual development program or the therapeutic you are moving forward. Therefore, that definitely has interest for individual investors, but also big pharma who have an interest in molecules that happen to be in your portfolio.

Going back to his email of February 7, 2014, Dr Dow explained that he and Colonel Smith had previously worked together on quinoline drug development at WRAIR. During the mid 2000s, Dr Dow had in fact conducted some of the key studies on which proved that mefloquine is neurotoxic. Dow’s email went on to state to Commander Manofsky that Colonel Smith and Colonel Caci “will be reaching out to you” to discuss “the patient safety and product development risks associated with” tafenoquine. Mentioning the results of the 2009 WRAIR study which found tafenoquine to be “the only antimalarial drug more neurotoxic than mefloquine”, Dow continued:

Scientifically, it would be a mistake to over-interpret [the WRAIR results] and to rush to judgement on a solution that may not achieve the solution we are all trying to seek.

With up to $350 million at stake for Dr Dow’s investors, what’s debatable is whether the “solution” he was trying to seek was, or is, indeed the same “solution” in the interests of those whose health might be placed at risk by this dangerous drug, when safer alternatives were, and are, already available on the market.

During the months that followed those two February 2014 emails from Dr Dow and Colonel Smith, what we can also reveal is that Commander Manofsky and Colonel Caci had arranged for a follow-up study on the Australian tafenoquine subjects to be undertaken by U.S. Navy Captain (Dr) Michael Hoffer, a specialist vestibular physician. The proposed study was to examine any long term damage to the vestibular system among the 1,540 subjects, including the 492 tafenoquine subjects of Study 033, which later provided the basis for Dr Dow’s application to the FDA via this 2017 “integrated safety analysis.”

On August 15, Commander Manofsky wrote:

Just wanting to see if you connected with Dr Hoffer at Balboa regarding possible vestibular analysis of the tafenoquine test subjects in East Timor.

Three days later, the reply from Colonel Smith was, “We obviously won’t be getting anything off the ground,” based on the pretext Captain Hoffer was on leave.

Over the coming weeks, we will continue to reveal and analyse key documents from the Tafenoquine Dossier such as these, including the 2014 60P-USAMMDA CRADA. We will also reveal similar parallel efforts by Australian tafenoquine veterans being stonewalled by their government officials after repeatedly requesting similar follow up studies. What is becoming clear is that these efforts were repeatedly thwarted, with up to $350 million at stake for the pharmaceutical industry and their cronies in key government appointments, as they facilitated the approval of a dangerous drug by the FDA and the TGA.

Editors note: We have approached the current USAMMDA commander, Colonel Gina G. Adam, for comment on the emails and welcome any future response.

“There is blood on the hands of the Army Malaria Institute,” says retired Australian Army Warrant Officer and tafenoquine test subject

“THE fraud and corruption involved in these [tafenoquine and mefloquine] drug trials is huge,” said retired Australian Army Warrant Officer Colin Brock in his testimony to a 2018 Senate inquiry hearing in the northern Queensland garrison city of Townsville. “The lying and deceit is incomprehensible.”

Warrant Officer Colin Brock, serving in Afghanistan

In today’s post we return to the Australian Army Malaria Institute’s (AMI) notorious clinical trials of tafenoquine in Bougainville (Papua New Guinea), East Timor and Australia at the turn of the century. As part of a commercial arrangement with the pharmaceutical industry which a former Director of the U.S. Walter Reed Army Institute of Research (WRAIR) described in 2018 as “naive” and “desperate”, the Australian Defense Forces subjected almost 4,000 troops to a series of highly controversial antimalarial drug trials considered to have been “manifestly unethical.”

One of these trials was the AMI “Study 033” for tafenoquine vs mefloquine prophylaxis involving a total of 654 Australian troops from the Townsville-based 1st Battalion, the Royal Australian Regiment (1 RAR) and supporting units. Among the 1 RAR battalion group soldiers deployed to the East Timor UN peacekeeping mission for seven months in 2000-2001, 492 were given the experimental drug tafenoquine, while a further 162 were given mefloquine.

Eight years after this trial, scientists from WRAIR (which developed both drugs) found that “tafenoquine is the only antimalarial more neurotoxic than mefloquine,” a drug from the same quinolines family, widely regarded as a suicide pill.

Mr Brock’s 20-year Army career included operational deployments to Somalia, East Timor and Afghanistan. During the East Timor peacekeeping deployment, then Corporal Brock commanded a mortar section of nine soldiers. He was one of dozens of drug trial subjects who testified to the Senate inquiry, and one of more than a hundred who made written submissions. Here are some highlights from his hard-hitting testimony, which can be found in full here.

At the beginning of the year 2000, 1 RAR was warned out for deployment to East Timor. I was a section commander in Mortar Platoon, Support Company. My section consisted of nine men, including me.

I am not sure of the specific date—I think it was sometime in September 2000—a battalion parade was held on the main parade ground of 1 RAR. We were formed up in companies and the commanding officer, Lieutenant Colonel John Calagari, briefed the battalion on a new malaria drug or drugs that we all were to take to prevent malaria. We were told that it was a trial to benefit the Defence Force. I now know the drugs to be mefloquine and tafenoquine. Lieutenant Colonel John Calagari then informed the battalion, ‘This drug is voluntary, but if you do not consent to take this drug, you will not deploy to East Timor.’ I can categorically state, 100 per cent, that he did say this. There was numerous talk about it after the parade. No-one in the battalion was going to say, ‘No, we won’t take it,’ as everyone wanted to deploy. If you knew about the Army culture, that is what you would want to do. If we knew of the consequences of these drugs, I and a lot of others would have told them to find someone else.

In my later years in Defence, I knew there was something not right with me. I thought it might have been PTSD, as I’d completed numerous deployments to some of the worst countries on Earth, but it was something else. My hearing was failing. There was ringing in my ears. I was having dizzy spells; vertigo issues, which I still have today; bouts of depression and anxiety; and anger issues. But, like a lot of people in Defence, you just put up with it. I loved being deployed, and nothing really fazed me.

I think it was in March 2016 that a forum was held at the Townsville RSL, which I attended with a number of other people who were severely affected by these drugs. A number of dignitaries attended, with key speakers and subject matter experts. Defence was represented by Air Vice Marshal Tracy Smart, Commander Joint Health. I have no words for Tracy Smart. All she did was deny any wrongdoing by Defence, saying the drug trials were conducting morally and ethically, and there was nothing wrong with us. She had no answers for us, just denial. One of my close friends, Chris Styles, had an open argument with her at the forum which was captured on visual and audio. Chris committed suicide less than two months later. Tracy Smart is a Defence toe-the-line person. She is fully aware of these drugs and does not care.

In May 2016, I was contacted by Brigadier Andrew Dunn as part of the IGADF inquiry into allegations of unethical and unlawful use of antimalarial drugs in Defence. This was a phone interview which lasted around 90 minutes. I answered truthfully all the questions asked of me. I have a clear recollection of these events, and one in particular. The main question I was asked was: what did Lieutenant Colonel John Caligari say on the parade ground as to the drug being voluntary? I answered: ‘John Caligari said, “The drug trial is voluntary, but if you do not consent to the trial you will not deploy to East Timor.”‘ As I said, I am 100 per cent correct that I heard this. I would not lie about this. I know the man’s reputation is at stake; I would not lie.

I received the findings for my part in this inquiry a while later. The report suggests that I basically lied to the inquiry—and so did four or five others that were with us—finding that John Caligari had never said those words. I was gobsmacked. He was an officer I respected, trusted and looked up to, as I had worked for him again in later years. He categorically denied it. There are hundreds of people from that 1 RAR parade ground who will agree with me. We are not liars. What would I have to gain by saying this? Nothing. Also, if you look at submission No.80, I don’t know if you have that with you, what he’s said in there—I saw that the other day in the submissions—is what I’m saying.

Everyone affected by these drugs wants answers. My section in East Timor consisted of nine fit men. Six out of the nine are now experiencing all of these symptoms and are unable to work; that’s a 75 per cent ratio. Why were Defence used as guinea pigs? Why were we forced to take these drugs? What do we have to do to get help—more suicides? There is blood on the hands of the malaria institute, Defence and the leaders of these so-called trials. I personally have been to two funerals as a direct result of these horrendous drugs, and it will keep happening. Just three days ago a former member of 1 RAR who was on these trials committed suicide. That was three days ago. It’s still happening. The fraud and corruption involved in these trials is huge. The lying and deceit is incomprehensible. People and organisations need to be held accountable for the damage they have done to hundreds if not thousands of officers and soldiers.

This is the first in a series of posts highlighting the testimonies of some of the thousands of ADF personnel who were subjected to these drug trials, which have been described as “the most shameful chapter in the recent history of the ADF.” Over the coming weeks we will post more of these first hand testimonies, from the subjects of the unethical drug trials which provided much of the basis for the 2018 regulatory approvals of Arakoda® in the US and Kodatef® in Australia. The evidence we already have is sufficient to prove that the official report from Study 033 and some of the other AMI tafenoquine trials are fraudulent.

Senior U.S. Army medical officer who previously raised doubts about the safety and efficacy of tafenoquine retires, gets job with drug manufacturer after landing them an $18+ million government contract

Changes in tafenoquine CYP 2D6-mediated clearance could potentially exacerbate any parent molecule-mediated toxicity despite drastically reducing its liver-stage efficacy mediated through CYP 2D6 metabolism.

The tafenoquine-CYP 2D interaction is also problematic due to the likelihood of CYP 2D6-mediated drug-drug interactions in humans with other antimalarial drugs and commonly prescribed medications.

Colonel Bryan Smith and colleagues, Differential Cytochrome P450 2D Metabolism Alters Tafenoquine Pharmacokinetics, 2015

RECENTLY retired U.S. Army Colonel (Dr) Bryan Smith is among a group of military doctors and scientists from the Walter Reed Army Institute of Research (WRAIR) and the U.S. Army Medical Materiel Development Activity (USAMMDA) who raised serious concerns about the safety and efficacy of tafenoquine, in a series of papers published in scientific journals from 2013 to 2015.

The papers began to be published four years after scientists at WRAIR discovered – in laboratory studies uncovered through FOIA requests by retired U.S. Army Dr Remington Nevin – that tafenoquine “is the only antimalarial more neurotoxic than mefloquine.” Tafenoquine is from a class of 8-aminoquinoline antimalarials which were originally discovered to have been neurotoxic during a WWII-era drug discovery program, on par with the Manhattan project in terms of scientific scale, which found more than 85 of these drugs caused lasting or permanent brain damage in primates subjected to pre-clinical safety testing. For safety reasons, these highly dangerous drugs were then excluded from the clinical testing program which ultimately led to the introduction of primaquine, the standard P. vivax malaria treatment drug for the past six decades.

The papers by Colonel Smith and his colleagues examine the role of the Cytochrome P450 2D6 (CYP2D6) enzyme in metabolizing the 8-aminoquinoline drug primaquine and it’s newer analogue tafenoquine. The studies were undertaken as part of the late-stage tafenoquine drug development process, almost 15 years after tafenoquine was tested on 1,540 Australian peacekeeping troops in a series of notorious drug trials in Bougainville (Papua New Guinea) and East Timor.

The devastating impact of the Australian Army tafenoquine drug trials

CYP2D6 is known to metabolize a quarter of all clinically used drugs and plays a key role in drug safety, efficacy and drug-drug interactions. For people with reduced CYP2D6 function, representing up to one third of some populations, certain drugs can be ineffective and/or dangerous. Additionally, many drugs can inhibit CYP2D6 function, resulting in dangerous drug-drug interactions. One such drug is chloroquine, another quinoline antimalarial which has commonly been co-administered with primaquine in the treatment of P. vivax malaria.

The papers cast serious doubts about the safety, efficacy and hence the commercial value of tafenoquine. In January 2018, researchers from GlaxoSmithKline (GSK) and Oxford University published the results of a large-scale clinical trial comparing tafenoquine to primaquine in the treatment of P. vivax malaria, which found both drugs failed to treat the serious disease in more than a quarter of patients.

The U.S. FDA and Australian Therapeutic Goods Administration had approved tafenoquine several months earlier. Australian neurotoxicologist Professor Jane Quinn and retired Australian Army Major Stuart McCarthy, responded to the GSK/Oxford study in the New England Journal of Medicine, raising further serious doubts about tafenoquine:

Although the participants in the trial by Llanos-Cuentas et al. were not all screened for CYP2D6 status, Baird et al. recently estimated that 38.8% of the population living at risk of P. vivax infection are unable to receive safe and effective primaquine therapy because of glucose-6-phosphate dehydrogenase (G6PD) deficiency and reduced CYP2D6 function. We therefore recommend that CYP2D6 allelotype screening be included in future clinical studies of tafenoquine to address unresolved safety and efficacy concerns before this drug is widely used for P. vivax eradication or prophylaxis in travelers worldwide.

The 8-aminoquinoline/CYP2D6 papers were published while Colonel Smith was the product manager for tafenoquine at USAMMDA, the U.S. Army agency responsible for medical product commercialization and approval. During this period, Colonel Smith oversaw the contractual work of Australian expatriate Dr Geoffrey Dow, a former U.S. Army employee who in 2010 founded his own company, 60 Degrees Pharmaceuticals (60P), then in 2014 was awarded the U.S. Army license for tafenoquine as part of an $18+ million contract to register the drug in the U.S. and Australia. The following year, 2015, Dr Dow stated that his motivation in seeking FDA approval for tafenoquine was to obtain a “priority review voucher” valued at up to $350 million.

USAMMDA promotional video including the tafenoquine U.S. FDA approval celebration in 2018

According to Colonel Smith’s written testimony to a 2018 Australian Senate Inquiry, he retired from the Army at the end of 2015 then immediately began employment with the pharmaceutical consulting firm Clinical Network Services (CNS). Since that time, he has also been employed as the 60P chief medical officer.

Since January 2016 I have been employed full-time as the Principal Medical Consultant for Clinical Network Services. Within this role I am contracted to also operate as the Chief Medical Officer for 60 Degrees Pharmaceuticals. Other than my salary as an active duty officer in the U.S. Army, my current Army retirement pay, and my current salary as Principal Medical Consultant for Clinical Network Services (CNS), I have received no other compensation of any kind for the work I have performed for USAMMDA, CNS, or 60 Degrees Pharmaceuticals.

Colonel Bryan Smith (retired), testimony to Australian Senate inquiry, 2018

After Colonel Smith had commenced his lucrative post-Army career at CNS/60P, three of his former U.S. Army colleagues co-authored a 2016 “current state of the art” paper on CYP2D6 primaquine metabolism with findings that have since been confirmed in a breakthrough study published in a July 2019 edition of Nature Communications, one of the world’s most prestigious scientific journals. The 2016 Marcsisin, Reichard & Pybus paper also made some highly significant conclusions for the commercial viability of tafenoquine (emphasis added):

In addition to addressing the questions raised above, there is a need for the development of liver stage/radical curative antimalarial drugs that do not require metabolism by polymorphic CYP enzymes. Currently, there are no drug candidates in the drug development pipeline that are radical curative that do not seem to require hepatic metabolism. The only other 8-aminoquineoline that is close to fielding and under late stage development for radical cure is tafenoquine. Tafenoquine is a single dose radical curative agent that is a promising alternative to primaquine, however, tafenoquine might also require hepatic metabolism for efficacy as indicated by pre-clinical testing in animal models. … there is a need for the discovery and development of new safer antimalarial agents that treat relapsing strains of malaria and do not require CYP 2D6 metabolism for activity.

This is the first in a series of posts about the dealings of Colonel Smith, Dr Dow, 60 Degrees Pharmaceuticals and their associates. Although Smith and his associates have denied any wrongdoing, in subsequent posts we will dig deeper into this aspect of a story that bears all the hallmarks of yet another pharmaceutical industry corruption racket.

Senior Australian Army doctor accused of culpability over the deaths of tafenoquine and mefloquine drug trial subjects

Australian Army Major Stuart McCarthy in 2015

Vice Admiral Griggs cannot wash his hands of this, try as he might. The ADF caused it, to our eternal shame. The AMI and the authors of those drug trial reports—among them the ADF’s director of military medicine, Colonel Leonard Brennan—bear direct responsibility for those deaths and the legacy of widespread chronic illness among coalition troops. 

Major Stuart McCarthy, testimony to Australian Senate inquiry, 2015

IN Bougainville and Timor, army medical officers also prescribed a drug known as tafenoquine to 1512 troops, even though it had not — and still has not — been approved for use by Australian authorities.

A series of allegations have now been made about the ethics of these trials and the impact they may have had on the mental health of the participants.

One serving army officer who took mefloquine, Major Stuart McCarthy, alleges the trials were “manifestly unethical” because officers compelled soldiers to take the drug without properly warning of the risks.

He’s supported by a US expert who believes the ADF trials were “deeply unethical”.

McCarthy alleges one commanding officer of troops headed for Timor told his men they would not be deployed unless they took part in the trial, which McCarthy says amounts to compulsion.

In evidence to a Senate committee last week, McCarthy named the ADF’s director of military medicine, Colonel Leonard Brennan, as having “direct responsibility” for the chronic illness and death of Australian and allied troops. Brennan is mentioned in academic journals as having been part of the “study team” that tested tafenoquine and he has co-authored articles about the testing of both drugs on soldiers.

Source: Paul Cleary, “Drug trial a test of ethics,” The Australian, September 11, 2015