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Foreign Affairs, Defence and Trade References Committee
30/08/2018
Use of the quinoline antimalarial drugs mefloquine and tafenoquine in the Australian Defence Force

REID, Mr Mark, Private capacity

[11:00]

CHAIR: Welcome. Thank you very much for your time. Information on parliamentary privilege and the protection of witnesses and evidence has been provided to you. For the Hansard record, could you please state the capacity in which you appear today.

Mr Reid : I am an Australian Army veteran and I was a study coordinator for study 033 in East Timor.

CHAIR: I now invite you to make a brief opening statement before we proceed to questions.

Mr Reid : Study 033 is the most comprehensive randomised control study of preventive antimalarial drugs conducted in living memory. There is very little prospect that a new preventive antimalarial will ever be registered after tafenoquine. There has been no underreporting of adverse events during ADF studies; and these studies were audited by both the TGA and the FDA, including the consenting process. This allegation has been made repeatedly by the Quinism Foundation. Ex-Army psychologist Mr Jaroslaw Michalski, in submission 84, has commented that he saw higher rates of psychiatric adverse events during study 033. This is indeed true. But we observed no similar incidents of abnormal dreams, nightmares or insomnia in civilians taking the identical dose of tafenoquine for just as long as the ADF soldiers. The insomnia cases all occurred within one day of arrival or two days of leaving East Timor and reflect pre- and near- end deployment anxiety, not drug effect.

Detection of psychiatric adverse events associated with deployment reflects the cooperation of our soldiers and very intensive interviewing conducted during these clinical trials. The adverse event reporting rates were the highest for the ADF—at nearly 95 per cent—out of the five key studies. All this data has been published in a peer reviewed medical journal. Very large well-controlled studies by Ecost and Schneiderman, analysing the risk of antimalarial drugs in war theatres with hundreds of thousands of US servicemen, showed the major risk factor for psychiatric adverse events is combat stress, not antimalarial drugs.

The 17 psychiatric adverse events reported to TGA over a five-day period in February 2017 were self-reported after a Facebook campaign more than 16 years after the studies ended. Only motion sickness, vertigo, anxiety, mild abnormal dreams and lethargy were captured in the study databases. It is extremely unlikely that the PTSD-like events occurring 16 years after the fact are connected to these clinical trials. I coordinated the submission of 152,000 pages of tafenoquine data to both the FDA and the TGA. Every piece of information we had was filed for independent review by these regulators and their expert advisory committees. There are no conspiracies here.

No-one is going to retire from selling tafenoquine. The reality is that malaria kills poor people and harms our soldiers. This is why the disease is largely ignored by pharmaceutical companies. Almost a billion doses of chloroquine have now been prescribed, and 35 million-plus doses of mefloquine and countless doses of hydroxychloroquine to treat rheumatoid arthritis and lupus, and there has been 60 years of primoquine use to treat vivax malaria relapses. Millions of lives have been saved but we have never seen a global pandemic of permanent brain injury from these quinoline drugs that have been used since World War II. We are now in the very real danger of repeating public health mistakes led by Dr Andrew Wakefield with the MMR vaccine and the allegations that this vaccine caused autism 20 years ago.

For our veterans that are suffering mental health problems today, the claims of the Quinism Foundation that they have chemically acquired brain injury is interrupting their treatment and their compensation. Our current and future soldiers risk a fatal infection if they read these social media commentaries and decide not to take their antimalarial drugs. The modern battlefield is already dangerous enough given the four-dimensional nature of warfare without adding to this risk with mass digital misinformation. There are now multiple-drug-resistant malaria parasites in South-East Asia. The newly adopted first-line treatment is artesunate-mefloquine. The public health community cannot afford to have this aggressive misinformation campaign spread from Australia. Multiple-resistant malaria in sub-Saharan Africa will be absolutely devastating.

I would also like to mention that I have taken tafenoquine, mefloquine, doxycycline and primaquine. I have not taken Malarone. Being a veteran, I am very sensitive to the needs of our veteran community. I am absolutely in agreement with the testimony of Corporal Armstrong and Major McCarthy that we need mental health resources for our soldiers. But we absolutely need to separate out the issue of mental health from protection of our forces with medical countermeasures. We can't recover from public health disasters easily. It takes years and years and years to correct the record and to be able to move on and support these people.

CHAIR: Thank you. The obvious question that comes to mind is the motivation for your appearance and evidence here today. Is it a matter of public interest? Is it a matter of public health? Are you representing anybody?

Mr Reid : I am representing myself as a veteran and in the interests of public health. My conflict of interest ended when I submitted my dossiers to the TGA and the FDA. My job there, under a consulting agreement, was to submit all pieces of evidence, negative and positive, so that our independent regulators could make a decision with their independent committees. That is where my conflict of interest ends. I don't mind who uses tafenoquine or who uses mefloquine. What's important is that we have the tools in our war chest to be able to swap people between medications if they don't tolerate them.

CHAIR: You mentioned another drug, Malarone, which I might have taken myself. Is that a commonly prescribed antimalarial treatment for travellers?

Mr Reid : It is.

CHAIR: What's the difference? Is it part of a suite of drugs?

Mr Reid : It is a suite of drugs. Malarone is not indicated for preventing vivax infection, which, as Major McCarthy indicated, it is the predominant strain of malaria in South-East Asia. It is currently a second-line therapy for the ADF. Mefloquine is our third-line therapy and doxycycline is our first-line therapy. The danger with doxycycline is that it is a suppressive drug. It allows the infection to occur in the liver, and then what happens is that you are basically just managing the blood infection by just knocking down the parasitemia. It has a half-life of 12 hours. The reason we saw such high crude attack rates in our East Timorese battalions is that, if a soldier misses his dose, he isn't protected and then he could come down with clinical malaria in the field. And then we use primaquine to eradicate what is living in the liver at the end. We need to move away from this ideology of using suppressive therapies to protect our soldiers. We need drugs that are safe and effective but kill what is in the liver as well as in the blood. This is what, hopefully, tafenoquine will offer in the future.

CHAIR: As Senator O'Sullivan said, there is always a list of side effects, whichever medication you take. It could be blood pressure tablets. It could be anything. Is there a connection between anxiety and indications of post-traumatic stress which go unreported in Defence and then the application of a drug? I presume you are not going to get deployed if you say you are suffering from anxiety. Is there a culture of underreporting significant issues which may then be complicated by the administration of mefloquine or tafenoquine or any of these things?

Mr Reid : Mefloquine now has a warning not to give it to someone who has a pre-existing psychiatric disorder, because it increases the risk of that psychiatric disorder presenting again.

CHAIR: In your experience, how does Defence deal with that issue? How do you know that you are not giving it to someone who has a pre-existing injury?

Mr Reid : I left the Army in 2007. When we did the 033 study, we very carefully looked at all the medical records to make sure that those soldiers were safe in taking both tafenoquine and mefloquine. I remember Colonel Nasveld working day and night reviewing those medical records. Fortunately, the ADF is now moving to an electronic health record system. So, in theory, we can now move faster in saying: 'Actually, that soldier would not benefit from being on mefloquine. We need to put him on Malarone, tafenoquine or doxycycline.' From our study records, there are very good examples of how we manage this. Actually, a corporal in Mr Armstrong's position presented to me on 12 December 2000 and said, 'I'm not feeling well.' I said to him, 'What's wrong?' and he started laying out his symptoms. Colonel Nasveld was next to me interviewing the other soldier. Colonel Nasveld said, 'Let me take this one.' We swapped over. We interrupted the interview. You can see in the medical records where my handwriting stops and Colonel Nasveld's records begin—and I showed that to the auditor. That soldier was taken off the study drugs. He saw a psychologist that afternoon and we put him on an anti-depressive treatment. He was kept in theatre. His depression resolved by day 84 but, subsequent to that tour, he came down with post-traumatic stress disorder. That soldier, like Corporal Armstrong, was a Rwanda veteran and he also had an intracranial brain injury. An intracranial brain injury predisposes you for depression, and he presented with a major depressive episode during our study. We have documented that. In my opinion, I don't think anywhere in Australia would have managed him better in terms of his care at that time.

Senator MOORE: Mr Reid, thank you for your evidence. There seem to be two major focuses of this process. You heard the earlier evidence, and I know that you have been following this. One of the recommendations from some of the previous witnesses is that there should be no trials using Australian Defence Force personnel. Do you have a view on that?

Mr Reid : I do. I think that is an incorrect decision.

Senator MOORE: Why?

Mr Reid : If you look at Professor Karunajeewa's evidence, the level of care increases when you conduct clinical trials. If you look at hospital records in the UK, those hospitals that conduct the most clinical trials have the best patient outcomes. Part of our success with 1 Battalion was the fact that we created so much awareness of malaria as a risk factor. It is the only infantry battalion that has ever deployed into a malarious area with no clinical cases in the field. And it wasn't just the drugs that achieved that; it was the actual awareness of having people there with a specific mandate of force protection under a controlled clinical trial. Actually, in the mefloquine studies—and it is in my submission—we didn't have enough good evidence of mass mefloquine administration. A lot of armies use it first line. I agree with Brigadier Wayne Ramsey, the retired director-general at the time. He was cautious about that. He didn't want an experimental drug trial being an inducement for the soldiers to go into the trial unnecessarily. He wanted the option of them taking open-label mefloquine. And that was a question from Senator O'Sullivan: how did we manage soldiers who didn't want to be on the study? That was our choice, as the medical team responsible for that battalion.

It doesn't matter what Colonel Caligari wanted. He wasn't there consenting those soldiers and advising them that it was a voluntary study. We were doing that at Lavarack Barracks medical centre, and we were offering them the choice: they could participate in the study; they could take open label mefloquine, provided they were supervised; or they could take doxycycline. As long as they were protected by an antimalarial, which was Colonel Caligari's requirement, it was up to us as a study team to manage who went on what. We had soldiers say: 'Absolutely not. I am not participating in this study.' 'That's fine; we'll put you on open label mefloquine.' 'No, I don't want to take that. I want to take doxycycline.' 'That's fine; we'll put you on doxycycline.' But they had to take an antimalarial.

So, to answer your question, we live in an evidence based world and the ADF is no different. If we're going to protect our forces—I'm not talking about the latest generation helicopters or ships or tanks or vehicles—with the very best medical countermeasures, we need to do clinical trials. We need to supervise our soldiers when we're introducing something new, and we did that with mefloquine. There was no way we were allowing 2 or 4 Battalion to go to East Timor without a study team supervising their use of mefloquine. Wayne Ramsey required that. It was a very cautious and appropriate opinion 20 years ago, until we had more experience with the drugs.

So we monitor these soldiers in the field taking these drugs. Even from our veterans' perspective, we don't innovate. We have a veteran here with what looks like PTSD—I'm not a medical officer—but, by his own testimony, there is something else going on. That needs to be investigated, and the forum for doing that is randomised clinical trials where we can take all the bias out of the equation and look at what the risk benefit is. Because every single drug you take is a poison. Paracetamol, aspirin and everything we take is a poison, and it comes down to risk benefit. What is the risk of our soldier being exposed to a nerve agent or malaria, and how do we counteract that?

Senator MOORE: You've obviously taken a strong interest in this and your submission was very useful. It seems that, across the world, since that time there have been more concerns raised about mefloquine. From my reading and so much else, it seems that a lot of the public awareness and concerns, particularly overseas, have come since 2000. There seem to be people asking questions now about what happened and what could happen in the future. From your perspective, you're saying in your submission that you think that people getting concerned and sharing concerns and being fearful may impact on their current treatment and may impact on their health all-round. Is there a middle road there somewhere, where you can address the concerns that people are raising without stopping the current treatments?

Mr Reid : We're in a difficult world today because of the access to social media and Dr Google. This applies across the board for all drugs and all vaccines. I encourage people to, by all means, read the commentary. But talk to talk to people before you make decisions not to take drugs. And, for goodness sake, if you're having symptoms of serious side effects with an antimalarial, report to you regimental aid post and tell them.

We don't put inexperienced soldiers into the field. They have been scrutinised, they have been trained, they have been distressed. They are valuable. We are not going to pull them out of the field for a drug reaction to an antimalarial. We're going to move them on to something else, because we need to retain that asset in the field. These people are valuable. So, from my testimony, we need options to protect our soldiers. We need to do clinical trials, but we need to be very mindful that what is being said is not always accurate and can be harmful.

CHAIR: In the spirit of looking for some middle ground, there are obviously a number of veterans who are aligning their PTSD and the severity, for want of a better word, of their PTSD to this malaria trial. Is there a case for the department to initiate a study to get to the bottom of that? Is it a large group of people? They're obviously getting compensated. They're obviously getting treated. They're saying that it should be a slightly different treatment. Would it be all that hard to draw up a clinical trial with these people to investigate and get to the bottom of it and give them the best possible outcome?

Mr Reid : There have already been studies done in hundreds of thousands of veterans from the US Army. This is the Yetcoss paper and the Schneiderman paper. We could repeat that. I suspect that the outcome would be the same. It's a question of where we best direct our resources. The sponsor of tafenoquine is actually conducting a long-term safety risks study in Australia and the US, age matched against the ADF. What we're looking for is: can we show that these reactions don't occur in a civilian population without the stress of combat. We want to repeat what we've seen already in the meta-analysis of the five clinical trials that clearly show that if you're not subjected to combat you don't experience these abnormal dreams and things. The studies are going to be different. Ours is a prospective, randomised controlled study. It is the best level of evidence, but it's 600 people. If you want to look at very, very rare outcomes you can't do a randomised controlled trial—it's prohibitively expensive. What we can do is observational studies—looking back at records and trying to work out where the risks fall, where is the risk and benefit—but they are subject to bias. There's recall bias, sample bias and selection bias. We would have to consider how to do those studies carefully, but there are precedents. I think it would be valuable to put this matter to rest.

Senator O'SULLIVAN: Just so I can get my head in this space, apart from your service in the ADF, what's your discipline? Do you have academic qualifications?

Mr Reid : I'm a qualified scientist, yes.

Senator O'SULLIVAN: What do you mean by that? You've got a degree in science majoring in any particular element of science?

Mr Reid : I have a bachelor of science with honours in microbiology and biochemistry, I have a master's in medical science and drug development, I have a master's in business administration and I am regulatory certified in Canada, the United States and the European Union.

Senator O'SULLIVAN: So I can get the background, what's your business? You assist clients—I shouldn't put words in your mouth. What's your business?

Mr Reid : I compile evidence to submit to regulators.

Senator O'SULLIVAN: On behalf of a client?

Mr Reid : Yes.

Senator O'SULLIVAN: Has any of your work been on behalf of any of the pharmaceuticals that have been involved in the manufacture of these drugs?

Mr Reid : I was approached by the US Army to assist them. They asked my advice on how to progress tafenoquine. I suggested that they compile every piece of data they had and submit it to regulators for regulatory review. Through a third party they contract me, because of my involvement in the East Timor study, which was our most comprehensive dataset in non-immune people. They contracted me to help review all their evidence, compile it and submit it to TGA and FDA.

Senator O'SULLIVAN: The third party was a contract clinical research organisation in the United States.

Senator O'SULLIVAN: My line of questioning has nothing—I want to get onto my line of questioning. Either directly or indirectly, has any of the work that you've done at any stage had any connection to any of the pharmaceuticals who manufacture any of the drugs that are the subject of this inquiry.

Mr Reid : Yes.

Senator O'SULLIVAN: Who would that be?

Mr Reid : Tafenoquine, obviously. 60 Degrees Pharmaceuticals and—

Senator O'SULLIVAN: Can you explain for the committee your direct or indirect involvement with that manufacturer.

Mr Reid : The US government cannot file drug applications. They're prohibited from doing it. So they sought a third-party company to actually take over the licence for tafenoquine, to enable that application to be submitted. No pharmaceutical company wanted to take it. The only company that was interested in tafenoquine as a chemoprophylaxis was 60 Degrees Pharmacuticals. I've consulted for them, and—

Senator O'SULLIVAN: The work that you referred to—a massive piece of work, by the look of it, on face value—you did on behalf of 60 Degrees?

Mr Reid : Sixty Degrees and the US government, who are the co-development partners for tafenoquine.

Senator O'SULLIVAN: Were the US government—

CHAIR: Can we just go back? Mr Reid, I think you mentioned earlier that no-one would look at these drugs because they were only used for poor people and the military. Is that what happened here?

Mr Reid : Yes.

CHAIR: So, because there's not a great market in the poor nations of the world and in the military for these drugs, there's no money in it for any pharmaceutical provider?

Mr Reid : That's correct.

Senator O'SULLIVAN: I just want to try and get these relationship lines, because they're important, as you'd appreciate, as we give weight to the various testimonies that are provided. Is it the case that the US military, using public funding, socialised funding, paid 60 Degrees to embark on this journey?

Mr Reid : No. They're not allowed to.

Senator O'SULLIVAN: Did they have a partnership with 60 Degrees?

Mr Reid : It's a data-sharing agreement.

Senator O'SULLIVAN: But, in the event that the drug miraculously becomes a perfect drug and has a turnover of a billion dollars a year, where would the US Army sit in that circumstance?

Mr Reid : The US Army would be paid royalties. If it ever achieved a billion-dollar sale, I would be extremely surprised.

Senator O'SULLIVAN: Of course. I appreciate that. When I give my examples, I give them in the extreme, because it saves spending a lot of time trying to explain them.

Mr Reid : Sure. Dr Geoff Dow has raised his own private funds to try and get tafenoquine approved so we can do something about the malaria problem globally. It is the only drug that has a prospect of helping eliminate malaria. He is millions of dollars in debt.

Senator O'SULLIVAN: As are so many entrepreneurs who pursue an idea to get registrations or patents around the world. I'm going to ask you a question, and it will allow me to measure, or weigh, your involvement. What financial benefit would you have received from when you accepted the appointment with 60 Degrees, or any other agency or associated agency, to this point in time? How are you remunerated for this massive effort?

Mr Reid : I am paid on a time-and-materials basis.

Senator O'SULLIVAN: Do you have a sense of what you may have received over the time?

Mr Reid : I've recently started my own consulting company, because I left my previous employer. I was paid a wage by my previous employer for 99 per cent of this work.

Senator O'SULLIVAN: Who was the previous employer?

Mr Reid : Clinical Network Services.

Senator O'SULLIVAN: With respect to the drug, what are the parameters and what is the nature of the relationship with 60 Degrees? You're a consultant to them. That much has been established. Do you have any equity interest if this drug were to go ahead and be approved?

Mr Reid : None at all.

Senator O'SULLIVAN: So your relationship has a beginning, a middle and an end with 60 Degrees?

Mr Reid : Absolutely.

Senator O'SULLIVAN: Clearly at some stage you've become convinced of the evidence you've given us based on your academic examination.

Mr Reid : Yes. I've taken six drugs to market, and I've never seen more convincing evidence of efficacy in a drug program than for this drug.

Senator O'SULLIVAN: But your initial connection with this was when you were in the military.

Mr Reid : Correct.

Senator O'SULLIVAN: You were in a section of the military that formed the view that a trial should occur. Were you involved in the construct of the trial?

Mr Reid : I was posted to the Army Malaria Institute when I corps transferred from the infantry, and my first and only assignment in malaria was running Study 033.

Senator O'SULLIVAN: My experience—which is limited with academic studies—is you'll lay down the parameters of a study before the study begins, including satisfaction around ethics and the like about informed consent, how that will be and so on and so forth. I imagine that would be a document that is presented as the basis for the decision to go ahead with the trial.

Mr Reid : Correct. It's called a clinical trial protocol.

Senator O'SULLIVAN: Of course. Do you have a copy of that in your possession in private life?

Mr Reid : No.

Senator O'SULLIVAN: So if we wanted to get that document to have a look at what the pre-thinking was around consent and informed consent and people who might resist and so on, that would be with the Australian Defence Force now.

Mr Reid : The document and all the informed consent forms are 12 kilometres to the northwest of this location.

Senator O'SULLIVAN: They are at Enoggera.

Mr Reid : Enoggera, yes.

Senator O'SULLIVAN: But my point is that, if this committee wanted to access and look at the pre-trial considerations, the only ones who have possession of that document would be the Australian Defence Force.

Mr Reid : The protocol was filed to the TGA and the FDA, so the TGA has a copy as well.

Senator O'SULLIVAN: Would that be on the public record? Would that be able to be accessed?

Mr Reid : No. It's part of a commercially confidential submission to the TGA.

CHAIR: But if we were going to Enoggera this afternoon, we could get a look at the document.

Mr Reid : I imagine so, yes, provided it's not got confidential patient information.

Senator O'SULLIVAN: No, you perhaps misunderstand the burden of my question. Prior to even a decision by the Australian Defence Force to conduct a trial, this document exists—it's the architecture of what they'll do if they decide to do it. Why would that be confidential on any level? I'm coming from the angle of transparency now. As something submitted to our regulators here and overseas, on which element could one make an argument that that's commercial in confidence?

Mr Reid : It's not my decision to make.

Senator O'SULLIVAN: No, I'm not asking you if it was your decision. You had reflected on it in your evidence, and I'm asking you why you think that would be the case.

Mr Reid : The substance of the study was published in 2010. All the relevant details of the study were published.

Senator O'SULLIVAN: I appreciate that, but my question is confined to the documentation that was prepared for submission to the Australian Defence Force in this case for them to be able to make a decision in the first instance. You're in a room, the decision-makers go through it and go: 'Look, I think you've covered all the bases. I think this is something we will do.' On your own evidence, you say that, when the application is made to the regulators, that document is submitted along with all that happens after that event. Is my understanding correct?

Mr Reid : Correct.

Senator O'SULLIVAN: My question to you is: our regulators publish bits and bobs, and some of it's commercial in confidence—I understand that; it's like a patent application—but what would be commercial in confidence in that original document that the world shouldn't be able to see? Given that we've certainly had thousands—I don't know how many—of our defence personnel subject to this trial, why would that still be commercial in confidence?

Mr Reid : I'm saying in general terms that anyone who wants a copy of that document can put in an FOI request.

Senator O'SULLIVAN: One last time, and I'm not trying to badger you: I'm reflecting on some evidence that you had given to this committee where, when I originally asked you whether a member of the public or one of these young men and women who've been through the trial could access this via the regulator's application, your answer was related to commercial in confidence over an ADF document that preset a trial. You can withdraw that if you choose to, but I'm asking you why you think that would be the case.

Mr Reid : I would personally have no objection to releasing the protocol. I would have reservations about releasing some datasets that can then be twisted, cherry-picked and put on social media.

Senator O'SULLIVAN: Mr Reid, please. With respect, I haven't asked you about the datasets that didn't even exist at the time that someone—

Mr Reid : Senator, I just answered your question. My answer is that I personally don't have any reservation about release of the protocol.

Senator O'SULLIVAN: I wasn't asking you about your reservation. I was asking you about your evidence to this committee that you didn't think it would be available in public space with transparency with the regulars because of commercial in confidence.

Mr Reid : They're not normally released.

Senator O'SULLIVAN: Let me share your concern.

Mr Reid : Protocols are not normally released.

Senator O'SULLIVAN: They may not be, but I'm asking you—

CHAIR: Perhaps it may assist the committee if we take Mr Reid's evidence at face value and ask Defence, the Therapeutic Goods Administration or whoever what their opinion is, because he's not in a position to make the decision. I accept his evidence as his evidence, but he's not in a position to make a decision.

Mr Reid : I can only advise. I can't make the decision for sponsors or co-development partners to release documents. Personally, I don't—

Senator O'SULLIVAN: So that I'm clear now—and I won't persist with it, Chair—a document formed by the Commonwealth of Australia and resourced by the Commonwealth of Australia through the Australian Defence Force that preceded a trial of our personnel and that is later attached to a commercial application to have a drug approved, in your view, would not be published because it was commercial in confidence? That's the evidence.

CHAIR: That's the evidence we have.

Senator O'SULLIVAN: I just want to be clear that that's the evidence I've heard, and I won't persist with it, Chair.

CHAIR: That's fine. We'll just ask the other people. Let's get a look at it.

Senator O'SULLIVAN: All right. I'll take Mr Reid's silence as meaning that I captured that. I have no further questions.

CHAIR: Thank you very much, Mr Reid, for your submission, for your appearance here today and for answering our questions.