Thank you very much, Mr. Chairman.
Good afternoon, ladies and gentlemen. I'm delighted to be here.
My name is Ashley Croft, and I'm a retired doctor from the British army. I trained in medicine in London, England, and joined the army in 1986, initially as a regimental medical officer attached to the Royal Horse Artillery as their doctor. I was in Germany and worked alongside the Royal Canadian Horse Artillery, which was very nice. Then I trained in tropical medicine, and I got involved in this field starting in about 1993, until I left the army in 2013.
I didn't want to get involved with malaria. I wanted to do legionnaires' disease, but early on I was told to start looking at this new drug, and I agreed to do so, because in the army you do what you're told. The new drug was mefloquine, Lariam, and during the next 20 years I did randomized controlled trials and systematic reviews of trials.
I'll come to my conclusion straight away—this is a very dangerous drug.
It's uniquely dangerous to soldiers. It is mind-altering and mood-changing, and also causes severely disrupted sleep, so it should not be given to soldiers as a malaria prophylaxis at all, in my view, especially since safer and more effective, or as effective, drugs are available and indeed have been available throughout this time. That's my position.
It wasn't the position I started with. To start with, I was told that this was a new drug, a good drug, and I was given proof that it was a good drug. However, my findings were the opposite of what I expected.
I should start with a little bit of my background. I'm a specialist in infectious disease medical microbiology. I have been working in the field of tropical medicine and travel medicine since about 1992. I'm based out of McGill where we have a very large clinic for both pre-travel preparation and post-travel assessment of people coming back ill. We do provide a lot of preparation. We don't work directly with the military as a rule, so that's not part of our involvement, but we certainly have major activity in terms of preparing people travelling to areas where malaria is a risk. We do see people coming back with various illnesses and we do see a lot of cases of malaria, unfortunately, almost universally in people who haven't taken any prevention prophylaxis.
I'm speaking as a physician and clinician, but I have to mention that I'm a member of CATMAT, which is the committee to advise on tropical medicine and travel for the Public Health Agency of Canada. I've actually been chair of that committee since the beginning of 2019. As a group we have been responsible for producing the guidelines. Under CATMAT, we produce guidelines on a variety of travel issues including malaria and recommendations for the prevention of malaria. I've been involved from that point of view, as well.
I think that the real issue for me is that malaria, of course, has the potential to be a severe disease with a lot of complications and it can be lethal. Prevention of malaria is extremely important and finding mechanisms to prevent malaria that are acceptable and tolerable to individuals is very important.
Essentially almost all cases of malaria can be prevented through a variety of measures, but in particular by taking medication during the time of exposure. Well over 95% of the cases of malaria that we see are in people who either were not taking any preventive medication, were taking it improperly or were perhaps taking the wrong medication.
Mefloquine has been one of the cornerstones of malaria prevention. It was first introduced in 1985. In Canada it was a little bit later—in the early 1990s. I don't think there's any controversy at all about whether mefloquine prevents malaria. There is generally wide agreement that mefloquine does prevent malaria and in terms of preventing malaria, it is roughly equivalent to any of the other approved and recommended drugs that are out there. The issue is not about efficacy against preventing malaria. The debate, I think, is entirely around safety and whether there's a significant difference in the safety and toxicity profile of mefloquine compared with other agents that are available.
As is typical within medicine, the issue is trying to strike a balance between the benefits of the drug versus its safety and tolerability. Although I admit there is some debate and some controversy, nevertheless there is also a lot of data. It's never perfect, but we do have a lot of data. We do have a lot of numbers that I think are quite reliable. Although we can never be completely definitive about some of these issues that are under debate, we do, I think, have a reasonable amount of confidence in the safety and tolerability issues with the drug.
There are definitely real medical debates around mefloquine that need to be considered, but there are also a lot of controversies that I think are not terribly scientific or are pseudoscientific and bear a certain resemblance to the kind of thing that's going on now with some of the vaccine issues.
I'm not going to talk any more about efficacy of prevention of malaria. I'm going to talk only about safety and tolerability issues.
To some extent, there's a problem with making a distinction between an association of taking the drug with adverse events versus the causality. It's always difficult, especially when you're talking about things that can be long term, to make that association. We see the same thing with vaccines and the idea of whether a measles vaccine causes autism. I think the scientific consensus is clearly that it doesn't. Nevertheless, many cases of autism appear at roughly the same time that people get vaccinated, so there is an appearance of causality that I think is not intuitive, to some people anyway, who are involved in the debate.
There is also some confusion about levels of evidence and that we never have 100% certainty in this business about the causality and that type of thing. There are always levels of confidence and levels of probability, and that's part of the problem.
There's the fact that, like vaccines, when you're giving something in a preventive nature.... We're talking not about giving a drug to treat an illness—mefloquine can also be used to treat malaria—but in this case we're talking about prevention. The trouble is that, just like vaccines, the risks are generally not going to happen to the same people who are going to get the benefit.
The people who benefit from the prevention of malaria are essentially invisible, because when the thing works, the people are well and don't get sick. You don't see in front of you the effects of the prevention; you see essentially that people are well. The adverse effects that can happen from any drug—mefloquine or any drug, or any vaccine—will happen not necessarily to the same people where you're preventing the disease. You don't know who those people are for whom you're going to prevent the disease. You can see adverse events that happen to some, hopefully, small proportion of people, whereas you don't actually see the benefit in front of you because that's a preventive effect.
There are obviously other problems that happen in all of medicine, but here as well. In some cases, there are vested interests and ulterior motives that some people may have, in terms of either promoting the drug or having problems with it. Of course, just like the vaccine world, there's been a lot of sensationalistic stuff over the many years in the media about mefloquine, and very prominent attention given to some particular cases of issues that may or may not have been related to the drug.
The problem with safety is that the most common types of studies that we use to study the efficacy of a drug, which are the so-called randomized controlled trials, are not great studies for safety and toxicity. The double-blind studies that are done are fantastic for trying to have a lot of confidence in the outcomes of the study, which is very critical in trying to decide whether a drug works or doesn't work, but because they're so complicated, the studies are relatively small and relatively limited in time.
When you have effects, adverse events that are rare or that may happen over the long term, they may not be captured in this gold standard of clinical evidence, which is the randomized controlled trial. For safety and tolerability, we're stuck more with so-called cohort studies, where groups of people are followed over time. The fact that they have received one drug or another drug, no drug at all or a placebo is not done in a randomized fashion, so the studies are prone to a certain type of bias. However, you can also open up those studies to much larger numbers of people so that it becomes possible to detect rarer types of adverse events, as is the case with the types of issues of mefloquine that we're talking about.
The studies give you less confidence sometimes about the true causal nature of taking the drug versus the adverse event, but you hopefully overcome that by having large studies and multiple patients all showing similar types of effects.
That's what we have basically for mefloquine. We have the randomized controlled studies, which in fact generally have never shown that mefloquine has a worse safety profile. It has a different safety profile, but not necessarily a worse safety profile than the other alternatives. It became known, because even in the randomized trials, there was a signal that there were some side effects of a neuropsychiatric nature that we were seeing more often with mefloquine than with other drugs.
The randomized controlled trials did not give any indication of a severe problem or a problem that was not reversible, and didn't give evidence that the overall tolerability or the overall severe adverse event rate was much different from that of the other drugs to which it was being compared. The big cohort studies were undertaken to also look at some of these things.
Again, it's a bit difficult sometimes, because we understand that some of these effects may be seen perhaps in different ways in different types of travellers; people who are going on short-term trips and have short-term exposure to the drug might not be the same as people who are on long-term trips and have long-term exposure. People who are in certain types of conditions, who are travelling under certain types of conditions, such as the military or other groups where there is a lot of stress related to the travel to begin with, and whether or not the drug might have some kind of additive effect on top of some of the risks associated with the underlying reason for the travel.... Those are difficult to untangle in some of these studies.
Nevertheless, as a group, I think the study.... There's a lot of data. When looking particularly at long-term adverse events, the long-term adverse events that are relatively rare don't seem to happen more often with mefloquine than with other agents, although the nature of things might be different. As I say, some of the neuropsychiatric types of things seem to be perhaps more common.
In terms of how many people discontinue the drug versus other drugs, compared to atovaquone-proguanil, which is one of the main common choices these days, a few more people tend to discontinue it than atovaquone-proguanil. With the main other drug that's used, doxycycline, about the same number of people discontinue.
The types of neuropsychiatric effects that are described in these studies are mostly things like insomnia, strange dreams and feelings of anxiety or a depressed mood. These are generally self-reported and not documented in a formal, objective kind of way, but in terms of long-term effects we have studies of hundreds of thousands of participants. When in these long-term studies and these big cohort studies you're comparing the drugs against each other, there has really not been a difference that's detected. What we have as evidence that there are long-term complications and sequelae of taking the drug are really case reports—some small case series—but we don't have evidence of comparing one drug against the other that—
I know this committee wants to look at the most recent research. My research is a bit historical now. The most recent research, which I think Dr. Libman will agree with, is the Cochrane review. I did the first Cochrane review of mefloquine, published in the British Medical Journal in 1997. It has now been updated four times. The most recent review, which looks at all the randomized controlled trials and tries to extract that type of data, came out in 2017.
To answer the question, that review looked at 20 different randomized controlled trials of mefloquine. It found that comparing it with, say, atovaquone-proguanil, three times more people taking mefloquine were likely to stop taking the drug because of side effects.
That really makes it not as effective. I know Dr. Libman is looking very doubtful, but the relative risk is 2.86, which I interpret as meaning you are three times more likely, if you're taking mefloquine, to stop your drug. If you stop your drug, you risk getting malaria.
Within that analysis, they are comparing mefloquine and atovaquone-proguanil. They find that 6% of mefloquine users discontinue the drug, 13% get insomnia, 14% get abnormal dreams, 6% get anxiety and 6% get depressed mood. That gives you a flavour of the types of figures one can expect, bearing in mind that these studies, these randomized controlled trials, tend to be done in perfectly healthy, unstressed populations. For soldiers, those figures are likely to be comparable or perhaps worse.
When you look at the comparison with doxycycline, the figures are even worse. Of mefloquine users, 31% get abnormal dreams, whereas only 3% of doxycycline users get abnormal dreams.
Doctors, thank you both for being here today. We appreciate that.
Dr. Croft, you mentioned the civilian population and travelling, and Dr. Libman, you're involved with travelling with CATMAT, etc. Part of what we've heard from veterans, not only in this study but in previous studies we've done, is about the serious side effects and issues they've had to deal with. As well, we also heard from civilians who have been travelling around the world and in Asia. They've been given mefloquine and then been told by Australians to get off that medication and take things like doxycycline.
With that said, Health Canada has come out with a checklist on contraindications for mefloquine, and basically in a change to their monograph, they've added that “the risk of permanent dizziness, vertigo, tinnitus and loss of balance has been clarified”. They've identified that for the health care practitioners and professionals, to make sure they're aware of that fact.
In fact, they even go down to the “Key messages to convey to patients” section, to say this:
Serious mental and nervous system side effects may occur at any time while taking mefloquine, and in a small number of people, may last for months or years after stopping mefloquine. In some people, dizziness, vertigo, tinnitus, and loss of balance may become permanent.
The Canadian military, in the last six months, has come out and said that they will no longer use mefloquine—
This was reported in February 1995 in the journal of the Canadian Medical Association. It's a report that would have been read by all Canadian doctors, including military doctors.
It was a case where two buddies were in a tent. One of them was taking mefloquine and the other was taking nothing, because he was a tough guy. They were prospecting for rocks in Tanzania. The guy taking mefloquine took it every Sunday, and everything was going fine. He was getting no side effects.
Then one day, three weeks into the trip, they shared a bottle of whisky on a Saturday night. The effect of that was to make the one who was taking the mefloquine psychotic, while the other one experienced nothing. He started getting auditory and visual hallucinations and was convinced his buddy was going to murder him, so he was going to murder him in exchange, but he controlled himself.
The next day he got very depressed for a day, and then he recovered. He felt a bit strange but by Tuesday he was all right, so everything was fine during the week.
The following weekend—this is all in the paper, by the way; these were Canadian geologists—exactly the same thing happened. They shared a bottle of whisky. The one taking mefloquine became psychotic and had hallucinations, was convinced his buddy was trying to murder him, and wanted to murder him in exchange. The next day, he took his mefloquine tablet and went into deep depression for a day, and by Tuesday was all right.
He decided it had to be the interaction between the mefloquine and alcohol. He decided to stop drinking whisky at the weekend and the rest of the trip he was fine. He came back to Canada and was seen at the Ottawa Civic Hospital. They said this looks like a serious interaction with intense alcohol exposure. They published the report, and of course, that didn't go down at all well with the drug company, because they didn't want a drug that was meant for tourists to have a precaution against alcohol with it.
They set up their own—what I call bogus—alcohol study, which they published the following year, which they carried out to discredit this very important, and in my view, very persuasive Canadian report. In the Dutch study, they got a population of 40 very healthy young people who were more or less teetotallers. They gave them a thimbleful of alcohol— 50 grams—in orange juice, over two hours. Some of them were taking mefloquine and some weren't, but they hadn't taken any mefloquine for a day. Then they put them out on the road and made them drive around and do some other tests and they published it as showing there was no effect of alcohol and mefloquine at all, at least not at low doses.
By that strategy, Roche were able to discredit this very important, in my view, hazard to taking mefloquine. It is one that the troops will inevitably face because that's the way soldiers drink. They don't drink moderately. They drink heavily once a week and if it happens to coincide with the day they take mefloquine, it seems to be a great risk, based on this Canadian study.
During my 20 years in the army I saw it again and again. It was very often the influence of taking alcohol at the same time as mefloquine that made soldiers act irrationally and completely out of character.
After some time, I persuaded to have a policy change in the British Army, which was introduced in December 2005. A policy letter came out: Soldiers taking mefloquine were not to take alcohol; female soldiers were not to take the oral contraceptive pill—it seems to have the same kind of effect— and they were not to take other prescription drugs.
That seemed to mitigate the risk. After that date we observed many fewer episodes of mefloquine-related events, if I may call them that.