Evidence of meeting #119 for Veterans Affairs in the 42nd Parliament, 1st session. (The original version is on Parliament’s site, as are the minutes.) The winning word was mefloquine.
A recording is available from Parliament.
Liberal
The Chair Liberal Neil Ellis
I call the meeting to order.
Pursuant to Standing Order 108(2), we are studying of the effects of mefloquine use among Canadian veterans. Before us we have Dr. Ashley Croft, consultant public health physician. We'll start with you, Dr. Croft. You have the floor.
Dr. Ashley Croft Consultant Public Health Physician, As an Individual
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.
Dr. Michael Libman Professor, Department of Medicine, McGill University Health Centre, As an Individual
Hello.
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—
Liberal
The Chair Liberal Neil Ellis
Dr. Libman, I'm sorry. You're down to about 30 seconds. I'll just get you to wrap up and then we'll have some questions.
Professor, Department of Medicine, McGill University Health Centre, As an Individual
Basically I would say that in terms of the status of the evidence of long-term psychiatric effects of mefloquine, we have case reports. We can't.... Despite studies of hundreds of thousands of subjects, we can't demonstrate that this is confirmed, and if there are these types of effects, we presume that they are actually very rare.
Ultimately, the choice of mefloquine versus other drugs is going to be an individual type of choice. Individuals will have different risk factors where you might want to choose one drug over the other for a whole variety of reasons. Whatever the problems are with mefloquine, they're not of a nature that you would want to take that option off the table entirely, in my opinion.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Thank you, Chair.
Thanks very much to both of you for being here today.
Dr. Libman, you've just become the chair—in 2019—of CATMAT. Is that correct?
Professor, Department of Medicine, McGill University Health Centre, As an Individual
That's correct.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Thank you.
Our surgeon general put out a report in June of 2017 in regard to mefloquine. When I look at the report, I see that a lot of the information came through CATMAT. Were you involved in the research that was done for that report for the surgeon general?
Professor, Department of Medicine, McGill University Health Centre, As an Individual
I'm not a malaria researcher. I haven't been involved in that particular research or, in fact, in research on mefloquine directly.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Not directly...okay. Thank you.
Dr. Ashley Croft, you mentioned this in a statement:
There is no organisation more entrenched than a government department whose senior members are anonymous and unaccountable to the general public. Safer alternatives to mefloquine (doxycycline and...[Malarone], for example) have been available for decades.
Would you like to make any comments on that, please?
Consultant Public Health Physician, As an Individual
Yes. Doxycycline has been available since 1991 at least, because that's when Pfizer licensed it. Potentially, it was an anti-malaria drug that could have been used in the nineties. In 1997, there was an important randomized controlled trial, which Professor Libman has referred to as being the “gold standard” of evidence, conducted in soldiers in Indonesia by an U.S. Army research team. This found that it was extremely effective at preventing malaria. The efficacy was 99%.
The tolerability of it was excellent as well.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
You do say there are safer alternatives to mefloquine. Why do you say that?
Consultant Public Health Physician, As an Individual
That's a safer alternative because it doesn't have the profile of neuropsychiatric events that have been seen with mefloquine from the very beginning. Right from the 1980s it was known that neuropsychiatric events were associated with this drug. In 1989, the World Health Organization put out a technical document that said that people operating heavy machinery should not use this drug. In 1991, they reiterated their concern about the neuropsychiatric events, saying there really needed to be more research about these events—what causes them, how they can be mitigated and how they can be prevented completely.
From the outset, mefloquine has been known to be unsafe in terms of its neuropsychiatric profile. That's why I said it's uniquely dangerous in soldiers because soldiers have to be at peak performance psychologically to do their jobs.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Dr. Libman, you mentioned it briefly, but I'd just like to ask this directly: How extensive is your background related to the study of mefloquine specifically?
Professor, Department of Medicine, McGill University Health Centre, As an Individual
I'm familiar with, I think, nearly all the research that's been done. I haven't participated in the research projects.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Are you familiar with the research of Dr. Ritchie, Dr. Nevin, Professor Jane Quinn from Australia and Dr. Edward Sellers? They've all been testifying at this committee.
Professor, Department of Medicine, McGill University Health Centre, As an Individual
Yes, I'm generally familiar with it. I can't say I've reviewed it specifically for now, but I've generally read most of it.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Okay.
Dr. Croft, how many veterans have you directly engaged with in regard to mefloquine and its impact on our soldiers? I guess in your case it would be Britain. Would it be in Canada as well?
Consultant Public Health Physician, As an Individual
When I was an army doctor working full time for the British army, I was involved in the policy side of infectious disease prevention, which included malaria. Since leaving the army I haven't been involved in veterans' organizations at all. I'm not involved in any lobbying groups. That was deliberate; I didn't want to give the impression that I was taking on a particular side. I've remained independent. I hope that answers the question.
Conservative
Cathay Wagantall Conservative Yorkton—Melville, SK
Okay, thank you.
Are you aware of what's been happening in the United States and Australia in regard to mefloquine and the approach they are now taking towards...? It's not individuals who are using the drug now. Even in Canada our surgeon general has now indicated it's the drug of last resort. I have a list of those who have taken the drug since 2003. The numbers have diminished to almost nil.
However, there are those who were impacted by this drug when it was supposed to be a study. The surgeon general commented that they did not identify any evidence that met their inclusion criteria addressing potential long-term adverse effects of mefloquine, yet our Health Canada monogram significantly changed, indicating that there can be long-term effects of this drug.
Consultant Public Health Physician, As an Individual
Do you mean in 1992-93? Yes, it was Somalia. That was before it was licensed.
Consultant Public Health Physician, As an Individual
I had some correspondence with MP John Cummins right about that time about this, and I understand the drug hadn't been licensed in Canada then, but it had been released under an investigational program by which it could be tried—